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1
Suci Widyastiti, Nyoman, Ima Arum Lestarini, Yetty Movieta Nancy, Umi S Intansari, and R. Lindeman. "LEUKEMIA MEGAKARIOBLASTIK AKUT PADA SEORANG ANAK." INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY 14, no. 2 (March 15, 2018): 77. http://dx.doi.org/10.24293/ijcpml.v14i2.906.
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Acute Megakaryoblastic Leukemia (FAB AML M7) occurs in all age groups with two peaks in distribution. The one is in adults and theother in children 1 to 3 years of age especially in those with Down’s syndrome. The diagnosis of AML M7 requires more than 30% of thenucleated bone marrow cells being megakaryoblasts. The AML M7 was under diagnosed before the availability of monoclonal antibodies.The more common types of AML MO-M6 have to be excluded by morphological and cytochemical analysis whereas immunology is neededto exclude ALL. The megakaryocytic nature of the leukemia has to be proven by ultrastructural demonstration of platelet peroxidase or byimmunological demonstration of CD61, CD42, CD41 on the surface of the leukemic blasts. Megakaryocytic/megakaryoblastic leukemiasshow a wide morphologic spectrum. Cytoplasmic blebs and protrusions are the most prominent feature of many cases. The nuclei ofthese cells are round with more finely reticulated chromatin and with prominent nucleoli. The megakaryoblastic nature of these cells canbe suggested by morphology. Cytochemistry is of limited diagnostic value in megakaryoblastic leukemias. Usually it is used to excludethe more common types of leukemia. An eighteen months girl was admitted to hospital with anemia and hepatosplenomegaly. There isdismorphic - hypertelorism face and enlargement of neck lymph nodes. The laboratory examination found anemia, hyperleukocytosis with75 % blast cells. Morphologically the blast cells show prominent blebs and cytoplasmic budding resemble features of budding platelets.The cytochemistry staining for granulocyte and erythrocyte lineages were negative. The expressions of lymphoid and myeloid lineagesmarkers by immunoflowcytometry method were also negative. Cytogenetic examination was followed. The physical and laboratoryexamination result conclude a child with Acute Megakaryoblastic Leukemia. Cytogenetic examination was followed
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KIZMAZOĞLU, Deniz, Eda ATASEVEN, Şebnem YILMAZ, Duygu ELİTEZ, Alper KÖKER, Taner ERDAĞ, and Hale ÖREN. "Acute Aspergillus Laryngotracheobronchitis in a Child with Acute Lymphoblastic Leukemia." LLM Dergi 3, no. 1 (January 15, 2019): 14–17. http://dx.doi.org/10.5578/llm.67851.
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Said, Burhanuddin, Maimun ZA, and Budiman Budiman. "LINEAGE SWITCH LEUKEMIA LIMFOBLASTIK AKUT MENJADI LEUKEMIA MIELOMONOSITIK AKUT PADA PEREMPUAN USIA 26 TAHUN (Lineage Switch From Acute Lymphoblastic Leukemia To Acute Myelomonocytic Leukemia at A 26 Years Old Woman)." INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY 21, no. 1 (April 15, 2018): 96. http://dx.doi.org/10.24293/ijcpml.v21i1.1266.
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A lineage switch from Acute Lymphoblastic Leukemia (ALL) to Acute Myeloid Leukemia (AML) is very rare. It was estimated between6− 9% of cases that occurred, especially lineage switch from ALL to Acute Myelomonoblastic Leukemia (AMMOL). The reviewers reporta case of a 26 years old women with the first clinical presentation were fever and double visions and diagnosed as B-Acute lymphoblasticleukemia ALL with CD13 and CD33 expression aberrations, based on Bone Marrow Aspiration (BMA) and immunoprephenotyping inHongkong Hospital. After induction therapy, in the second month, BMA was done and found 10% blast, so it couldn’t be assessed ascomplete remission. After two (2) months, she comes back to Indonesia to follow continuing the treatment. She was suffered from severeheadache and blurred vision. The blast cell morphology of BMA showed myeloblast 25% and monoblast 60%, consistent with the diagnosisof AMMOL. Moreover, both findings were quite specific for each common cell ALL and acute myelomonocytic leukemia. These findingssupport that this case is completely different leukemic clones occurred at each leukemic expression. Exogenic factor such as chemotherapyand endogenic factor due to chromosomal abnormalities is supposed to be the cause of this lineage switch during the treatment.
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AKAY, Olga Meltem, and Betül Zeynep ERSOY. "Ph-like Acute Lymphoblastic Leukemia." LLM Dergi 2, no. 3 (July 16, 2018): 53–59. http://dx.doi.org/10.5578/llm.67277.
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Biró, Adrienn, László Ternyik, Miklós Egyed, István Bálint, Veronika Czoma, Béla Kajtár, and Zsolt Káposztás. "Appendicitis képében jelentkező akut promyelocytás leukaemia kiújulása allogén csontvelő-transzplantációt követően." Orvosi Hetilap 161, no. 51 (December 20, 2020): 2171–74. http://dx.doi.org/10.1556/650.2020.31943.
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Összefoglaló. Az akut myeloid leukaemia ellátása primeren hematológiai feladat, relapsusa során is ritka a sebészeti szövődmény. Esettanulmányunkban egy 46 éves férfi beteget mutatunk be, akinél rutinvérvétel során felfedezett akut promyelocytás leukaemia miatt történt hematológiai kezelés. Alapbetegsége komplett molekuláris remisszióba jutott, ezt követően fenntartó kezeléseket kapott, de betegsége kiújult. Reindukciós kezelést követően fehérvérsejtszáma normalizálódott, de nem jutott molekuláris remisszióba. További kezelés után a férfi testvérétől gyűjtött őssejttel allogén csontvelő-transzplantáció történt. Közel egy éve molekuláris remisszióban volt a beteg, amikor jelentkeztek jobb alhasi panaszai neutropenia, a C-reaktív protein magas értéke és pozitív hasi ultrahang mellett. Akutan laparoszkópos módszerrel távolítottuk el a láthatóan gyulladt féregnyúlványt. A hisztológiai feldolgozás során az akut promyelocytás leukaemia manifesztációja igazolódott. Tekintettel arra, hogy közben csontvelői relapsus is kialakult, újabb reindukciós kezelés, és másik testvérétől vett őssejtekkel ismételten allogén csontvelő-transzplantáció történt. Az általunk ismert irodalomban appendicitis képében jelentkező akut promyelocytás leukaemia relapsusáról nem találtunk közleményt, ezért tartottuk esetünket publikációra érdemesnek. Orv Hetil. 2020; 161(51): 2171–2174. Summary. The treatment of acute myeloid leukemia is primarily hematological. Surgical complications are rare even during relapse. We present the case of a 46-year-old man who was diagnosed with acute promyelocytic leukemia after a routine blood test. Following hematological treatment, molecular remission was achieved, and he was on maintenance therapy, when his leukemia relapsed. He received re-induction treatment and his white blood cell count normalised, however, molecular remission was not reached. After further treatment, allogeneic bone marrow transplantation was performed with stem cells collected from his brother. He developed right lower quadrant abdominal pain with neutropenia, elevated C-reactive protein and abdominal ultrasound report showed thickened appendix after nearly one year of molecular remission. We performed en emergency laparoscopic appendicectomy to remove the inflamed appendix. Histology confirmed acute promyelocytic leukemia manifestation in the appendix. Given the repeated bone marrow relapse, he received re-induction treatment and allogeneic bone marrow transplantation again with stem cells collected from his another brother. To the best of our knowledge, no previous report in the literature can be found of appendicitis mimicking relapse of acute promyelocytic leukemia, thus, this case report holds merit for publication. Orv Hetil. 2020; 161(51): 2171–2174.
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Wey, Shiuan, Biquan Luo, Chun-Chih Tseng, Min Ni, Hui Zhou, Yong Fu, Deepa Bhojwani, William L. Carroll, and Amy S. Lee. "Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling." Blood 119, no. 3 (January 19, 2012): 817–25. http://dx.doi.org/10.1182/blood-2011-06-357384.
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Abstract Traditionally, GRP78 is regarded as protective against hypoxia and nutrient starvation prevalent in the microenvironment of solid tumors; thus, its role in the development of hematologic malignancies remains to be determined. To directly elucidate the requirement of GRP78 in leukemogenesis, we created a biallelic conditional knockout mouse model of GRP78 and PTEN in the hematopoietic system. Strikingly, heterozygous knockdown of GRP78 in PTEN null mice is sufficient to restore the hematopoietic stem cell population back to the normal percentage and suppress leukemic blast cell expansion. AKT/mTOR activation in PTEN null BM cells is potently inhibited by Grp78 heterozygosity, corresponding with suppression of the PI3K/AKT pathway by GRP78 knockdown in leukemia cell lines. This is the first demonstration that GRP78 is a critical effector of leukemia progression, at least in part through regulation of oncogenic PI3K/AKT signaling. In agreement with PI3K/AKT as an effector for cytosine arabinoside resistance in acute myeloid leukemia, overexpression of GRP78 renders human leukemic cells more resistant to cytosine arabinoside-induced apoptosis, whereas knockdown of GRP78 sensitizes them. These, coupled with the emerging association of elevated GRP78 expression in leukemic blasts of adult patients and early relapse in childhood leukemia, suggest that GRP78 is a novel therapeutic target for leukemia.
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Xu, Rongzhen, Yingzi Yu, Xiaoying Zhao, Zhiwen He, Yun Liang, and Xiaohong Zhang. "SHP-2 Tyrosine Phosphatase Directly Controls the Proliferative Potential of Neoplasm Cells of Human Leukemia." Blood 104, no. 11 (November 16, 2004): 4286. http://dx.doi.org/10.1182/blood.v104.11.4286.4286.
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Abstract Our previous studies have indicated a stringent requirement of SHP-2 tyrosine phosphatase for normal hematopoiesis, but little is known whether SHP-2 plays a role in human leukemogenesis. Here, we show that SHP-2 plays a pivotal role in regulating the proliferating potential of human leukemia cells. We identified three types of SHP-2 proteins: m-, n- and c-SHP-2 proteins from both leukemic and normal hematopoietic cells. The m- and n-SHP-2 proteins (termed as active SHP-2) are derived from the c-SHP-2 protein (inactive SHP-2), and highly expressed on the internal membrane of rapidly proliferating cells at S/G2 phase, and in nucleus of mitotic cells at prophase and prometaphase, respectively, whereas the c-SHP-2 protein is ubiquitously expressed in the cytoplasm of both proliferating and resting cells. Intriguingly, we found that both active SHP-2 protein and its mRNA were constitutively overexpressed in leukemic blasts from various human leukemia cell lines and nearly all cases of various subtypes of human leukemia tested, relative to normal hematopoietic progenitors. Moreover, the expression level of active SHP-2 protein is positively correlated with the hyperproliferative phenotype of leukemia patients, and inversely associated with differentiation degree of hematopoietic cells. Most importantly, block of SHP-2 expression induces apoptosis and growth inhibition of leukemic clonogenic cells both in vitro and in vivo. In addition, we found that both PI3k/Akt and Ras/Erk signaling pathways are constitutively activated in human leukemias. Finally, we identified no mutation in PTPN11 among all tested leukemia patients. Based on these findings, we propose that SHP-2 tyrosine phosphatase plays an essential role in human leukemogenesis in which it may directly controls the proliferative potential of neoplastic cells of human leukemia via regulating signaling pathways involved in survival, growth and apoptosis of leukemia cells such as PI3k/Akt and Ras/Erk signaling pathways.
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Kharas, Michael G., Rachel Okabe, Jared J. Ganis, Maricel Gozo, Tulasi Khandan, Mahnaz Paktinat, D. Gary Gilliland, and Kira Gritsman. "Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice." Blood 115, no. 7 (February 18, 2010): 1406–15. http://dx.doi.org/10.1182/blood-2009-06-229443.
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Abstract Human cancers, including acute myeloid leukemia (AML), commonly display constitutive phosphoinositide 3-kinase (PI3K) AKT signaling. However, the exact role of AKT activation in leukemia and its effects on hematopoietic stem cells (HSCs) are poorly understood. Several members of the PI3K pathway, phosphatase and tensin homolog (Pten), the forkhead box, subgroup O (FOXO) transcription factors, and TSC1, have demonstrated functions in normal and leukemic stem cells but are rarely mutated in leukemia. We developed an activated allele of AKT1 that models increased signaling in normal and leukemic stem cells. In our murine bone marrow transplantation model using a myristoylated AKT1 (myr-AKT), recipients develop myeloproliferative disease, T-cell lymphoma, or AML. Analysis of the HSCs in myr-AKT mice reveals transient expansion and increased cycling, associated with impaired engraftment. myr-AKT–expressing bone marrow cells are unable to form cobblestones in long-term cocultures. Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) rescues cobblestone formation in myr-AKT–expressing bone marrow cells and increases the survival of myr-AKT mice. This study demonstrates that enhanced AKT activation is an important mechanism of transformation in AML and that HSCs are highly sensitive to excess AKT/mTOR signaling.
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McQueen, Teresa, Marina Konopleva, and Michael Andreeff. "Activity of Targeted Molecular Therapeutics Against Primary AML Cells: Putative Role of the Bone Marrow Microenvironment." Blood 106, no. 11 (November 16, 2005): 2304. http://dx.doi.org/10.1182/blood.v106.11.2304.2304.
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Abstract In hematological malignancies, there are reciprocal interactions between leukemic cells and cells of the bone marrow (BM) microenvironment such as mesenchymal stem cells (MSC). It is speculated that specific BM niches may provide a sanctuary for subpopulations of leukemic cells to evade chemotherapy-induced death and allow acquisition of a drug-resistant phenotype. In this study, we compared anti-leukemia effects of Ara-C and various signal transduction and apoptosis inhibitors in a co-culture system of primary AML and human bone marrow-derived MSC. AML blasts from 11 primary AML samples with high (>70%) blast count were co-cultured with MSC for 24 hours, after which they were exposed to the indicated concentrations of inhibitors for 48–96 hrs. Concentrations were selected on the basis of preliminary cell line studies which determined efficient inhibition of drug targets. Induction of apoptosis was analyzed by Annexin V flow cytometry after gating on the CD90 APC(−) (non-MSC) population. MSC protected leukemic blasts from spontaneous apoptosis in all 11 samples studied (mean annexinV positivity, 49.5±7.2% vs 25.3±4.8%, p<0.001) and from Ara-C-induced cytotoxicity in 6 out of 11 samples (p=0.02). No difference in the degree of protection was noted when MSC from older vs. younger donors were used (not shown). Co-culture of leukemic cells with MSC resulted in significant (p<0.03) suppression of inhibitor-induced apoptosis for all agents tested (Table 1), however PI3K/AKT inhibitors seemed to overcome MSC-mediated resistance. In addition, specific inhibitors of Bcl-2 and MDM2 induced apoptosis not only in suspension, but also in the MSC co-culture system, while Raf-1/MEK inhibitors were less effective. The AKT inhibitor A443654 caused apoptosis induction not only in leukemic cells, but also in MSC, which likely accounted for its high efficacy in stromal co-cultures (53±6% annexin V+). In a different study (Tabe et al, ASH 2005), we report that interactions of leukemic and BM stromal cells result in the activation of PI3K/ILK/AKT signaling in both, leukemic and stromal cells. We therefore propose that disruption of these interactions by specific PI3K/AKT inhibitors represents a novel therapeutic approach to eradicate leukemia in the BM microenvironment via direct effects on leukemic cells and by targeting activated BM stromal cells. Furthermore, Bcl-2 and MDM2 inhibitors appear to retain their efficacy in stroma-cocultured AML cells, while the efficacy of chemotherapy and Raf/MEK inhibitors in these conditions may be reduced. Further studies are aimed at the elucidation of the role of the BM microenvironment and its ability to activate specific signaling pathways in the pathogenesis of leukemias and on efforts to disrupt the MSC/leukemia interaction (Zeng et al, ASH 2005). Focus on this stroma-leukemia-stroma crosstalk may result in the development of strategies that enhance the efficacy of therapies in hematological malignancies and prevent the acquisition of a chemoresistant phenotype. Table 1. Leukemia Cell Apoptosis in a MSC/AML Co-Culture System Target Bcl-2/XL MDM2 PI3K AKT Raf-1 MEK Apoptosis was determined as percentage of Annexin V(+)CD90(−) cells, and calculated by the formula: % specific apoptosis = (test − control) x 100 / (100 − control). Compound, concentration Ara-C, 1 μM ABT-737, 0.1 μM Nutlin-3A, 2.5 μM LY294002, 10 μM A443654, 1 μM BAY43-9006, 2.5 μM CI1040, 3 μM AML 28±7 69±7 45±7 53.8±13.3 75±7 35±11 27±11 AML + MSC 16±4 38±6 28±6 31.2±6.9 53±6 18±8 15±5
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Yang, Jun, Xin Liu, Susan B. Nyland, Ranran Zhang, Lindsay K. Ryland, Kathleen Broeg, Kendall Thomas Baab, Nancy Ruth Jarbadan, Rosalyn Irby, and Thomas P. Loughran. "Platelet-derived growth factor mediates survival of leukemic large granular lymphocytes via an autocrine regulatory pathway." Blood 115, no. 1 (January 7, 2010): 51–60. http://dx.doi.org/10.1182/blood-2009-06-223719.
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Abstract Large granular lymphocyte (LGL) leukemia results from chronic expansion of cytotoxic T cells or natural killer (NK) cells. Apoptotic resistance resulting from constitutive activation of survival signaling pathways is a fundamental pathogenic mechanism. Recent network modeling analyses identified platelet-derived growth factor (PDGF) as a key master switch in controlling these survival pathways in T-cell LGL leukemia. Here we show that an autocrine PDGF regulatory loop mediates survival of leukemic LGLs of both T- and NK-cell origin. We found high levels of circulating PDGF-BB in platelet-poor plasma samples from LGL leukemia patients. Production of PDGF-BB by leukemic LGLs was demonstrated by immunocytochemical staining. Leukemic cells expressed much higher levels of PDGFR-β transcripts than purified normal CD8+ T cells or NK cells. We observed that phosphatidylinositol-3-kinase (PI3 kinase), Src family kinase (SFK), and downstream protein kinase B (PKB)/AKT pathways were constitutively activated in both T- and NK-LGL leukemia. Pharmacologic blockade of these pathways led to apoptosis of leukemic LGLs. Neutralizing antibody to PDGF-BB inhibited PKB/AKT phosphorylation induced by LGL leukemia sera. These results suggest that targeting of PDGF-BB, a pivotal regulator for the long-term survival of leukemic LGLs, may be an important therapeutic strategy.
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Zeng, Zhihong, Yue Xi Shi, Twee Tsao, YiHua Qiu, Steven M. Kornblau, Keith A. Baggerly, Wenbin Liu, et al. "Targeting of mTORC1/2 by the mTOR kinase inhibitor PP242 induces apoptosis in AML cells under conditions mimicking the bone marrow microenvironment." Blood 120, no. 13 (September 27, 2012): 2679–89. http://dx.doi.org/10.1182/blood-2011-11-393934.
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Abstract The interactions between the bone marrow (BM) microenvironment and acute myeloid leukemia (AML) is known to promote survival of AML cells. In this study, we used reverse phase-protein array (RPPA) technology to measure changes in multiple proteins induced by stroma in leukemic cells. We then investigated the potential of an mTOR kinase inhibitor, PP242, to disrupt leukemia/stroma interactions, and examined the effects of PP242 in vivo using a mouse model. Using RPPA, we confirmed that multiple survival signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), were up-regulated in primary AML cells cocultured with stroma. PP242 effectively induced apoptosis in primary samples cultured with or without stroma. Mechanistically, PP242 attenuated the activities of mTORC1 and mTORC2, sequentially inhibited phosphorylated AKT, S6K, and 4EBP1, and concurrently suppressed chemokine receptor CXCR4 expression in primary leukemic cells and in stromal cells cultured alone or cocultured with leukemic cells. In the in vivo leukemia mouse model, PP242 inhibited mTOR signaling in leukemic cells and demonstrated a greater antileukemia effect than rapamycin. Our findings indicate that disrupting mTOR/AKT signaling with a selective mTOR kinase inhibitor can effectively target leukemic cells within the BM microenvironment.
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Yoshimi, Akihide, Susumu Goyama, Naoko Watanabe-Okochi, Yumiko Yoshiki, Yasuhito Nannya, Eriko Nitta, Shunya Arai, et al. "Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins." Blood 117, no. 13 (March 31, 2011): 3617–28. http://dx.doi.org/10.1182/blood-2009-12-261602.
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Abstract Evi1 (ecotropic viral integration site 1) is essential for proliferation of hematopoietic stem cells and implicated in the development of myeloid disorders. Particularly, high Evi1 expression defines one of the largest clusters in acute myeloid leukemia and is significantly associated with extremely poor prognosis. However, mechanistic basis of Evi1-mediated leukemogenesis has not been fully elucidated. Here, we show that Evi1 directly represses phosphatase and tensin homologue deleted on chromosome 10 (PTEN) transcription in the murine bone marrow, which leads to activation of AKT/mammalian target of rapamycin (mTOR) signaling. In a murine bone marrow transplantation model, Evi1 leukemia showed modestly increased sensitivity to an mTOR inhibitor rapamycin. Furthermore, we found that Evi1 binds to several polycomb group proteins and recruits polycomb repressive complexes for PTEN down-regulation, which shows a novel epigenetic mechanism of AKT/mTOR activation in leukemia. Expression analyses and ChIPassays with human samples indicate that our findings in mice models are recapitulated in human leukemic cells. Dependence of Evi1-expressing leukemic cells on AKT/mTOR signaling provides the first example of targeted therapeutic modalities that suppress the leukemogenic activity of Evi1. The PTEN/AKT/mTOR signaling pathway and the Evi1-polycomb interaction can be promising therapeutic targets for leukemia with activated Evi1.
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Király, Péter Attila, Krisztián Kállay, Dóra Marosvári, Gábor Benyó, Anita Szőke, Judit Csomor, and Csaba Bödör. "Familiáris myelodysplasiás szindróma és akut myeloid leukaemia klinikai és genetikai háttere." Orvosi Hetilap 157, no. 8 (February 2016): 283–89. http://dx.doi.org/10.1556/650.2016.30375.
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Myelodysplastic syndrome and acute myeloid leukaemia are mainly sporadic diseases, however, rare familial cases exist. These disorders are considered rare, but are likely to be more common than currently appreciated, and are characterized by the autosomal dominant mutations of hematopoietic transcription factors. These syndromes have typical phenotypic features and are associated with an increased risk for developing overt malignancy. Currently, four recognized syndromes could be separated: familial acute myeloid leukemia with mutated CEBPA, familial myelodysplastic syndrome/acute myeloid leukemia with mutated GATA2, familial platelet disorder with propensity to myeloid malignancy with RUNX1 mutations, and telomere biology disorders due to mutations of TERC or TERT. Furthermore, there are new, emerging syndromes associated with germline mutations in novel genes including ANKRD26, ETV6, SRP72 or DDX41. This review will discuss the current understanding of the genetic basis and clinical presentation of familial leukemia and myelodysplasia. Orv. Hetil., 2016, 157(8), 283–289.
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Harir, Noria, Christian Pecquet, Marc Kerenyi, Karoline Sonneck, Boris Kovacic, Remy Nyga, Marie Brevet, et al. "Constitutive activation of Stat5 promotes its cytoplasmic localization and association with PI3-kinase in myeloid leukemias." Blood 109, no. 4 (October 12, 2006): 1678–86. http://dx.doi.org/10.1182/blood-2006-01-029918.
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Abstract Persistent activation of Stat5 is frequently found in hematologic neoplasms. Studies conducted with constitutively active Stat5 mutants (Stat51*6 and cS5F) have shown that deregulated Stat5 activity promotes leukemogenesis. To investigate the oncogenic properties of these mutants, we used cS5F-expressing bone marrow cells which induce a multilineage leukemia when transplanted into recipient mice. Here, we show by immunocytochemistry that cS5F is localized mainly in the cytoplasmic compartment of leukemic cells, suggesting that the transforming nature of cS5F may be associated with a cytoplasmic function. In support of this hypothesis, we found that cS5F forms a complex with the p85 subunit of the phosphatidylinositol 3-kinase (PI3-K) and the scaffolding adapter Gab2 in leukemic bone marrow cells, resulting in the activation of Akt/PKB, a crucial downstream target of PI3-K. By using transducible TAT-Gab2 or TAT-Akt recombinant proteins, we were able to demonstrate that activation of the PI3-kinase/Akt pathway by cS5F molecules through Gab2 is essential for induction of cell growth. We also found that persistently phosphorylated Stat5 in primary cells from patients with myeloid leukemias has a cytoplasmic localization. These data suggest that oncogenic Stat5 proteins exert dual transforming capabilities not only as transcriptional activators but also as cytoplasmic signaling effectors.
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ULAŞ, Beliz Bahar, and Pervin TOPÇUOĞLU. "New Agents in the Treatment of Acute Myeloid Leukemia." LLM Dergi 3, no. 4 (January 31, 2020): 67–75. http://dx.doi.org/10.5578/llm.68329.
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McQueen, Teresa, Yoko Tabe, Marina Konopleva, and Michael Andreeff. "Inhibition of PI3K or Integrin-Linked Kinase (ILK) Target Primary AML Cells within the Bone Marrow Microenvironment in the In Vitro Co-Culture System." Blood 108, no. 11 (November 16, 2006): 1903. http://dx.doi.org/10.1182/blood.v108.11.1903.1903.
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Abstract In hematological malignancies, there are reciprocal interactions between leukemic cells and cells of the bone marrow microenvironment such as marrow stromal cells (MSC). It is proposed that specific niches within the bone marrow microenvironment provide a sanctuary for subpopulations of leukemic cells to evade chemotherapy-induced death, and we indeed demonstrated that MSC protect primary AML cells from Ara-C induced apoptosis in vitro (Konopleva, Leukemia 2002). Integrin-linked kinase (ILK) has been shown to directly interact with β integrins and phosphorylate AKT in a PI3-kinase(PI3K)-dependent manner to promote cell survival and proliferation. In this study, we tested the hypothesis that selective inhibition of ILK signaling will provide a novel approach for targeting both leukemic cells and cells in their surrounding microenvironment. Direct co-culture of human MSC and leukemic NB4 cells results in activation of PI3K/ILK/AKT signaling as evidenced by enhanced ILK kinase activity, elevated phospho(p)-Akt, p-GSK3β and nuclear translocation of β-catenin. Both, PI3K inhibitor LY294002 (10μM) and specific ILK inhibitor QLT0267 (10μM) inhibited stroma-induced activation of AKT and suppressed GSK phosphorylation. This resulted in massive induction of apoptosis which was not abrogated by stromal co-culture (AnnexinV positivity %, MSC(−) vs MSC(+); 51.4+2.5 vs 55.8+3.5 p=0.26, LY 47.0+8.1 vs 47.9+6.1 p=0.85, 48hrs). In contrast, MSC co-culture effectively blocked apoptosis induced by MEK inhibitor PD98059 despite activation of pERK (62.5+3.2% vs 45.6+2.3%, p=0.02). We next examined anti-leukemia effects of PI3K and ILK inhibitors in the co-culture system of primary AML and human MSC. AML blasts from 7 primary AML samples with high (>54%) blast count were co-cultured with MSC for 24 hours, after which they were exposed to 10μM LY294002 or QLT0267 for 4–8 days. After this period, induction of apoptosis was analyzed in non-adherent AML cells by Annexin V flow cytometry after gating on the CD90-negative (non-MSC) population. To control for differences in spontaneous apoptosis, we calculated % specific apoptosis as (test - control) x 100 / (100 - control). MSCs protected leukemic blasts from spontaneous apoptosis in all 7 samples studied (mean annexin V positivity, 49.5±7.2% vs 25.3±4.8%, p<0.001). In contrast, inhibition of PI3K/ILK signaling induced unopposed apoptosis even in MSC co-cultures (% specific apoptosis, LY294002, 30.3±4.8%; LY+MSC, 28.3±7.7%; QLT0267, 26.9±9.8%; QLT+MSC, 33.1±9.3%, p>0.3 comparing cell death in the presence or absence of MSC). This resulted in corresponding loss of viability (% of control, LY294002, 66.0±11.0%; LY+MSC, 57.6±11.2%; QLT0267, 66.4±7.28%; QLT+MSC, 50.4±11.3%, p>0.1 comparing viability in the presence or absence of MSC). These observations indicate that disruption of leukemia/stroma interactions by specific PI3K/ILK inhibitors represents a novel therapeutic approach to eradicate leukemia in the bone marrow microenvironment. Further studies are aimed at the elucidation of the role of the BM microenvironment and its ability to activate specific signaling pathways in the pathogenesis of leukemias. Focus on this stroma-leukemia crosstalk may result in the development of strategies that alleviate the acquisition of a chemoresistant phenotype and enhance the efficacy of therapies in hematological malignancies.
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Rahmadin, Bayu, Irza Wahid, and Rismawati Yaswir. "Profil Penderita Leukemia Mieloblastik Akut di Bagian Penyakit Dalam RSUP Dr. M. Djamil Padang." Jurnal Kesehatan Andalas 6, no. 3 (February 20, 2018): 495. http://dx.doi.org/10.25077/jka.v6.i3.p495-501.2017.
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Jenis leukemia yang paling umum ditemukan pada orang dewasa adalah leukemia mieloblastik akut. Tujuan penelitian ini adalah untuk mengetahui profil penderita Leukemia Mieloblastik Akut di bagian Penyakit Dalam RSUP Dr. M. Djamil Padang. Penelitian ini bersifat deskriptif retrospektif yang dilaksanakan pada Februari – Mei 2015. Populasi penelitian ini adalah semua pasien leukemia mieloblastik akut yang dirawat di bagian penyakit dalam RSUP Dr. M. Djamil Padang antara Januari 2014 sampai Desember 2014. Sampel untuk penelitian ini adalah bagian dari populasi yang memenuhi kriteria inklusi yaitu berjumlah 35 orang. Data diambil melalui rekam medis dan pengolahan data dilakukan secara manual. Hasil penelitian ditemukan pasien leukemia mieloblastik akut terbanyak pada kelompok umur 20-39 tahun sebanyak 16 orang (45,71%). Berdasarkan jenis kelamin, lebih banyak ditemukan pada perempuan sebanyak 18 orang (51,43%). Berdasarkan klasifikasi French-American-British (FAB), tipe leukemia mieloblastik akut yang terbanyak yaitu tipe M4 sebanyak 20 orang (57,14%). Sebanyak 17 orang mengalami anemia berat (48,57%). Terdapat 21 orang mengalami hiperleukositosis (60%). Seluruh pasien leukemia mieloblastik akut mengalami trombositopenia (100%). Terdapat 32 orang dengan presentasi blast >30% (91,43%).
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Rahmadin, Bayu, Irza Wahid, and Rismawati Yaswir. "Profil Penderita Leukemia Mieloblastik Akut di Bagian Penyakit Dalam RSUP Dr. M. Djamil Padang." Jurnal Kesehatan Andalas 6, no. 3 (February 20, 2018): 495. http://dx.doi.org/10.25077/jka.v6i3.728.
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Jenis leukemia yang paling umum ditemukan pada orang dewasa adalah leukemia mieloblastik akut. Tujuan penelitian ini adalah untuk mengetahui profil penderita Leukemia Mieloblastik Akut di bagian Penyakit Dalam RSUP Dr. M. Djamil Padang. Penelitian ini bersifat deskriptif retrospektif yang dilaksanakan pada Februari – Mei 2015. Populasi penelitian ini adalah semua pasien leukemia mieloblastik akut yang dirawat di bagian penyakit dalam RSUP Dr. M. Djamil Padang antara Januari 2014 sampai Desember 2014. Sampel untuk penelitian ini adalah bagian dari populasi yang memenuhi kriteria inklusi yaitu berjumlah 35 orang. Data diambil melalui rekam medis dan pengolahan data dilakukan secara manual. Hasil penelitian ditemukan pasien leukemia mieloblastik akut terbanyak pada kelompok umur 20-39 tahun sebanyak 16 orang (45,71%). Berdasarkan jenis kelamin, lebih banyak ditemukan pada perempuan sebanyak 18 orang (51,43%). Berdasarkan klasifikasi French-American-British (FAB), tipe leukemia mieloblastik akut yang terbanyak yaitu tipe M4 sebanyak 20 orang (57,14%). Sebanyak 17 orang mengalami anemia berat (48,57%). Terdapat 21 orang mengalami hiperleukositosis (60%). Seluruh pasien leukemia mieloblastik akut mengalami trombositopenia (100%). Terdapat 32 orang dengan presentasi blast >30% (91,43%).
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Gökdere, Sare, Zeliha Güzelküçük, Melek Işık, Eylem Şerife Kaymaz, Belgin Gülhan, and Neşe Yaralı. "Akut Lenfositik Lösemili Bir Çocuk Olguda Stafilokoksik Haşlanmış Deri Sendromu." Journal of Pediatric Infection 13, no. 4 (December 31, 2019): 214–16. http://dx.doi.org/10.5578/ced.201959.
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Setiawan, Agus, Indarini Indarini, Lyana Setiawan, Siti Boedina Kresno, Nugroho Prayogo, and Arini Setiawati. "CASPASE-3 AKTIF DI LEUKEMIA MIELOSITIK AKUT (LMA) DAN LEUKEMIA LIMFOBLASTIK AKUT (LLA)." INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY 19, no. 3 (October 14, 2016): 141. http://dx.doi.org/10.24293/ijcpml.v19i3.411.
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Dysregulation of apoptosis plays an essential role either in leukemogenesis or treatment response. Caspase-3 is a cysteine protease that functions as the final common mediator of apoptosis. The expression of the active caspase-3 is presumed as a predictor of prognosis and is able to predict the chemotherapy sensitivity. The aim of this study is to identify and to know the profile of active caspase-3 in Acute Myeloid Leukaemia (AML) and Acute Lymphoblastic Leukaemia (ALL), to correlate its expression in marrow and peripheral blood mononuclear cells, and to verify the extent of its use as a complete remission predictor after induction treatment. The study subjects consisted of patients who were diagnosed as AML and ALL with marrow and peripheral blood examination performed at the Department of Clinical Pathology Dharmais Cancer Hospital and CiptoMangunkusumo Hospital. Based on this study, it is revealed that the active caspase-3 expression in mononuclear marrow cells was higher in AML compared to ALL (p=0.033), active caspase-3 expression in marrow showed a strong correlation (r=0.764; p=0.001) to peripheral blood mononuclear cells in ALL and a medium correlation (r=0.594; p=0.042) in AML. The expression of the active caspase-3 in ALL patients was lower in complete remission patients compared to the non-complete remission patients. Regarding to this study it is recommended to measure the active caspase-3 along with molecules integrating in apoptosis signaling pathways such as cytochrome-c and in the formation of apoptosome.
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Volk, Andrew, Yechen Xiao, Junping Xin, Dewen You, Rachel Schmidt, Shubin Zhang, Wei Wei, Peter Breslin, Sucha Nand, and Jiwang Zhang. "Sensitizing Leukemic Cells to NF-κB Inhibitor Treatment by Repressing TNFα-Mediated, NF-κB-Independent Survival Signaling." Blood 120, no. 21 (November 16, 2012): 1878. http://dx.doi.org/10.1182/blood.v120.21.1878.1878.
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Abstract Abstract 1878 NF-κB activation is essential for leukemic cell and stem cell (LSC) survival and self-renewal, but is significantly less essential for similar functions in normal bone marrow hematopoietic stem/progenitor cells (HSPCs). As a result, LSCs are more sensitive to both pharmacologic and genetic NF-κB inhibition than HSPCs. These sensitivities suggest that NF-κB signaling could be a potential therapeutic target in the treatment of leukemia. However, high doses of NF-κB inhibitor treatment are also associated with significant inflammation-mediated toxicity to liver, skin and other tissues. Therefore, new approaches are needed that will be able to protect normal tissues while simultaneously enhancing the effects of NF-κB inhibition on leukemic cells. By utilizing genetic knock-out HSPC/leukemia models in combination with small molecule inhibitors, we searched for factors that could sensitize leukemic cells to NF-κB inhibition while simultaneously protecting HSPCs. We demonstrated that targeted inhibition of TNFα induced NF-κB-independent signaling would be a useful approach to treat leukemia in combination with NF-κB inhibition. We found that deactivating TNFα signaling either by genetic deletion of its receptors or through neutralizing the ligand with an antibody can significantly enhance NF-κB inhibition-induced leukemic cell elimination. In contrast, deactivation of TNFα signaling can significantly protect normal HSPCs from NF-κB inhibitor-induced death. Mechanistic studies revealed that TNFα stimulates several similar signals in both leukemic cells and HSPCs, including NF-κB, ERK, AKT, p38 and JNK. In order to determine which of these signals would best augment NF-κB inhibition, we performed biochemical analyses and searched for candidate survival signals activated downstream of TNFα and that operated independently of NF-κB. This analysis revealed that TNFα-induced ERK and AKT signals are NF-κB dependent, while TNFα-induced p38 and JNK signals are NF-κB independent. Inhibition of p38 enhanced leukemic cell growth, and was therefore ruled out as a candidate. Our analyses showed that JNK was activated by TNFα stimulation, operated independently of NF-κB activation, and also repressed leukemic cell growth. Further study confirmed that TNFα-dependent JNK activation has opposite functions in HSPCs and leukemic cells: JNK acts by promoting cell survival in leukemic cells while inducing cell death in HSPCs. We confirmed this result by inactivating the JNK signal via small molecule inhibitor, and found that we could significantly sensitize leukemic cells to NF-κB inhibition while protecting normal HSPCs from TNFα-mediated cell death associated with NF-κB inhibition. Mechanism analysis suggested that TNFα represses the growth of HSPCs by a JNK-RIP1/RIP3-dependent necroptosis mechanism, whereas TNFα promotes the expansion of leukemic cells by inducing the parallel activation of NF-κB-dependent AKT/ERK signaling and NF-κB-independent JNK signaling. In conclusion, our studies suggest the simultaneous inhibition of both NF-κB and TNFα-induced NF-κB-independent signals like JNK might provide a more comprehensive approach for targeted treatment of leukemias that also protects against deleterious inflammation in the bone marrow and other tissues. Disclosures: Nand: Celgene: Research Funding.
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Rusanti, Rahmi, Yetti Hernaningsih, Endang Retnowati, Mia Ratwita Andarsini, and Andy Cahyadi. "CORRELATION OF BLAST PERCENTAGE TO CD34 OF BONE MARROW IN ALL PEDIATRIC PATIENTS." INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY 24, no. 1 (March 29, 2018): 53. http://dx.doi.org/10.24293/ijcpml.v24i1.1156.
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Leukemia Limfoblastik Akut (LLA) adalah penyakit keganasan sel progenitor limfoid yang berasal dari sumsum tulang. Tanda khasdari diagnosis leukemia akut adalah sel blas. Pemeriksaan mikroskopis dilakukan untuk menentukan persentase sel blas pada diagnosisleukemia akut. Immunophenotyping merupakan metode diagnostik yang dapat membantu menegakkan diagnosis pada keganasanhematologi. CD34 merupakan antigen yang sering digunakan untuk identifikasi sel induk hemopoeisis atau blas. Penelitian ini bertujuanuntuk mengetahui kenasaban antara persentase blas dengan ekspresi CD34 di sumsum tulang di pasien leukemia limfoblastik akut anaksebelum dan sesudah pengobatan kemoterapi fase induksi.
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Pulikkan, John Anto, Dmitri Madera, Liting Xue, Paul Bradley, Sean Francis Landrette, Ya-Huei Kuo, Saman Abbas, Lihua Julie Zhu, Peter Valk, and Lucio Hernán Castilla. "Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling." Blood 120, no. 4 (July 26, 2012): 868–79. http://dx.doi.org/10.1182/blood-2012-03-414649.
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Abstract Oncogenic mutations in components of cytokine signaling pathways elicit ligand-independent activation of downstream signaling, enhancing proliferation and survival in acute myeloid leukemia (AML). The myeloproliferative leukemia virus oncogene, MPL, a homodimeric receptor activated by thrombopoietin (THPO), is mutated in myeloproliferative disorders but rarely in AML. Here we show that wild-type MPL expression is increased in a fraction of human AML samples expressing RUNX1-ETO, a fusion protein created by chromosome translocation t(8;21), and that up-regulation of Mpl expression in mice induces AML when coexpressed with RUNX1-ETO. The leukemic cells are sensitive to THPO, activating survival and proliferative responses. Mpl expression is not regulated by RUNX1-ETO in mouse hematopoietic progenitors or leukemic cells. Moreover, we find that activation of PI3K/AKT but not ERK/MEK pathway is a critical mediator of the MPL-directed antiapoptotic function in leukemic cells. Hence, this study provides evidence that up-regulation of wild-type MPL levels promotes leukemia development and maintenance through activation of the PI3K/AKT axis, and suggests that inhibitors of this axis could be effective for treatment of MPL-positive AML.
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Sari, Teny Tjitra, Endang Windiastuti, Gitta Reno Cempako, and Yoga Devaera. "Prognosis Leukemia Limfoblastik Akut pada Anak Obes." Sari Pediatri 12, no. 1 (November 23, 2016): 58. http://dx.doi.org/10.14238/sp12.1.2010.58-62.
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Latar belakang. Obesitas merupakan salah satu masalah gizi yang banyak ditemukan pada anak. Beberapapenelitian menunjukkan hubungan obesitas pada peningkatan risiko relatif beberapa keganasan. Keganasanyang paling sering ditemukan pada anak adalah leukemia limfoblastik akut. Bagaimana prognosisleukemia limfoblastik akut pada anak obes?Tujuan. Mengetahui prognosis pasien leukemia limfoblastik akut anak dengan obesitas.Metode. Studi deskriptif menggunakan data registrasi semua pasien baru leukemia limfoblastik akut pada1 Januari 2007 – 31 Desember 2009 di Departemen Ilmu Kesehatan Anak FKUI/RSCM.Hasil. Selama penelitian tiga tahun didapatkan 12 pasien leukemia limfoblastik akut dan obesitas denganprevalens 6,1%. Usia berkisar 2-14 tahun dengan rerata 6,4 tahun. Sembilan dari 12 pasien merupakankelompok risiko tinggi dan sebagian besar (6 dari 9 pasien) datang dengan jumlah rerata leukosit adalah101.650/mm3 (66.700-159.000/mm3). Remisi pada fase induksi didapatkan pada 10 dari 12 pasien. Relapsterjadi pada tiga pasien, semuanya terjadi pada fase pemeliharaan dengan tempat relaps adalah sumsumtulang (dua pasien) dan intrakranial (satu pasien). Dua dari tiga subjek penelitian yang relaps, meninggaldunia dengan penyebab kematian perdarahan intrakranial.Kesimpulan. Obesitas mempengaruhi prognosis pada pasien leukemia limfoblastik akut anak.
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Pinilih, Astri, and Bambang Sudarmanto. "Hubungan Kadar Serum Kuprum dengan Fungsi Fagositosis Neutrofil pada Anak Leukema Limfositik Akut." Sari Pediatri 20, no. 4 (January 28, 2019): 197. http://dx.doi.org/10.14238/sp20.4.2018.197-201.
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Latar belakang. Leukemia merupakan keganasan sel darah yang berasal dari sumsum tulang. Defek kualitatif neutrofil seperti kelainan kemotaksis, fagositosis dan migrasi neutrofil terjadi pada leukemia. Kuprum adalah mikronutrien yang berperan dalam fungsi neutrofil dan makrofag. Penurunan jumlah neutrofil dan gangguan fungsi neutrofil dikaitkan dengan defisiensi kuprum.Tujuan. Mengetahui hubungan kadar serum kuprum dengan fungsi fagositosis neutrofil pada anak leukemia limfositik akut.Metode. Penelitian observasional analitik dengan metode potong lintang pada 25 anak leukemia limfositik akut usia 1 – 10 tahun di RSUP Dr. Kariadi Semarang. Kadar serum kuprum dan indeks fungsi fagositosis diukur dan dianalisis dengan menggunakan korelasi Pearson.Hasil. Dua puluh lima anak yang memenuhi kriteria, terdiri dari 18 lelaki (72%) dan 7 perempuan (28%). Status gizi terdiri dari status gizi baik 12 anak (48%) dan malnutrisi 13 anak (52%). Fase kemoterapi terbanyak adalah induksi dan konsolidasi pada 17 anak (68%). Rerata kadar serum kuprum normal yaitu 1254,8 (464,77) µg/L. Rerata indeks fagositosis neutrofil menurun yaitu 53,08 (20)%. Tidak terdapat hubungan kadar serum kuprum dengan fungsi fagositosis neutrofil pada anak leukemia limfositik akut (p=0,364)Kesimpulan. Rerata indeks fagositosis neutrofil rendah pada anak leukemia limfositik akut dibandingkan nilai normal. Rerata kadar serum kuprum normal pada anak leukemia limfositik akut. Tidak terdapat hubungan kadar serum kuprum dengan fungsi fagositosis neutrofil pada anak leukemia limfositik akut.
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Indrasari, Yulia Nadar, and Ana Murtasyidah. "ACUTE MEGAKARYOBLASTIC LEUKEMIA." INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY 25, no. 3 (April 25, 2019): 364. http://dx.doi.org/10.24293/ijcpml.v25i3.1503.
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Leukemia megakarioblastik akut (AMegL) dibagi dalam tiga kelompok berdasarkan patofiosiolgi, usia, respon terhadap terapi dan prognosis. Kelompok tersebut adalah AMegL yang terjadi pada anak-anak dengan sindrom Down (DS-AMegL), AMegL yang terjadi pada anak-anak yang tidak memiliki sindrom Down (non-DS-AMegL) dan AMegL pada orang dewasa non-DS (AMegL dewasa). AMegL pada anak tanpa sindrom Down juga disebut leukemia megakarioblastik pediatrik akut atau AMegL anak.1Dasar diagnosis AMegL atau AML M7 menurut FAB adalah adanya sel lini megakariosit 30% atau lebih dari seluruh sel.2 Sedangkan diagnosis AMegL menurut panduan WHO 2016 adalah leukemia akut dengan > 20% blast dimana > 50% adalah lini megakariosit. Sel megakariosit lebih jelas terlihat pada mikroskop elektron yang bereaksi positif terhadap platelet peroksidase2 atau menggunakan antibodi marker terhadap CD41/gpIIb, CD42b/gpIb, CD61/gpIIIa, faktor Von Willebrand dan pengecatan LAT.3 Temuan sitogenetika berbeda antara ketiga jenis AMegL sesuai dengan perbedaan patofisiologinya. WHO (2016) menyebutkan leukemia megakarioblastik akut ke dalam kriteria AML not otherwise specific (NOS). AmegL adalah leukemia akut dengan > 20% blast dimana > 50% adalah lini megakariosit. Kriteria ini mengeksklusi AML dengan mielodisplasia (acute myeloid leukemia with myelodysplasia related change; AMLMRC), AML yang berhubungan dengan terapi, dan AML dengan kelainan genetik rekuren, seperti AML dengan t(1;22)(p13.3;q13.1), inv(3)(q21.3q26.2), atau t(3;3)(q21.3;q26.2). DS-AMegL juga diklasifikasikan sendiri ke dalam Myeloid Leukemia associated Down Syndrome.3Prognosis AMegL pada pasien dewasa yang diobati jauh di bawah bentuk AMegL lainnya. Waktu kelangsungan hidup rata-rata hanya 18 hingga 41 minggu dengan tingkat kelangsungan hidup 5 tahun hanya 10-11 persen. Perbaikan besar dalam statistik ini kemungkinan akan membutuhkan pendekatan pengobatan baru yang diarahkan pada mekanisme yang mendasari penyakit ini.1
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Gadhoum, Samah Z., and Jasmeen S. Merzaban. "Anti-CD44 Antibodies Inhibit Both mTORC1 and mTORC2 Activities in Acute Myeloid Leukemia." Blood 120, no. 21 (November 16, 2012): 2620. http://dx.doi.org/10.1182/blood.v120.21.2620.2620.
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Abstract Abstract 2620 The role of aberrant signaling pathways such as the PI3K/Akt and the mammalian target of rapamycin (mTor) in the uncontrolled growth and survival in cancer including acute myeloid leukemia (AML) is now clearly demonstrated; and inhibitors of mTor such as Rapamycin are currently being used in clinical trials for their potent anti-neoplastic effects. While leaving normal hematopoiesis unaffected, anti-CD44 monoclonal antibodies (mAbs) have been shown to reverse the blockage of differentiation responsible for the leukemic phenotype, inhibit proliferation of the leukemic clones, and in some types of leukemia, induce the apoptosis of leukemic blasts. However, the molecular mechanisms underlying these effects are yet to be resolved. Here, we show that anti-CD44 mAb-induced differentiation of the HL60 cell line (AML type 2), is accompanied by a marked decrease in the phosphorylation of mTor with no affect on the total expression of mTor. This decrease was strongly correlated with an inhibition of the PI3K/Akt pathway as shown by the decrease of Akt phosphorylation on Thr308. Moreover, we observed that anti-CD44 mAbs induce a decrease of phosphorylation of p70S6k (on Thr 389) as well a decrease in the phosphorylation of Akt on Ser 473, which directly reflect the activity of mTORC1 and mTORC2 respectively. This result strongly suggests that CD44 triggering inhibits the activity of both mTORC1 and mTORC2 complexes. Previous studies have shown that the activity of mTORC1 is constitutively active in most leukemic patients, while it has been suggested that the inhibition of mTORC2 activity could have an anti-leukemic effect. Our finding unveils a new role for anti-CD44 mAbs as potent mTor inhibitors, heretofore, adding a key argument to the promise of CD44 as a strong therapeutic target in AML. Disclosures: No relevant conflicts of interest to declare.
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ŞEN, Tuğba, Bilge BÜLBÜL ŞEN, Mehmet YALDIZ, Emine Nur RİFAİOĞLU, Özlem EKİZ, Zeynel Abidin TAŞ, and Hasan KAYA. "Adult T-Cell Acute Lymphoblastic Leukemia; Skin Involvement: Case Report." Turkiye Klinikleri Journal of Dermatology 25, no. 1 (2015): 28–31. http://dx.doi.org/10.5336/dermato.2014-42726.
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Schittenhelm, Marcus M., Hartmut Doehner, Konstanze Doehner, Lothar Kanz, Michael C. Heinrich, and Kerstin M. Kampa-Schittenhelm. "Efficacy Analysis of the Novel Dual PI3K-MTORC1/2 Inhibitors NVP-BGT226 and NVP-BEZ235 in Acute Leukemia." Blood 120, no. 21 (November 16, 2012): 2474. http://dx.doi.org/10.1182/blood.v120.21.2474.2474.
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Abstract Abstract 2474 Introduction: Dysregulation of the PI3Kinase/AKT pathway is involved in the pathogenesis of many human malignancies. Constitutive phosphorylation of AKT is frequently found in acute leukemia but the underlying molecular mechanisms remain unclear and mutations in the PI3K/AKT pathway are uncommon in leukemia. In some cases, constitutive AKT activation can be linked to gain-of function tyrosine kinase mutations upstream of the PI3K/AKT pathway. While inhibitors of the PI3K/AKT pathway appear attractive for tumor therapy, so far response rates to PI3K inhibitor treatment of various neoplasms are moderate. Furthermore, MTORC1 inhibitors, targeting downstream of AKT, have the disadvantage of activating AKT via feed-back mechanisms. We here comparatively studied two novel dual PI3K-MTORC1/2 inhibitors, NVP-BEZ235 and NVP-BGT226, with regard to their ability to inhibit proliferation and to induce apoptosis in different leukemia cell models as well as in primary leukemia samples. Methods: Expression of phospho-AKT protein levels was determined in 74 leukemia patient blood and bone marrow samples by flow cytometry. Protein and functional viability assays evaluating the effects of NVP-BEZ235 and NVP-BGT226 were performed in several leukemia cell lines, mutant-tyrosine kinase cell models and with primary leukemia blasts and bone marrow cells. Antineoplastic activity was assessed in proliferation and apoptosis experiments. Immunoblots were performed to confirm consecutive suppression of AKT signaling. Results: AKT is generally expressed in acute leukemia at significantly higher levels as compared to healthy donor samples (p < 0.05, students t-test). Dual targeting of the PI3K-AKT-MTOR pathway profoundly inhibited AKT signaling, leading to antiproliferative effects in vitro and ex vivo. Moreover, both agents potently induced apoptosis in a subset of leukemia samples with BGT226 being the more effective agent and displaying IC50s at the low nanomolar level. Cell cycle analyses revealed that NVP-BGT226 overrides the G1-arrest observed with NVP-BEZ235-treated cells. Importantly, normal mononuclear cells revealed lower phospho-AKT expression levels and relative insensitivity towards dual PI3K-MTORC1/2 inhibition. Conclusion: Our data provide a strong rationale for clinical evaluation of the tested dual PI3K-MTORC1/2 inhibitors in acute leukemias. Disclosures: No relevant conflicts of interest to declare.
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Kampa-Schittenhelm, Kerstin M., Figen Akmut, Barbara Illing, and Marcus M. Schittenhelm. "Induction Of Apoptosis By The Dual PI3K/Mtor Inhibitor NVP-BEZ235 Is Impaired By a Profound G1/G0 Arrest In Acute Leukemia Which Can Be Overcome By Combination Approaches." Blood 122, no. 21 (November 15, 2013): 3856. http://dx.doi.org/10.1182/blood.v122.21.3856.3856.
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Abstract Introduction Constitutive phosphorylation of AKT is frequently found in acute leukemia. In a proportion of patients, activation of the PI3K/AKT pathway can be linked to gain-of-function tyrosine kinase mutations. We have previously shown that TKI only incompletely inactivate AKT signaling. PI3K/AKT pathway inhibitors are attractive for targeting this pathway. However, most inhibitors lead to G1/G0 arrest. Likely for this reason, response rates to PI3K inhibitor treatment were moderate in various neoplasms. We here demonstrate that the dual PI3K-MTORC1/2 inhibitor NVP-BEZ235, which is currently under clinical investigation in relapsed acute leukemia, mediates a profound G1/G0 arrest in cells harboring leukemia-driving FLT3 ITD or BCR-ABL1 mutations, impairing induction of apoptosis. Furthermore, combination with TKI or chemotherapy overcomes cellular resistance. Methods Proliferation and apoptosis assays were performed in leukemia cell lines, an isogenic Ba/F3 cell model harboring mutant-KIT, FLT3 or ABL1 isoforms and primary leukemic cells as well as healthy donor cells. Immunoblots were performed to study effects on AKT signaling pathways including downstream effectors of autophagy (p-ULK1), proliferation, cell cycle (p70S6Kinases, cyclinD, pRB) and apoptosis (caspases). Isobolograms were created to compute combination indices. Results NVP-BEZ235 profoundly inhibited phosphorylation of AKT and p70S6K, leading to a potent antiproliferative effect in the low nanomolar range in most cell lines as well as patient blasts. However, no meaningful induction of apoptosis was observed. Instead, a sustained G1/G0 cell cycle arrest with dephosphorylation of RB and upregulation of cyclinD, induction of protective autophagy pathways (via ULK1) and absence of cleaved caspase 3 was detected. An isogenic Ba/F3 model confirmed the low proapoptotic efficacy especially for FLT3 ITD and BCR-ABL1. In an attempt to overcome NVP-BEZ235 induced cell cycle arrest, we co-treated leukemic cells with specific TK inhibitors or chemotherapeutics such as daunorubicin in a fixed dose-dilution ratio. Combination indices revealed additive to superadditive proapoptotic effects for all tested combinations. Conclusion We provide evidence that the antileukemic activity of NVP-BEZ235 in acute leukemia with mutations in tyrosine kinases is abrogated due to induction of profound G1/G0 cell cycle arrest which can be overcome by combination with TKI or chemotherapy. Disclosures: No relevant conflicts of interest to declare.
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DEMİRCİOĞLU, Sinan, Ayvaz YELER, and Ali DOĞAN. "Evaluation of Serum B12 Level in Patients with Acute Myeloid Leukemia." LLM Dergi 2, no. 4 (October 30, 2018): 89–92. http://dx.doi.org/10.5578/llm.67773.
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Shin, Jae-Won, and David J. Mooney. "Dose-Response Titration In a Bone Marrow Niche Model Reveals AKT As a Target That Modulates Sensitivity Of Myeloid Leukemia To Extracellular Matrix Mechanics: Implications In Drug Resistance." Blood 122, no. 21 (November 15, 2013): 1292. http://dx.doi.org/10.1182/blood.v122.21.1292.1292.
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Abstract Background Acute Myeloid Leukemia (AML) is a cell-autonomous disorder with genetic heterogeneity, and response to existing therapies is not curative. Emerging evidence pinpoints the bone marrow (BM) milieu as a non-autonomous contributor to the pathophysiology of myeloid leukemia, suggesting a novel therapeutic strategy to target the disease. While soluble and adhesion molecules from the BM regulating leukemia are beginning to be characterized, cells can also generate force and sense the mechanical properties of the BM niche. The BM niche is disrupted in some cases of leukemia, including the dysregulation of osteoblastic lineage cells that could lead to altered extracellular matrix mechanics and drug resistance. Deregulation of the serine/threonine kinase AKT has been associated with a number of cancers, including AML. Interestingly, AKT is required for sensing of matrix stiffness in some solid tumors, but its significance in leukemia is unknown. This study is based on the hypothesis that myeloid leukemic cell proliferation is regulated by matrix mechanics via AKT signaling pathway. We have developed a new model system to test this hypothesis, and to characterize drugs that specifically target the ability of leukemic cells to sense the physical properties of the BM niche. Methods The BM niche consists of heterogeneous micro-mechanics ranging from viscous to elastic regions. To model this in vitro, we used an alginate-based hydrogel conjugated with an integrin-binding RGD peptide to culture cells in a three-dimensional space, multi-well setting. Mechanical properties of the hydrogel were controlled by Ca2+ cross-linking and characterized by a rheometer. Human myeloid leukemia cell lines were characterized in this culture system: AML with MLL-AF9 translocations (MOLM-14 and NOMO-1), AML without MLL-AF9 (U-937), and Acute Promyelocytic Leukemia (HL-60). After encapsulating cells across different matrix mechanics, dose response analyses were performed. Results Without gel cross-linking, the alginate fluid recapitulates the known viscosity value of BM (40∼400 cP). Upon Ca2+ cross-linking, a viscoelastic solid is formed with a minimum elastic modulus at 50 Pa. All of the tested leukemic cells show 2∼3 fold increased cell proliferation in the soft solid (50 Pa) compared to the viscous fluid after one week culture. In contrast, increasing the stiffness of the solid further to 1000 Pa decreases proliferation by 1.5∼2 fold, suggesting a biphasic mechanical response from fluid to solid. Higher ligand density suppresses the cell number of HL-60 and U-937, while it increases that of MLL-AF9+ cells by ∼2 fold. On the other hand, primary normal CD34+BM cells are not sensitive to the transition from fluid to soft solid. The dose response curves of a DNA-synthesis inhibitor cytosine arabinoside show no change in potency or cooperativity across different matrix mechanics, indicating that higher doses of this drug are required to overcome increased leukemic cell number in soft solid relative to fluid. In contrast, pharmacological modeling predicts that the inhibition of bona-fide mechano-regulatory factors should eliminate the initial difference in cell number caused by matrix mechanics as the drug dose starts to increase. As a result, dose-response curves from different matrix mechanics will converge at a specific dose, followed by merging of the curves with higher doses. Dose response titration of MK-2206, a potent allosteric inhibitor of AKT phosphorylation at Ser473 (pS473-AKT), which was recently used in a Phase I study of solid tumors, indicates that AKT may fit the profile of mechano-regulatory targets in myeloid leukemia. MK-2206 decreases the cell number in the soft solid but not in the fluid until the dose reaches a point of convergence for the curves. As a result, the drug potency is increased by 2 fold from fluid to soft solid for both U-937 and MOLM-14, whereas the cooperativity is decreased by 3 fold for U-937. A similar trend was observed at the molecular level based on the dose-response curves of pS473-AKT expression evaluated by intracellular flow cytometry analyses. Conclusions The results suggest that AKT is a potential target to modulate sensitivity of myeloid leukemia to matrix mechanics. More broadly, this study provides a strategy to screen for drugs that target sensing of extracellular matrix mechanics by myeloid leukemia and overcome microenvironment-mediated drug resistance. Disclosures: No relevant conflicts of interest to declare.
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Vidovic, Karina, Emelie Svensson, Ake Borg, Johan Vallon-Christersson, Carin Lassen, Petra Hakansson, Johan Richter, Tor Olofsson, Thoas Fioretos, and Urban Gullberg. "Signaling from the Oncogenic Fusion Protein BCR/ABL1 Leads to Expression of Wilms’ Tumor Gene 1 Protein (WT1), Which Induces Transcriptional Repression of Interferon Consensus Sequence Binding Protein (ICSBP) in Human Cells." Blood 108, no. 11 (November 16, 2006): 4322. http://dx.doi.org/10.1182/blood.v108.11.4322.4322.
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Abstract The Wilms’ tumor gene 1 (WT1) encodes a transcription factor highly expressed in most leukemias. Overexpression of WT1 and the fusion protein AML1-ETO in transgenic mice rapidly induces acute myeloid leukemia (AML), indicating an oncogenic effect by WT1. However, mechanisms behind expression of WT1 in leukemic cells, as well as mechanisms downstream of WT1, are largely unknown. Here, we report that the fusion protein BCR/ABL1, associated with chronic myeloid leukemia (CML), increases expression of WT1 mRNA and protein, which induces transcriptional represssion of ICSBP. Inhibition of BCR/ABL1 signaling by imatinib mesylate reduced WT1 mRNA levels in five different human CML cell lines, confirming previous reports (Cilloni D et al. Cancer 101:979, 2004). In extended investigations, we show that signaling via the phosphatidylinositol-3 kinase (PI3K)-Akt pathway is critical for BCR/ABL1 induced WT1 expression, while independent of JAK-STAT signaling. BCR/ABL1 signaling did not affect half-life of WT1 mRNA, but inhibition of BCR/ABL1 or PI3K strongly suppressed the transcriptional activity of WT1 promoter/enhancer reporters, indicating that BCR/ABL1 signaling increases transcription of the WT1 gene. Downstream of WT1, we report the interferon consensus sequence binding protein (ICSBP) gene as a new target gene of WT1. Increased levels of WT1 reduced the amount of ICSBP mRNA in both normal progenitors and in U937 leukemic cells. Moreover, WT1 repressed transcription from the ICSBP-promoter. Finally, we report that forced expression of BCR/ABL1 in human CD34+ bone marrow progenitor cells resulted in increased expression of WT1 mRNA and protein and repressed levels of ICSBP mRNA and protein, indicating that WT1 can repress expression of ICSBP. In contrast to the almost ubiquitously high expression of WT1 in leukemia, expression of ICSBP is very low or absent in most leukemias, consistent with the notion of WT1 as a repressor of ICSBP in vivo. Moreover, several reports point out ICSBP as an important suppressor gene in CML. Our results provide a mechanistic explanation for BCR/ABL1 induced repression of ICSBP via induction of WT1, and a general mechanism by which high expression of WT1 could contribute to repression of ICSBP also in other leukemias.
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Price, Colles O., Ping Chen, Zejuan Li, Yuanyuan Li, Anissa Wiley, Chunjiang He, Hao Huang, et al. "MLL-Rearrangements Result in Upregulation of Mir-9 and Subsequent Inhibition of the Tumor Suppressor TGFBI." Blood 118, no. 21 (November 18, 2011): 2453. http://dx.doi.org/10.1182/blood.v118.21.2453.2453.
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Abstract Abstract 2453 Acute Leukemia represents one of the most deadly cancers in the United States. Clinical treatments in leukemia have progressed significantly through the use of therapies targeted specifically to chromosomal translocations. The success of these therapies has provided a model for future treatment in various cancers. However, there are various subtypes of leukemia where five-year survival and relapse rates have poor clinical outcome, indicating that new therapies are needed. A particular leukemia subtype, namely mixed lineage leukemia (MLL)-rearranged leukemia that is a result of chromosomal rearrangements leading to fusions between MLL and partner genes, is associated with a dismal outcome. Therapeutic targeting of MLL rearrangements has proven challenging as there have been dozens of described rearrangements. We have performed both messenger RNA (mRNA) and microRNA (a class of small non-coding RNA) microarray analyses on over 100 leukemia patient samples and have identified that microRNA-9 (miR-9) is highly upregulated in MLL-associated leukemias. Through correlating expression of miR-9 and those of its predicted target genes, we identified TGFbeta-induced protein (TGFBI) as a potential target of miR-9 that exhibited a significantly (P<0.05) inverse correlation of expression with miR-9 in acute leukemia. Our further luciferase reporter/mutagenesis assays show that TGFBI is a direct target of miR-9. TGFBI has been described as a tumor suppressor in breast, lung and ovarian tumors through two mechanisms, AKT inhibition and microtubule stabilization, but its involvement in leukemia has never been reported. We found that TGFBI expression was decreased while miR-9 was upregulated in MLL-rearrangement acute myeloid leukemias. Upon further testing we discovered that exogenous expression of miR-9 increased proliferation and enhanced the colony-forming ability of progenitor cells infected with MLL-AF9 fusions. Expression of TGFBI was sufficient to inhibit proliferation and significantly reduced the colony-forming ability of MLL-AF9. This reduction in colony-forming ability was also observed when MLL-AF9 progenitor cells were infected with TGFBI and miR-9 together, showing that TGFBI expression is sufficient to block the effects of miR-9 overexpression. We suspect that TGBFI expression modulates AKT in MLL-rearranged leukemias, thus making it susceptible to combination of standard leukemia chemotherapies with AKT-inhibitors. We will test the effects on NVP-BEZ235, a PI3K/mTOR inhibitor in phase II clinical trials, alone and in combination with other chemotherapies against MLL-rearrangement leukemias. We expect that the specific targeting of this pathway in these leukemias will be highly efficacious. Thus these studies could identify a novel therapeutic strategy for the treatment of MLL-rearrangement leukemias that is more effective and specific than the current therapies. Disclosures: No relevant conflicts of interest to declare.
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Andreeff, Michael, Sergej Konoplev, Rui-Yu Wang, Zhihong Zeng, Teresa McQueen, Yue-Xi Shi, L. Jeffrey Medeiros, et al. "Massive Mobilization of AML Cells into Circulation by Disruption of Leukemia/Stroma Cell Interactions Using CXCR4 Antagonist AMD3100: First Evidence in Patients and Potential for Abolishing Bone Marrow Microenvironment-Mediated Resistance." Blood 108, no. 11 (November 16, 2006): 568. http://dx.doi.org/10.1182/blood.v108.11.568.568.
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Abstract The chemokine receptor CXCR4 is critically involved in migration of hematopoietic cells to the stromal derived factor (SDF-1α)-producing bone marrow microenvironment. CXCR4 is regulated in part by mutant FLT3 signaling, but in a series of 122 AML samples with diploid karyotype and lack of FLT3 mutation (ITD), high CXCR4 expression negatively correlated with DFS and OS (p=0.03 and p=0.04, respectively), after multivariate analysis (Konoplev, ASH 2006). We hypothesized that inhibition of SDF-1α-/CXCR4 interactions would result in mobilization of leukemic blasts from the bone marrow into circulation. The in vivo effect of the CXCR4 antagonist AMD3100 was studied in three patients with AML, who had insufficient mobilization of CD34+ cells for autologous stem cell transplantation with G-CSF and/or cytoxan. The combination of G-CSF (10 μg/kg QD) and AMD3100 (240 μg/kg QD SC starting on d4 and repeated for 3–4 days) resulted in massive mobilization of leukemic cells into the circulation in a time-dependent fashion, as determined by flow cytometry and interphase FISH analysis of their respective cytogenetic abnormalities. Patient # Cytogenetics % (+) cells % (+) cells Apheresis FCM Day 2 Day 4/5 CD34x106/kg 1 Trisomy 21 22.6 57.0 FCM CD7/33 22.0 2 Trisomy 9 28.6 68.6 Inv 16 29.0 75.8 4.8 FCM CD13/33 74.0 3 Mono 17 40.4 53.4 5q31 37.5 49.6 8.7 FCM CD13/33 50.0 We and others have previously demonstrated that stroma/leukemia interactions mediate protection of leukemic cells from chemotherapy-induced apoptosis (Konopleva et al, Leukemia2002:1713). We then tested the hypothesis that CXCR4 inhibition would result in increased sensitivity to chemotherapy, using AMD3465, the second generation small-molecule CXCR4 inhibitor with greater potency than AMD3100. Results demonstrate inhibition of surface expression of CXCR4 and of SDF-1α-, and stroma(MS-5)-induced migration of AML cells. In vitro co-culture systems with stromal cells significantly protected leukemic cells (p < 0.01), while AMD3465 decreased stroma-mediated protection from AraC and Busulfan apoptosis and downregulated AKT signaling in AML cells. In a murine model of luciferase labeled Baf-FLT3ITD leukemias, AMD3465 induced massive dissemination of leukemia, which was abrogated by treatment with Sorafenib, a potent FLT3ITD inhibitor (Zhang, ASH 2006). Taken together, our data suggest that SDF-1α/CXCR4 interactions contribute to the resistance of leukemic cells to chemotherapy-induced apoptosis. Disruption of these interactions by CXCR4 inhibition results in leukemia dissemination and chemosensitization. Our results in leukemia patients provide first in man proof-of principle for a novel strategy of targeting the leukemia cell/bone marrow microenvironment interactions. A clinical trial testing this concept in patients with AML is under development.
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YILDIRIM, Rahşan, İlker BAY, Elif YILMAZEL UÇAR, Ömer TOPDAĞI, Fuat ERDEM, and Leyla SAĞLAM. "Simultaneous Presentation of Acute Monoblastic Leukemia and Lung Cancer." Turkiye Klinikleri Archives of Lung 19, no. 1 (2018): 30–32. http://dx.doi.org/10.5336/archlung.2017-59253.
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Yang, Mingzhen, Xiaoyu Zhang, Zhenqi Huang, Qingsheng Li, Lin Wang, and Qinhua Liu. "The Apoptosis of Acute Myeloid Leukemia Cell Line (SHI-1 cells) Induced by Bortezomib In Vitro." Blood 116, no. 21 (November 19, 2010): 4382. http://dx.doi.org/10.1182/blood.v116.21.4382.4382.
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Abstract Abstract 4382 Background: The proteasome plays a critical role in the regulation of many cellular processes, including the cell cycle and tumor growth. The proteasome inhibitor Bortezomib has been used in multiple myeloma and other lymphoid malignancies because of its antitumor activity. Here we investigated the induction of apoptosis by proteasome inhibitor Bortezomib in human acute myeloid leukemia (AML) cell lines SHI-1 cells and try to explore the mechanism of anti-leukemia. Method: We incubated SHI-1 leukemic cells with different concentration of bortezomib. cell proliferation was detected with MTT, apoptosis was measured by FCM, the protein expression of PI3K and p-Akt were determined by Western blot. Result: 0.5ug/ml bortezomib suppressed SHI-1 cells proliferation and induced SHI-1 cells apoptosis after incubated 24hr, 100ug/ml bortezomib suppressed 61.7% SHI-1 cells proliferation. Apoptosis increased obviously with the increasing bortezomib concentration and the culture time, about 39.77% SHI-1 cells were apoptosis when bortezomib concentration was 100ug/ml, the leukemia cell apoptosis was significant at 150ng/ml bortezomib, the protein expression of PI3K, and p-Akt gradually declined with bortezomib concentration increasing, The protein expression of PI3K and p-Akt in SHI-1 cells decreased 50.6% and 71.6% respectively at 100ug/ml bortezomib for 48hr.when 150ng/ml bortezomib incubated with leukemia cells for 24 hours, The protein expression of PI3K and p-Akt were lowest. Conclusion: Bortezomib could inhibit SHI-1 cells proliferation and induce leukemia cells apoptosis, and could down-regulate the expression of PI3K and p-Akt significantly, this might be the one of mechanisms that bortezomib induce SHI-1 cells apoptosis, we presume that bortezomib inhibit proliferation of acute myelogenous leukemia cells through effect of PI3K/Akt signaling pathways. Disclosures: No relevant conflicts of interest to declare.
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Sativa, Shania Ocha. "PENGARUH GENETIK, GAYA HIDUP DAN LINGKUNGAN PADA KEJADIAN LEUKEMIA MIELOBLASTIK AKUT." JIMKI: Jurnal Ilmiah Mahasiswa Kedokteran Indonesia 8, no. 1 (February 26, 2020): 83–88. http://dx.doi.org/10.53366/jimki.v8i1.42.
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ABSTRAK Leukemia Mieloblastik Akut merupakan salah satu kelainan sel darah berupa keganasan yang ditandai dengan proliferasi dan pertumbuhan dari sel hematopoietik yang imatur di dalam sum-sum tulang dan darah. Pasien dengan AML memiliki gejala khas seperti mudah lelah, sulit bernapas atau sesak, perdarahan, dan tanda-tanda infeksi yang merupakan akibat dari kegagalan sumsum tulang. Penyakit ini dapat didiagnosis dengan pemeriksaan darah lengkap, analisis darah tepi, serta pemeriksaan sampel sumsum tulang. Insidensi penyakit ini tinggi pada orang dewasa. Hampir 80% kasus leukemia akut terjadi pada orang dewasa dan 20% kasus leukemia akut terjadi pada anak-anak. Kejadiannya meningkat seiring dengan bertambahnya usia seseorang. Oleh karena penyebab pasti dari leukemia belum diketahui, beberapa faktor risiko terkait pernyakit ini telah diidentifikasi. Beberapa faktor risiko absolut dan relatif dari leukemia akut dikelompokkan menjadi faktor genetik, gaya hidup dan lingkungan. Merokok, obesitas, konsumsi alkohol serta asupan makanan berpengaruh terhadap perkembangan dari leukemia sendiri. Faktor risiko lingkungan yang dapat menyebabkan AML ialah paparan benzen, radiasi ionisasi dosis tinggi, agen kemoterapetik, dan paparan zat atau bahan elektromagnetik. Kata Kunci: Faktor Risiko, Keganasan, Leukemia Mieloblastik Akut ABSTRACT Acute Myeloblastic Leukemia (AML) is a blood cell disorder in the form of malignancy characterized by the proliferation and growth of immature hematopoietic cells in the bone marrow and blood. Patients with AML have typical symptoms such as fatigue, difficulty breathing or tightness, bleeding, and signs of infection that result from bone marrow failure. The disease can be diagnosed by a complete blood count, peripheral blood analysis, and examination of bone marrow samples. The incidence of this disease is high in adults. Nearly 80% of cases of acute leukemia occur in adults and 20% of cases of acute leukemia occur in children. The incidence increases with age. Because the exact cause of leukemia is unknown, several risk factors associated with this disease have been identified. Some absolute and relative risk factors for acute leukemia are grouped into genetic, lifestyle and environmental factors. Smoking, obesity, alcohol consumption and food intake influence the development of leukemia itself. Environmental risk factors that can cause AML are benzene exposure, high dose ionizing radiation, chemotherapeutic agents, and exposure to substances or electromagnetic materials. Keywords: Risk Factor, Malignancy, Acute Myeloid Leukemia
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Medyouf, Hind, Samuel Gusscott, Carol Wai, Marcus Leung, Florence Armstrong, Francoise Pflumio, Michael Pollak, and Andrew P. Weng. "IGF Signaling Is Critical for Growth and Survival of T-Cell Acute Lymphoblastic Leukemia Cells and Is Potentiated by Notch Upregulation of IGF1R." Blood 112, no. 11 (November 16, 2008): 3811. http://dx.doi.org/10.1182/blood.v112.11.3811.3811.
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Abstract T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of immature T cell progenitors in which we described activating mutations of Notch1 to occur in over 50% of cases. As well, others have identified loss-of-function mutations in Sel10/Fbw7 to occur in 8–16% of cases, which also enhance Notch signaling. Notably, inhibition of Notch signaling in these cells induces growth arrest and in some cases apoptosis as well. Subsequent studies have characterized c-myc as a critical downstream target of Notch signaling in this context. More recently, mutations in PTEN (occurring in 17% of cases) were shown to potentiate PI3K/Akt signaling and proposed to confer resistance to Notch signaling inhibition, but then impose “addiction” to PI3K/Akt. Most leukemias likely derive cooperative growth/survival signals from Notch and PI3K/Akt pathways, as evidenced by synergistic effects of gamma-secretase inhibitors (GSI) which block Notch signaling and rapamycin which blocks mTOR downstream of PI3K/Akt. In mouse models, combined activation of c-myc and b-catenin with inactivation of PTEN elicited T-ALL which was devoid of Notch mutations, suggesting Notch signaling coordinately activates c-myc, Wnt, and PI3K/Akt signaling pathways. In studying the mechanism for PI3K/Akt activation in T-ALL with activated Notch signaling, we examined insulin-like growth factor receptor-1 (IGF1R) as a candidate upstream initiator of PI3K/Akt activation. We observed IGF1R expression consistently in T-ALL cells from primary human leukemias and cell lines, as well as in primary mouse leukemias derived experimentally by retroviral transduction of marrow with activated forms of Notch1. In all cases, inhibition of IGF1R signaling either with blocking antibody or small molecule kinase inhibitors resulted in growth suppression and apoptosis of leukemia cells. We further observed that inhibition of Notch signaling either by small molecule GSI or transduction with a dominant negative coactivator, Mastermind, resulted in a 2–3 fold decrease in IGF1R expression. Given that the PI3K/Akt/mTOR pathway is known to be important for growth/survival of T-ALL leukemia cells, we hypothesized that Notch might be potentiating activation of this pathway by upregulating IGF1R expression. In fact, we found leukemia cells with active Notch and higher IGF1R levels showed 20-fold greater sensitivity to IGF-1 ligand induced Akt activation as compared to leukemia cells with inactive Notch and lower IGF1R levels. This enhanced signaling output cannot be explained by Notch suppression of PTEN as this effect was noted in both PTEN wild-type and PTEN null leukemia cells. Additionally, cells with wild type PTEN demonstrated only minimal if any changes in PTEN protein levels after Notch inhibition as measured by a highly quantitative flow cytometry assay. In sum, we have identified IGF-1 signaling as being critical to growth and survival of T-ALL leukemia cells, and provide evidence that Notch may potentiate PI3K/Akt signaling by upregulating expression of IGF1R. These data are of immediate clinical relevance as several IGF1R inhibitors are currently in Phase 3 clinical trial and hopefully will provide additional therapeutic options to refractory/relapsed patients and/or in combination with front-line therapy in newly diagnosed patients.
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Z A, Maimun, and Budiman Budiman. "LEUKEMIA LIMFOBLASTIK AKUT PADA DEWASA DENGAN FENOTIP BILINEAGE (LIMFOID-B DAN T)." INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY 13, no. 2 (March 15, 2018): 72. http://dx.doi.org/10.24293/ijcpml.v13i2.886.
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In this report we describe a patient with adult acute lymphoblastic leukemia with bilineage phenotypic. He was found to have massive right pleural effusion with mediastinal shift to the contra lateral side. There was also a smaller left pleural effusion. He had multiple bilateral cervical lymphadenopathy, tense ascites and bilateral pedal oedema up to the shins. He was otherwise clinically stable.His full blood count on admission showed Hb of 11.4 g/dl, platelets of 59 X 109/L and WBC of 12.99 × 109/L with blasts of 26%. His renal function was normal with a creatinine of 107 micromoles/L. Bone marrow trephine biopsy showed features consistent with acute lymphoblast leukemia-L1. Flow cytrometry of his blood was suggestive of bilineage phenotypic acute lymphoblast leukaemia. It showeda single population of blasts (about 31%) which expressed cCD3+, CD4-, CD7+, CD5-, CD19+, CD34+, TdT+, cytoplasm IgM, CD79a+ and 30% are CD10+, and there was aberrant CD33+ expression with no evidence of MPO or CD117 expression. Cytogenesis of the bone marrow trephine biopsy showed numerical and structural abnormalities in nine out of the seventeen cells analysed. These abnormalitiesare 43~47,XY, add (1)(p34.2), add(2)(p13), i(17)(q10), +21[cp9].
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Çayıröz, Pınar, Mehmet Umut Çayıröz, Utku Iltar, and Erdal Kurtoğlu. "Kırım-Kongo Kanamalı Ateşi ile Eş Zamanlı Akut Lenfoblastik Lösemi Tanısı Alan Olgu." Mikrobiyoloji Bulteni 54, no. 2 (April 15, 2020): 326–33. http://dx.doi.org/10.5578/mb.69381.
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Mandawat, Aditya, Warren Fiskus, Andrea Jakubowski, Rekha Rao, Zixuan Wang, Pravina Fernandez, Yongchao Wang, et al. "Pan-Histone Deacetylase (HDAC) Inhibitor LBH589 Depletes CXCR4 Levels and Signaling, Exerting Synergistic Anti-Leukemia Activity in Combination with CXCR4 Antagonists." Blood 110, no. 11 (November 16, 2007): 537. http://dx.doi.org/10.1182/blood.v110.11.537.537.
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Abstract The trafficking and mobilization of normal hematopoietic progenitors and their leukemic counterparts is programmed in part by chemotactic gradients of CXCL12, which are transduced by CXCR4. This mechanism also results in decreased sensitivity to pro-apoptotic and anti-leukemic agents, mediated through CXCR4 activation of Akt and Raf phosphorylation and/or harboring in a microenvironmental niche. Both CXCL12 and CXCR4 are overexpressed in AML and expression of CXCR4 has been associated with a poor prognosis. Moreover, inhibition of CXCR4 with AMD3100 enhanced the sensitivity of leukemic myeloblasts to anti-leukemic agents. We therefore explored therapeutic mechanisms to decrease CXCR4 expression and tested them in combination with AMD3100 as well as a new generation CXCR4 inverse agonist, FC131. Exposure to 10 to 50 nM of the pan-HDAC inhibitor LBH589 (Novartis) depleted mRNA and protein levels of CXCR4 in the cultured human acute leukemia OCI-AML3, HL-60 and Jurkat cells, as well as in primary AML cells in a dose and time-dependent manner. LBH589 depleted CXCR4 levels in the presence or absence of 10 nM of CXCL12 in the culture medium. LBH589 mediated depletion of CXCR4 levels was partly due to decreased CXCR4 mRNA levels (by RT-PCR analysis). LBH589 induced acetylation of heat shock protein (hsp) 90 and attenuated the binding of CXCR4 to hsp90 with subsequent degradation of CXCR4 by the proteasome. LBH589 treatment also increased hsp70 levels and acetylation, as well as its binding to CXCR4, which also resulted in increased extra-cellular, cell surface co-localization of CXCR4 and hsp70. This was markedly inhibited by siRNA-mediated knockdown of hsp70 in HL-60 cells. While exposure of cultured and primary AML cells to CXCL12 markedly increased cytosolic levels of p-AKT and p-ERK1/2, co-treatment with LBH589 markedly attenuated the phosphorylation of AKT and ERK1/2 induced by CXCL12, resulting in apoptosis of up to 50% of cultured and primary AML cells. Treatment with AMD3100 (10 uM for 24 hours) alone decreased levels of CXCR4, p-AKT and p-ERK1/2, without significantly increasing apoptosis of AML cells. Notably, co-treatment with LBH589 and AMD3100 caused greater depletion of CXCR4, p-AKT and p-ERK1/2 levels, and exerted synergistic apoptotic effects against AML cells with combination indices of < 1.0 utilizing isobologram and median effect analyses. Co-treatment with LBH589 and FC131 (10 nM for 24 hours), which is a more potent CXCR4 antagonist than AMD3100, also induced synergistic apoptosis of cultured and primary AML cells. Taken together, these findings provide direct evidence that CXCR4 is a novel target depleted by LBH589 in AML cells. Furthermore, our in vitro findings highlight the novel combination of LBH589 and a CXCR4 antagonist, AMD3100 or FC131, exerts a synergistic effect on acute leukemia cells. These findings strongly support the in vivo testing of this synergistic combination in the therapy of human acute leukemias that express CXCR4.
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Fatikasari, Andi Cindy, Welinda Dyah Ayu, and Muhammad Amir Masruhim. "Kajian Penggunaan Obat Kemoterapi pada Pasien Leukemia Anak Di RSUD Abdul Wahab Sjahranie Kota Samarinda." Proceeding of Mulawarman Pharmaceuticals Conferences 8 (December 31, 2018): 111–18. http://dx.doi.org/10.25026/mpc.v8i1.312.
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Leukemia merupakan penyakit keganasan sel darah yang berasal dari sumsum tulang, ditandai oleh proliferasi sel-sel darah putih yang tidak teratur dan tidak terkendali. Leukemia akut adalah keganasan yang paling umum terjadi pada anak-anak. Tujuan penelitian ini yaitu untuk mengetahui karakteristik pasien, regimen kemoterapi, ketepatan dosis, efek samping serta penanganan efek samping kemoterapi leukemia. Metode penelitian yang digunakan yaitu non eksperimental. Data yang di peroleh diambil secara prospektif dan teknik pengambilan data secara total sampling menggunakan data rekam medik serta data hasil wawancara dengan jumlah total sebanyak 29 responden. Hasil penelitian menunjukkan bahwa pasien yang mengalami leukemia akut lebih banyak diderita oleh perempuan sebesar 52%, pada kelompok usia pra-sekolah 3-5 tahun sebesar 38%, dan jenis leukemia akut terbanyak adalah jenis ALL tipe L1 sebesar 59%. Regimen kemoterapi leukemia terbanyak adalah kombinasi Methotrexate IT-Vincristin sebesar 37% dengan ketepatan dosis sebesar 100% dihitung berdasarkan BSA (Body Surface Area). Efek samping regimen kemoterapi terbanyak adalah mual-muntah sebesar 97% dengan penanganan efek samping mual-muntah adalah ondansetron.
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Longo, Pablo, Stefania Gobessi, Luca Laurenti, Simona Sica, Giuseppe Leone, and Dimitar G. Efremov. "Introduction of Constitutivelly Active Akt in Primary CLL B-Cells Results in Upregulation of Mcl-1, Bcl-XL and Cyclin D3 and Promotes Leukemic Cell Survival." Blood 108, no. 11 (November 16, 2006): 2805. http://dx.doi.org/10.1182/blood.v108.11.2805.2805.
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Abstract The PI3K/Akt and Raf/MEK/ERK pathways are key regulators of various cellular responses, including proliferation, survival, differentiation, migration and malignant transformation. These pathways are activated in chronic lymphocytic leukemia B-cells by a number of survival or growth stimulatory signals, such as immobilized anti-IgM antibodies, interleukin-4, phorbol-ester, CXCL12, or stimulatory CpG oligonucleotides. Moreover, enhanced activation of Akt has been implicated in the pathogenesis of the CLL-like disorder that develops in mice transgenic for the TCL1 oncogene. To further delineate the relative contribution of the PI3K/Akt and Raf/MEK/ERK pathways in regulating leukemic cell growth and survival, we introduced constitutively active Akt or constitutively active MEK2 in primary CLL B-cells by nucleofection. Expression of constitutively active Akt consistently promoted survival, as evidenced by a higher percentage of Annexin V/PI negative cells after 48 hours in culture (median 52%) compared to samples transfected with control vector (median 31%). Immunoblot analysis of several important antiapoptotic proteins revealed that enforced activation of Akt upregulates Mcl-1 and Bcl-xL, whereas no changes were observed in the levels of Bcl-2. Expression of constitutively active Akt also induced an increase in size and granularity of the leukemic cells, indicating increased metabolic activity. These changes were associated with significant induction of cyclin D3, indicating that activation of Akt is required for both leukemic cell survival and cell cycle progression. In contrast, introduction of constitutively active MEK2 induced sustained activation of ERK, but showed only a modest increase in the percentage of viable CLL B-cells (median 36%) and no significant changes in the levels of any of the investigated antiapoptotic proteins. These experiments provide direct evidence that sustained activation of Akt promotes leukemic cell survival and upregulates Mcl-1, an antiapoptotic protein that has been associated with resistance to chemotherapy in patients with CLL.
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Hiroki, Haruka, Masatoshi Takagi, Yuko Ishi, Jinhua Piao, and Tomohiro Morio. "PARP Inhibition Sensitize BCR-ABL1 Positive Cel." Blood 134, Supplement_1 (November 13, 2019): 3367. http://dx.doi.org/10.1182/blood-2019-127853.
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Introduction: BCR-ABL1 play a key role in the development of chronic myelogenous leukemia and a part of Ph1 positive acute lymphoblastic leukemia (ALL). BCR-ABL1 functions as a tyrosine kinase. Whereas, BCR-ABL1 induces genomic instability by downregulation of BRCA1. An innate error of BRCA1, a molecule involved in the homologous recombination repair pathway, causes hereditary breast and ovarian cancer. PARP inhibitor (PARPi) induces synthetic lethality in BRCA defective cell. Therefore, PARP inhibitor is expected to induce efficient cell death with BCR-ABL1 positive cell. In addition, in some previous reports, reduction of PARP1 activity leads to the upregulation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway and BCR-ABL1 tyrosine kinase activates PI3K/AKT pathway. These findings suggest activation of the PI3K/AKT pathway leading to PARPi resistance in BCR-ABL1 positive leukemic cells. Here, we demonstrate that PARP inhibition attenuates BCR-ABL1 mediated leukemogenesis and aberration of factors associated with PARP inhibitor resistance induces cell death to fully transformed leukemic cells. Method: Bone marrow-derived mononuclear cells (MNC) from wild type mice and BCR-ABL1 transgenic (Tg) mice were exposed to PARPi in vivo, and cell death was analyzed Annexin-V positivity. PARPi sensitivity to BCR-ABL1 expressed cell was also investigated in vivo bone marrow transplantation model using mouse hematopoietic stem cell (HCS) infected with BCR-ABL1 expressing retrovirus. To evaluate more precisely the results obtained in vitro and in vivo transplantation model, the genetical approach was also performed. The Parp1 knockout (KO) mice were crossed with BCR-ABL1 Tg mice. Then, Leukemia development and subsequent mouse death were observed. In vitro, HR activity was examined using DR-GFP assay. Genomic instability was investigated using the breakage-fusion-bridge (BFB) generation.Maintenance of HSC as a progenitor of the leukemic cell was analyzed by repopulation activity using colony assay. The growth-inhibitory effect was assessed using BCR-ABL positive cell lines with PARPi and PI3K inhibitor. Results: BCR-ABL1 Tg mice derived MNC showed more hypersensitivity to PARPi. Mouse HCS was infected with BCR-ABL1 expressing retrovirus and transplanted lethally Olaparib or vehicle was administrated intraperitoneal injection one day after transplantation. BCR-ABL1 mediated leukemic death was observed 1 month after transplantation in sham-treated mouse, whereas, Olaparib treated mouse did not develop BCR-ABL1 mediated leukemia. Parp1 KO BCR-ABL1 Tg mice attenuated leukemia development and extended their survival compared with BCR-ABL1 Tg mice. In vitro experiment revealed HR activity was down-regulated by BCR-ABL1 expression in DR-GFP assay. The number of BFB generation was increased in BCR-ABL1 Tg with Parp1 KO background. The colony-forming activity of BCR-ABL1 positive HSC was totally abolished by PARP inhibition after 3 times serial replating, whereas sham-treated HSC retained repopulation activity. However, the effect of PARPi on BCR-ABL positive leukemic cell lines was controversial. Therefore, leukemic cell lines were treated with the PARPi and inhibitors toward the molecules associated with PARPi resistance. As a result, a combination of PARPi with PI3K inhibitor effectively induce cell death in PARPi resistant BCR-ABL1 positive leukemic cell lines. Conclusion and discussion: Tyrosine kinase inhibitor (TKI) is the gold standard of the therapeutic option of BCR-ABL1 positive leukemia. However, TKI monotherapy is not sufficient for complete eradication of leukemic cells. It is highly expected that molecules effectively induce cell death to leukemic cells combined with TKI. PARPi would be one of these candidates. However, PARPi could not induces efficient death in all of the cancer cells that carry the mutation of molecules associated with the HR defect. Comprehensive genetic analysis to reveal PARPi resistance is important for HRR defective cancer cells. Combination therapy of PARPi and inhibitorstoward the molecules associated with PARPi resistance would be a good therapeutic option for Ph1 positive leukemia. Disclosures No relevant conflicts of interest to declare.
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Lamy, Thierry, Aline Moignet, and Thomas P. Loughran. "LGL leukemia: from pathogenesis to treatment." Blood 129, no. 9 (March 2, 2017): 1082–94. http://dx.doi.org/10.1182/blood-2016-08-692590.
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AbstractLarge granular lymphocyte (LGL) leukemia has been recognized by the World Health Organization classifications amongst mature T-cell and natural killer (NK) cell neoplasms. There are 3 categories: chronic T-cell leukemia and NK-cell lymphocytosis, which are similarly indolent diseases characterized by cytopenias and autoimmune conditions as opposed to aggressive NK-cell LGL leukemia. Clonal LGL expansion arise from chronic antigenic stimulation, which promotes dysregulation of apoptosis, mainly due to constitutive activation of survival pathways including Jak/Stat, MapK, phosphatidylinositol 3-kinase–Akt, Ras–Raf-1, MEK1/extracellular signal-regulated kinase, sphingolipid, and nuclear factor-κB. Socs3 downregulation may also contribute to Stat3 activation. Interleukin 15 plays a key role in activation of leukemic LGL. Several somatic mutations including Stat3, Stat5b, and tumor necrosis factor alpha-induced protein 3 have been demonstrated recently in LGL leukemia. Because these mutations are present in less than half of the patients, they cannot completely explain LGL leukemogenesis. A better mechanistic understanding of leukemic LGL survival will allow future consideration of a more targeted therapeutic approach than the current practice of immunosuppressive therapy.
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CENGİZ SEVAL, Güldane, Tuba CANDAR, Meltem AYLI, Çağlar COŞARDERELİOĞLU, Selda DEMİRTAŞ, Gülsüm ÖZET, Simten DAĞDAŞ, Murat ALBAYRAK, and Harika OKUTAN. "Serum Cystatin C in Patients with Acute Leukemia and its Prognostic Importance." LLM Dergi 1, no. 1 (January 15, 2017): 1–4. http://dx.doi.org/10.5578/llm.46510.
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A, Maimun Z., and Budiman Budiman. "LEUKEMIA LIMFOBLASTIK AKUT PADA DEWASA DENGAN FENOTIP BILINEAGE (LIMFOID-B DAN T)." INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY 13, no. 2 (February 22, 2017): 72. http://dx.doi.org/10.24293/ijcpml.v13i2.750.
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In this report we describe a patient with adult acute lymphoblastic leukemia with bilineage phenotypic. He was found to have was found to have massive right pleural effusion with mediastinal shift to the contra lateral side. There was also a smaller left pleural effusion. He had multiple bilateral cervical lymphadenopathy, tense ascites and bilateral pedal oedema up to the shins. He was otherwise clinically stable. His full blood count on admission showed Hb of 11.4 g/dl, platelets of 59 X 109/L and WBC of 12.99 × 109/L with blasts of 26%. His renal function was normal with a creatinine of 107 micromoles/L. Bone marrow trephine biopsy showed features consistent with acute lymphoblast leukemia-L1. Flow cytrometry of his blood was suggestive of bilineage phenotypic acute lymphoblast leukaemia. It showed a single population of blasts (about 31%) which expressed cCD3+, CD4-, CD7+, CD5-, CD19+, CD34+, TdT+, cytoplasm IgM, CD79a+ and 30% are CD10+, and there was aberrant CD33+ expression with no evidence of MPO or CD117 expression. Cytogenesis of the bone marrow trephine biopsy showed numerical and structural abnormalities in nine out of the seventeen cells analysed. These abnormalitiesare 43~47,XY, add (1)(p34.2), add(2)(p13), i(17)(q10), +21[cp9].
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Cai, Dali, Ying Wang, Oliver G. Ottmann, Peter J. Barth, Andreas Neubauer, and Andreas Burchert. "FLT3-ITD–, but not BCR/ABL-transformed cells require concurrent Akt/mTor blockage to undergo apoptosis after histone deacetylase inhibitor treatment." Blood 107, no. 5 (March 1, 2006): 2094–97. http://dx.doi.org/10.1182/blood-2005-08-3317.
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Leukemias are differentially sensitive to histone deacytelase inhibitor (HDI)–induced apoptosis, but molecular reasons for this remain unclear. We here show that BCR/ABL-, but not FMS-like tyrosine kinase 3 (FLT3)–internal tandem duplication (ITD)–transformed 32D cells or primary acute myeloid leukemia (AML) blasts undergo apoptosis after treatment with the HDI valproic acid (VPA) plus all-trans retinoic acid (VPA/ATRA). A particular VPA/ATRA responsiveness of Philadelphia chromosome–positive (Ph+) acute lymphatic leukemia (ALL) was confirmed in a therapy-refractory patient in vivo. HDI-stimulated apoptosis in Ph+ cells was caspase dependent, but independent from Akt pathway inhibition. Conversely, separate blockage of the Akt/mTor-signaling pathway was a prerequisite for overcoming apoptosis resistance to VPA/ATRA in FLT3-ITD cells, and primary AML blasts (n = 9). In conclusion, constitutive Akt activation causes apoptosis resistance to VPA/ATRA in AML, but not in Ph+ leukemia. This warrants the application of HDI-based therapies in poor-risk Ph+ ALL, and the use of Akt/mTor inhibitors to overcome HDI resistance in AML.
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Longo, Pablo G., Luca Laurenti, Stefania Gobessi, Simona Sica, Giuseppe Leone, and Dimitar G. Efremov. "The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells." Blood 111, no. 2 (January 15, 2008): 846–55. http://dx.doi.org/10.1182/blood-2007-05-089037.
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Sustained engagement of the B-cell receptor (BCR) increases apoptosis resistance in chronic lymphocytic leukemia (CLL) B cells, whereas transient stimulation usually has an opposite effect. The antiapoptotic BCR signal has been associated with prolonged activation of the PI3K/Akt and MEK/ERK pathways, which are key regulators of survival and proliferation in various cell types. To further define the relative contribution of the Akt and ERK kinases in regulating CLL B-cell survival, we introduced constitutively active mutants of Akt and MEK in primary CLL B cells and evaluated changes in the expression of relevant pro- and antiapoptotic proteins. Sustained activation of Akt resulted in increased leukemic cell viability and increased expression of the antiapoptotic proteins Mcl-1, Bcl-xL, and X-linked inhibitor of apoptosis protein (XIAP), thus largely recapitulating the effects of sustained BCR stimulation. Constitutively active MEK2 also up-regulated XIAP, but did not show a significant impact on leukemic cell survival. Down-regulation of Mcl-1 by siRNA treatment induced rapid and potent apoptosis in CLL B cells and blocked the antiapoptotic effect of sustained BCR stimulation, whereas down-regulation of Bcl-xL and XIAP did not affect leukemic cell viability. These data demonstrate that Akt and Mcl-1 are major components of a survival pathway that can be activated in CLL B cells by antigen stimulation.