To see the other types of publications on this topic, follow the link: Neoplastic Leukemia.
Journal articles on the topic 'Neoplastic Leukemia'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Neoplastic Leukemia.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Sandoval, Salemiz, Martina Pigazzi, and Kathleen M. Sakamoto. "CREB: A Key Regulator of Normal and Neoplastic Hematopoiesis." Advances in Hematology 2009 (2009): 1–8. http://dx.doi.org/10.1155/2009/634292.
Full textAbstract:
The cAMP response element-binding protein (CREB) is a nuclear transcription factor downstream of cell surface receptors and mitogens that is critical for normal and neoplastic hematopoiesis. Previous work from our laboratory demonstrated that a majority of patients with acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) overexpress CREB in the bone marrow. To understand the role of CREB in leukemogenesis, we examined the biological effect of CREB overexpression on primary leukemia cells, leukemia cell lines, and CREB overexpressing transgenic mice. Our results demonstrated that CREB overexpression leads to an increase in cellular proliferation and survival. Furthermore, CREB transgenic mice develop a myeloproliferative disorder with aberrant myelopoiesis in both the bone marrow and spleen. Additional research from other groups has shown that the expression of the cAMP early inducible repressor (ICER), a CREB repressor, is also deregulated in leukemias. And, miR-34b, a microRNA that negative regulates CREB expression, is expressed at lower levels in myeloid leukemia cell lines compared to that of healthy bone marrow. Taken together, these data suggest that CREB plays a role in cellular transformation. The data also suggest that CREB-specific signaling pathways could possibly serve as potential targets for therapeutic intervention.
2
Azizidoost, Shirin, Sadegh Babashah, Fakher Rahim, Mohammad Shahjahani, and Najmaldin Saki. "Bone marrow neoplastic niche in leukemia." Hematology 19, no. 4 (November 25, 2013): 232–38. http://dx.doi.org/10.1179/1607845413y.0000000111.
Full text
3
Sonneck, Karoline, Richard Fritz, Leonhard Muellauer, Karoline V. Gleixner, Matthias Mayerhofer, Stefan Florian, Marc Kerenyi, et al. "Detection of Activated STAT5 in the Cytoplasm of Neoplastic Cells in Patients with AML, CML, and Systemic Mastocytosis." Blood 108, no. 11 (November 1, 2006): 2305. http://dx.doi.org/10.1182/blood.v108.11.2305.2305.
Full textAbstract:
Abstract The signal transducer and activator of transcription 5 (STAT5) has recently been implicated as essential pro-oncogenic factor in the pathogenesis of myeloid leukemias in mice (Cancer Cell2005;7:87–99). More recently, STAT5 activation has also been described to occur in human leukemias. However, so far, little is known about the expression of activated/tyrosine phosphorylated STAT5 (pSTAT5) in various myeloid neoplasms and about the distribution of pSTAT5 in the cellular compartments of the normal and leukemic bone marrow (bm). We have examined the expression of pSTAT5 in the bm in patients with acute myeloid leukemia (AML, FAB M0, n=3, M1, n=6, M2, n=4, M3, n=5, M4, n=5, M5, n=4, M6, n=5, M7, n=4), chronic myeloid leukemia (CML, chronic phase, n=4, accelerated phase, n=5, blast phase, n=5), and systemic mastocytosis (SM, n=30), as well as in the normal bm (n=5). Expression of pSTAT5 was determined on paraffin-embedded bm sections by immunohistochemistry using the pSTAT5-specific antibody AX1. In the normal bm, the antibody AX1 was found to react with megakaryocytes and immature myeloid progenitor cells, whereas erythroid cells and mature granulocytic cells did not stain positive for AX1. In patients with AML and CML, the distribution of pSTAT5 showed a similar pattern. In fact, pSTAT5 was found to be expressed in leukemic blast cells without differences among FAB types as well as megakaryocytic cells, but not in erythroid cells. In patients with SM, neoplastic mast cells were found to be immunoreactive for pSTAT5. Interestingly, in all patients and all cells examined, pSTAT5 was found to be localized in the cytoplasm rather than in the nucleus. The cytoplasmic distribution of pSTAT5 in neoplastic cells was confirmed by immunocytochemical staining experiments performed on primary isolated neoplastic cells (AML, CML, mastocytosis) and respective cell lines (U937, KG1, K562, KU812, HMC-1). In each case, the reactivity of neoplastic cells with the AX1 antibody was abrogated by preincubation of the antibody with a pSTAT5-specific blocking peptide. Moreover, the expression of cytoplasmic pSTAT5 in the leukemic cell lines was demonstrable by flow cytometry. To study the molecular mechanisms underlying STAT5-activation in neoplastic cells, Ba/F3 cells with doxycycline-inducible expression of disease-specific oncoproteins, namely BCR/ABL (CML) and KIT-D816V (SM) were employed. Induction of these oncoproteins in Ba/F3 cells resulted in massive activation of pSTAT5 and DNA binding activity as shown by EMSA and supershift assays. In summary, our data show that neoplastic cells in AML, CML, and SM express cytoplasmic pSTAT5, and that disease-related oncoproteins contribute to STAT5-activation. The particular cytoplasmic localization of pSTAT5 in neoplastic cells suggests that apart from its function as a transcription factor, pSTAT5 may have an additional role as a cytoplasmic regulator in these malignancies.
4
Freiman, Anatoli, Channy Y. Muhn, Michel Trudel, and Robin C. Billick. "Leukemia Cutis Presenting with Fingertip Hypertrophy." Journal of Cutaneous Medicine and Surgery 7, no. 1 (January 2003): 57–60. http://dx.doi.org/10.1177/120347540300700110.
Full textAbstract:
Background: Patients with leukemia often manifest cutaneous findings, which include nonspecific lesions and specific leukemic infiltrates termed leukemia cutis. Objective: A case of leukemia cutis involving distal finger pads is reported and literature describing hand involvement of specific leukemic infiltrates is reviewed. Methods and Results: An 80-year-old woman with a 10-year history of chronic lymphocytic leukemia developed painful symmetric tumors of her distal finger pads. Histopathological examination of the biopsy specimen revealed infiltration by neoplastic lymphocytes. Only a few cases of leukemia cutis involving the hands have been reported in the literature, none with this particular presentation. The clinical and histopathologic features of leukemia cutis are reviewed. Conclusion: This case emphasizes the importance of obtaining a biopsy specimen for histopathological examination of any suspicious skin lesion in a patient with leukemia.
5
Digel, W., M. Schmid, G. Heil, P. Conrad, S. Gillis, and F. Porzsolt. "Human interleukin-7 induces proliferation of neoplastic cells from chronic lymphocytic leukemia and acute leukemias." Blood 78, no. 3 (August 1, 1991): 753–59. http://dx.doi.org/10.1182/blood.v78.3.753.753.
Full textAbstract:
Abstract The biologic effects of interleukin-7 (IL-7) and the expression of specific IL-7 membrane receptors on isolated neoplastic cells from previously untreated patients with chronic lymphocytic leukemia as well as acute leukemias were investigated in vitro. Leukemic cells were incubated for up to 6 days with various concentrations of IL-7 (0.01 to 2,000 U/mL). Neoplastic cells of the T- or B-phenotype from chronic as well as from acute leukemias proliferated in a dose-dependent manner. Cells from acute myeloid leukemias also proliferated in response to IL- 7. An optimal proliferative effect was achieved between 96 and 120 hours with 200 U/mL IL-7. Combinations of IL-7 with IL-2 and tumor necrosis factor-alpha showed an additive effect on [3H]TdR incorporation. IL-7 binding assays gave a value of approximately 33 to 180 high-affinity (kd approximately 20 pmol/L) binding sites/cell and approximately 241 to 3,280 low-affinity (kd approximately 600 pmol/L) binding sites/cell. Receptor expression correlated with the proliferation in response to IL-7. These data indicate that IL-7 can induce proliferation of relatively mature tumor cells, and that this effect is not restricted to the lymphoid lineage.
6
Digel, W., M. Schmid, G. Heil, P. Conrad, S. Gillis, and F. Porzsolt. "Human interleukin-7 induces proliferation of neoplastic cells from chronic lymphocytic leukemia and acute leukemias." Blood 78, no. 3 (August 1, 1991): 753–59. http://dx.doi.org/10.1182/blood.v78.3.753.bloodjournal783753.
Full textAbstract:
The biologic effects of interleukin-7 (IL-7) and the expression of specific IL-7 membrane receptors on isolated neoplastic cells from previously untreated patients with chronic lymphocytic leukemia as well as acute leukemias were investigated in vitro. Leukemic cells were incubated for up to 6 days with various concentrations of IL-7 (0.01 to 2,000 U/mL). Neoplastic cells of the T- or B-phenotype from chronic as well as from acute leukemias proliferated in a dose-dependent manner. Cells from acute myeloid leukemias also proliferated in response to IL- 7. An optimal proliferative effect was achieved between 96 and 120 hours with 200 U/mL IL-7. Combinations of IL-7 with IL-2 and tumor necrosis factor-alpha showed an additive effect on [3H]TdR incorporation. IL-7 binding assays gave a value of approximately 33 to 180 high-affinity (kd approximately 20 pmol/L) binding sites/cell and approximately 241 to 3,280 low-affinity (kd approximately 600 pmol/L) binding sites/cell. Receptor expression correlated with the proliferation in response to IL-7. These data indicate that IL-7 can induce proliferation of relatively mature tumor cells, and that this effect is not restricted to the lymphoid lineage.
7
Rezanka, Louis J., Jennifer L. Rojko, and James C. Neil. "Feline Leukemia Virus: Pathogenesis of Neoplastic Disease." Cancer Investigation 10, no. 5 (January 1992): 371–89. http://dx.doi.org/10.3109/07357909209024796.
Full text
8
Gleixner, Karoline V., Mayerhofer Matthias, Anja Vales, Alexander Gruze, Michael Kneidinger, Gregor Hoermann, Maria T. Krauth, et al. "Targeting of Heat Shock Protein 32 (Hsp32) in Neoplastic Cells by Styrene Maleic Acid Zinc Protoporphyrin (SMA-ZnPP) Is Associated with Reduced Growth and Induction of Apoptosis." Blood 108, no. 11 (November 16, 2006): 4323. http://dx.doi.org/10.1182/blood.v108.11.4323.4323.
Full textAbstract:
Abstract Heat shock protein 32 (Hsp32), also known as heme oxygenase-1 (HO-1), is a stress-related survival factor that has recently been implicated in enhanced survival of neoplastic cells. We here show that Hsp32/HO-1 is expressed abundantly in primary neoplastic cells in various solid tumors and hematopoietic neoplasms such as acute myeloid leukemia (AML) or chronic myeloid leukemia (CML), and in respective cell lines including the AML cell lines HL60, KG1, KG1a, and U937, CML cell lines K562 and KU812, eosinophilic leukemia cell line EOL-1, mast cell leukemia cell line HMC-1, myeloma cell lines RPMI8226 and U266, breast cancer cell line MDA MB 231, lung cancer cell line A549, pancreatic carcinoma cell line BxPC-3, colon carcinoma cell lines COLO201, COLO205, COLO320DM, and DLD-1, and the ovarian carcinoma cell line OVCAR-3. Expression of Hsp32 mRNA was demonstrable by RT-PCR and Northern blotting, and expression of the Hsp32 protein by Western blotting and immunocytochemistry. The CML-specific oncoprotein BCR/ABL and the transforming oncoprotein KIT D816V that is expressed in neoplastic mast cells, were found to promote expression of Hsp32 in Ba/F3 cells. In order to examine the functional role of Hsp32 in neoplastic cells, a specific siRNA was employed. Expression of Hsp32 siRNA resulted in reduced viability and induction of apoptosis in all cell lines tested. To further explore the value of Hsp32 as a target in neoplastic cells, a novel specific Hsp32-targeting compound, styrene maleic acid copolymer zinc protoporphyrin micelles (SMA-ZnPP) was applied. Exposure to SMA-ZnPP resulted in a significant decrease in proliferation determined by 3H-thymidine uptake, in all cell lines as well as in all primary neoplastic cells tested (AML, n=5; CML, n=5; mastocytosis, n=3; breast cancer, n=2; lung cancer, n=1). As assessed by AnnexinV-staining, Tunel assay and electron microscopy, the growth-inhibitory effects of SMA-ZnPP were found to be associated with induction of apoptosis. In each cell type, the effect of SMA-ZnPP on growth was dose-dependent and found to occur at pharmacologic concentrations (IC50 1–30 μM). Moreover, SMA-ZnPP was found to synergize with various anti-neoplastic drugs (tumor cell lines: cisplatin, leukemias: cytarabine, myeloma: bortezomib) in producing growth inhibition. In summary, these data show that Hsp32/HO-1 is an important survival factor and novel interesting target in various hematopoietic and non-hematopoietic neoplasms. Based on these data, it seems desirable to explore the value of the Hsp32-targeting drug SMA-ZnPP in clinical trials in patients with leukemias and solid tumors.
9
Ruan, Yongsheng, Hye Na Kim, Heather Ogana, and Yong-Mi Kim. "Wnt Signaling in Leukemia and Its Bone Marrow Microenvironment." International Journal of Molecular Sciences 21, no. 17 (August 28, 2020): 6247. http://dx.doi.org/10.3390/ijms21176247.
Full textAbstract:
Leukemia is an aggressive hematologic neoplastic disease. Therapy-resistant leukemic stem cells (LSCs) may contribute to the relapse of the disease. LSCs are thought to be protected in the leukemia microenvironment, mainly consisting of mesenchymal stem/stromal cells (MSC), endothelial cells, and osteoblasts. Canonical and noncanonical Wnt pathways play a critical role in the maintenance of normal hematopoietic stem cells (HSC) and LSCs. In this review, we summarize recent findings on the role of Wnt signaling in leukemia and its microenvironment and provide information on the currently available strategies for targeting Wnt signaling.
10
Pandey, Sony, Mustafa Moazam, Kurtis Eisermann, Jeffrey Hord, Gail Fraizer, and Steven J. Kuerbitz. "The Importance of WT1 in Leukemia." Blood 118, no. 21 (November 18, 2011): 4645. http://dx.doi.org/10.1182/blood.v118.21.4645.4645.
Full textAbstract:
Abstract Abstract 4645 Acute leukemias collectively comprise the most common group of malignancies in the pediatric age group. Increasingly, therapeutic approach and prognosis are influenced by leukemia-specific cytogenetic abnormalities and genetic alterations, thus highlighting the importance of identifying novel prognostic markers. The Wilms’ tumor suppressor gene WT1 is expressed in leukemic blasts and is found to be mutated in approximately 10 percent of leukemia cases. Although it is unclear whether WT1 acts as an oncogene or a tumor suppressor gene in leukemia, it is known to regulate genes involved in cancer progression, including the angiogenic and mitogenic factor, VEGF. Previous studies in kidney and prostate cell lines identified potential WT1 binding sites on the VEGF-A gene promoter and demonstrated that WT1 transcriptionally regulated VEGF expression. Thus, we hypothesized that WT1 transcriptionally regulates VEGF expression in leukemia. To examine WT1 and VEGF expression patterns in pediatric Acute Lymphocytic Leukemia (ALL), Acute Myeloid Leukemia (AML) and non-neoplastic bone marrow samples, we performed quantitative real time PCR. It was observed that WT1 and VEGF expression varied depending upon the type and sub-type of leukemia. Furthermore, to understand the significance of WT1 expression, we over-expressed GFP- WT1 in Molt-4 cells (T-ALL), HL-60 (AML) and K562 cells (CML) and then quantified mRNA levels of VEGF and the potential WT1 target genes CCNA1 and JAG. The results showed that WT1 levels induced variable expression of VEGF, CCNA1 and JAG in these different leukemic cell lines. Elevated expression of WT1 genes harboring mutations of the zinc finger (ZF) DNA binding domain has also been described in a subset of leukemias and has been associated with a poor prognosis. We therefore screened pediatric acute leukemia samples for novel ZF mutations that would abrogate its ability to regulate VEGF and other target genes. Conversely, a well described SNP rs16754 (in exon 7 of the WT1 gene) identified as a good prognostic marker in Cytogenetically Normal AML (CN-AML) was observed in our pediatric population as both homozygous and heterozygous variants of the WT1 gene. Our long term goal is to determine the molecular basis of the prognostic impact associated with variant WT1 expression in pediatric and adult leukemias. Disclosures: No relevant conflicts of interest to declare.
11
Colbatzky, F., and W. Hermanns. "Acute Megakaryoblastic Leukemia in One Cat and Two Dogs." Veterinary Pathology 30, no. 2 (March 1993): 186–94. http://dx.doi.org/10.1177/030098589303000212.
Full textAbstract:
The clinical, hematologic, and histologic features of acute megakaryoblastic leukemia are described for an 8-year-old female Domestic Shorthair cat, a 3-year-old female mixed-breed dog, and a 3-year-old male German Shepherd Dog. The neoplastic cells were characterized as belonging to the megakaryocytic lineage. The following techniques were used: electron microscopy; detection of antibodies against human von Willebrand factor (vWF) and human platelet glycoprotein GP IIIa using a modified avidin biotin peroxidase complex technique on formalin-fixed paraffin sections; and enzyme histochemical methods on plastic sections for alkaline phosphatase, acid phosphatase, myeloperoxidase, α-naphthyl acetate esterase, α-naphthyl butyrate esterase, naphthol AS acetate esterase, and naphthol AS-D chloroacetate esterase. In addition, benign megakaryocytic cells, platelets, and neoplastic cells were labeled with lectins that have partially been shown to bind to platelet glycoproteins of other species. In healthy cats and dogs, the megakaryocytes and platelets reacted with lectins PSA, LCA, PHA-L, and WGA. Megakaryocytes and platelets from healthy cats were also labeled by lectin PNA. The lectins PHA-L and WGA reacted with neoplastic cells from the cat and both dogs. Lectin PNA bound to neoplastic cells from the cat, and lectins PSA, LCA, and SBA bound to neoplastic cells from both dogs. For the retrospective examination of paraffin-embedded material, the detection of vWF and GP IIIa appears to be the most reliable method for the identification of megakaryocytic cells.
12
Manukyan, Gayane, Tomas Papajik, Zuzana Mikulkova, Renata Urbanova, Veronika Smotkova Kraiczova, Jakub Savara, Milos Kudelka, Peter Turcsanyi, and Eva Kriegova. "High CXCR3 on Leukemic Cells Distinguishes IgHVmut from IgHVunmut in Chronic Lymphocytic Leukemia: Evidence from CD5high and CD5low Clones." Journal of Immunology Research 2020 (June 20, 2020): 1–10. http://dx.doi.org/10.1155/2020/7084268.
Full textAbstract:
Despite the shared pattern of surface antigens, neoplastic cells in chronic lymphocytic leukemia (CLL) are highly heterogeneous in CD5 expression, a marker linked to a proliferative pool of neoplastic cells. To further characterize CD5high and CD5low neoplastic cells, we assessed the chemokine receptors (CCR5, CCR7, CCR10, CXCR3, CXCR4, CXCR5) and adhesion molecules (CD54, CD62L, CD49d) on the CD5high and CD5low subpopulations, defined by CD5/CD19 coexpression, in peripheral blood of CLL patients (n=60) subgrouped according to the IgHV mutational status (IgHVmut, n=24; IgHVunmut, n=36). CD5high subpopulation showed a high percentage of CXCR3 (P<0.001), CCR10 (P=0.001), and CD62L (P=0.031) and high levels of CXCR5 (P=0.005), CCR7 (P=0.013) compared to CD5low cells expressing high CXCR4 (P<0.001). Comparing IgHVmut and IgHVunmut patients, high levels of CXCR3 on CD5high and CD5low subpopulations were detected in the IgHVmut patients, with better discrimination in CD5low subpopulation. Levels of CXCR3 on CD5low subpopulation were associated with time to the next treatment, thus further confirming its prognostic value. Taken together, our analysis revealed higher CXCR3 expression on both CD5high and CD5low neoplastic cells in IgHVmut with a better prognosis compared to IgHVunmut patients. Contribution of CXCR3 to CLL pathophysiology and its suitability for prognostication and therapeutic exploitation deserves future investigations.
13
Shangguan, Dihua, Zehui Charles Cao, Ying Li, and Weihong Tan. "Aptamers Evolved from Cultured Cancer Cells Reveal Molecular Differences of Cancer Cells in Patient Samples." Clinical Chemistry 53, no. 6 (June 1, 2007): 1153–55. http://dx.doi.org/10.1373/clinchem.2006.083246.
Full textAbstract:
Abstract Background: Molecular-level differentiation of neoplastic cells is essential for accurate and early diagnosis, but effective molecular probes for molecular analysis and profiling of neoplastic cells are not yet available. We recently developed a cell-based SELEX (systematic evolution of ligands by exponential enrichment) strategy to generate aptamers (designer DNA/RNA probes) as molecular probes to recognize neoplastic cells. Methods: We tested 6 cell-SELEX–generated aptamers with equilibrium dissociation constants in the nanomolar to subnanomolar range: sgd5, selected from Toledo cells, a human diffuse large-cell lymphoma cell line (B-cell), and sgc8, sgc3, sgc4, sgd2, and sgd3 from CCRF-CEM cells, a human precursor T cell acute lymphoblastic leukemia (T-ALL) cell line. Aptamers were labeled with fluorescein isothiocyanate fluorophores and then used to recognize, by flow cytometric analysis, neoplastic cells in cultured hematopoietic cell lines and clinical samples. Results: Aptamer sgd5 recognized only its target cells. Aptamers sgc3, sgd2, sgd3, sgc4, and sgc8, selected from a T-cell leukemia cell line, identified all of the cultured T-cell leukemia cell lines with relatively high fluorescence intensity. Aptamers sgc8, sgc3, and sgd3 showed good selectivity toward T-ALL cells and almost no binding to normal hematopoietic cells or lymphoma and myeloma cells. Selected aptamers also detected targets on the cell membranes of neoplastic cells in patient samples. Conclusions: Aptamers selected against cultured neoplastic cells can effectively be used as molecular probes for recognition of neoplastic cells in patient samples. Cell-based aptamer selection can be used to generate aptamer probes to obtain molecular signatures of neoplastic cells in patient samples.
14
Douay, L., C. Hu, MC Giarratana, S. Bouchet, J. Conlon, RL Capizzi, and NC Gorin. "Amifostine improves the antileukemic therapeutic index of mafosfamide: implications for bone marrow purging." Blood 86, no. 7 (October 1, 1995): 2849–55. http://dx.doi.org/10.1182/blood.v86.7.2849.2849.
Full textAbstract:
Abstract One of the principal challenges of cancer chemotherapy is the relative inability of most anticancer drugs to distinguish between normal and neoplastic tissues. Consequently, a broad range of toxicities are experienced by patients, especially myelosuppression. Amifostine, a phosphorylated aminothiol, increases the selectivity of specific anticancer drugs for neoplastic cells by protecting normal tissues. One potential application of this protector is during bone marrow purging to selectively remove contaminating cancer cells. This study took normal or leukemic marrow from human subjects and evaluated the ability of amifostine to selectively protect normal bone marrow progenitor cells versus leukemic progenitor cells from the cytotoxic effect of mafosfamide. The dose response of mafosfamide amifostine on leukemia colony-forming units or normal marrow progenitor cells was determined and the LD95 was calculated. Amifostine pretreatment resulted in a statistically significant protection of granulocyte-macrophage colony-forming units and erythroid blast-forming units from the toxicity of mafosfamide (P = .031). Thus, amifostine protection of normal marrow progenitor cells allows a higher LD95 concentration of mafosfamide to be used in ex vivo purging. In contrast, amifostine pretreatment increased the cytotoxicity of mafosfamide on the fresh human leukemia progenitor cells (P = .006). The dual effect of amifostine protection of normal marrow progenitor cells coupled with amifostine-induced sensitization of the leukemia cells increases the possible cell-kill of leukemic stem cells. With amifostine pretreatment, at the LD95 concentrations of mafosfamide for marrow progenitor cells, there was an estimated 6 log increase in cell-kill of the leukemia cells. This selective cell-kill offers the potential for lowering the incidence of leukemic relapse, while preserving more normal stem cells for autologous transplantation.
15
Douay, L., C. Hu, MC Giarratana, S. Bouchet, J. Conlon, RL Capizzi, and NC Gorin. "Amifostine improves the antileukemic therapeutic index of mafosfamide: implications for bone marrow purging." Blood 86, no. 7 (October 1, 1995): 2849–55. http://dx.doi.org/10.1182/blood.v86.7.2849.bloodjournal8672849.
Full textAbstract:
One of the principal challenges of cancer chemotherapy is the relative inability of most anticancer drugs to distinguish between normal and neoplastic tissues. Consequently, a broad range of toxicities are experienced by patients, especially myelosuppression. Amifostine, a phosphorylated aminothiol, increases the selectivity of specific anticancer drugs for neoplastic cells by protecting normal tissues. One potential application of this protector is during bone marrow purging to selectively remove contaminating cancer cells. This study took normal or leukemic marrow from human subjects and evaluated the ability of amifostine to selectively protect normal bone marrow progenitor cells versus leukemic progenitor cells from the cytotoxic effect of mafosfamide. The dose response of mafosfamide amifostine on leukemia colony-forming units or normal marrow progenitor cells was determined and the LD95 was calculated. Amifostine pretreatment resulted in a statistically significant protection of granulocyte-macrophage colony-forming units and erythroid blast-forming units from the toxicity of mafosfamide (P = .031). Thus, amifostine protection of normal marrow progenitor cells allows a higher LD95 concentration of mafosfamide to be used in ex vivo purging. In contrast, amifostine pretreatment increased the cytotoxicity of mafosfamide on the fresh human leukemia progenitor cells (P = .006). The dual effect of amifostine protection of normal marrow progenitor cells coupled with amifostine-induced sensitization of the leukemia cells increases the possible cell-kill of leukemic stem cells. With amifostine pretreatment, at the LD95 concentrations of mafosfamide for marrow progenitor cells, there was an estimated 6 log increase in cell-kill of the leukemia cells. This selective cell-kill offers the potential for lowering the incidence of leukemic relapse, while preserving more normal stem cells for autologous transplantation.
16
Valentine, B. A., and S. P. Mcdonough. "B-Cell Leukemia in a Sheep." Veterinary Pathology 40, no. 1 (January 2003): 117–19. http://dx.doi.org/10.1354/vp.40-1-117.
Full textAbstract:
Necropsy examination was performed on an 8.5-year-old Finnish ewe euthanatized because of progressive respiratory distress, cachexia, and weakness. Significant postmortem findings included a diffusely enlarged, dark-red friable liver, mild splenomegaly, and mild mesenteric lymphadenopathy. Examination of multiple tissue sections revealed intravascular atypical mononuclear cells in all tissues examined, with a leukemic pattern of infiltration of mesenteric lymph nodes, liver, lung, and spleen. Neoplastic cells were positive for CD79a and negative for CD-3, BLA.36, and CD68 leukocytic markers. The final diagnosis was B-cell leukemia.
17
Foa, R., MT Fierro, D. Raspadori, M. Bonferroni, S. Cardona, A. Guarini, AG Tos, PF di Celle, A. Cesano, and L. Matera. "Lymphokine-activated killer (LAK) cell activity in B and T chronic lymphoid leukemia: defective LAK generation and reduced susceptibility of the leukemic cells to allogeneic and autologous LAK effectors." Blood 76, no. 7 (October 1, 1990): 1349–54. http://dx.doi.org/10.1182/blood.v76.7.1349.1349.
Full textAbstract:
Abstract The capacity to generate lymphokine-activated killer (LAK) cells and the susceptibility of the neoplastic cells to both allogeneic and autologous LAK effectors were studied in B and T chronic lymphoproliferative disorders. While in B-cell chronic lymphocytic leukemia (B-CLL) the depressed natural killer function could be restored after a 7-day incubation with recombinant interleukin (IL-2), B-CLL mononuclear cells showed a reduced LAK activity compared with normal LAK cells. Furthermore, in all but 1 of the 20 B-CLL samples tested the leukemic cells were totally resistant to autologous LAK effectors. In most cases the leukemic cells were also resistant to normal allogeneic LAK cells. Competition experiments demonstrated that the patients' LAK cells, as well as normal LAK effectors, were capable of recognizing B-CLL cells, pointing, therefore, to a postbinding cytolytic defect. In hairy cell leukemia (HCL) an overall reduced LAK activity against allogeneic targets was documented, but, at variance from B-CLL, hairy cells were often susceptible to the lytic effect of normal LAK cells, and in half of the cases tested the neoplastic population was also sensitive in an autologous system. Similarly to B- CLL, in the great majority of T chronic lymphoproliferative disorders studied, the pathologic cells were resistant to normal and autologous LAK effectors and a defective LAK generation was found. These results demonstrate that in most B and T chronic leukemias the LAK function is defective and, when inducible, does not appear directed against the leukemic population. The possibility of exploiting an immunotherapeutic approach with IL-2/LAK cells in the management of chronic lymphoproliferative disorders does not gain support by these findings.
18
Foa, R., MT Fierro, D. Raspadori, M. Bonferroni, S. Cardona, A. Guarini, AG Tos, PF di Celle, A. Cesano, and L. Matera. "Lymphokine-activated killer (LAK) cell activity in B and T chronic lymphoid leukemia: defective LAK generation and reduced susceptibility of the leukemic cells to allogeneic and autologous LAK effectors." Blood 76, no. 7 (October 1, 1990): 1349–54. http://dx.doi.org/10.1182/blood.v76.7.1349.bloodjournal7671349.
Full textAbstract:
The capacity to generate lymphokine-activated killer (LAK) cells and the susceptibility of the neoplastic cells to both allogeneic and autologous LAK effectors were studied in B and T chronic lymphoproliferative disorders. While in B-cell chronic lymphocytic leukemia (B-CLL) the depressed natural killer function could be restored after a 7-day incubation with recombinant interleukin (IL-2), B-CLL mononuclear cells showed a reduced LAK activity compared with normal LAK cells. Furthermore, in all but 1 of the 20 B-CLL samples tested the leukemic cells were totally resistant to autologous LAK effectors. In most cases the leukemic cells were also resistant to normal allogeneic LAK cells. Competition experiments demonstrated that the patients' LAK cells, as well as normal LAK effectors, were capable of recognizing B-CLL cells, pointing, therefore, to a postbinding cytolytic defect. In hairy cell leukemia (HCL) an overall reduced LAK activity against allogeneic targets was documented, but, at variance from B-CLL, hairy cells were often susceptible to the lytic effect of normal LAK cells, and in half of the cases tested the neoplastic population was also sensitive in an autologous system. Similarly to B- CLL, in the great majority of T chronic lymphoproliferative disorders studied, the pathologic cells were resistant to normal and autologous LAK effectors and a defective LAK generation was found. These results demonstrate that in most B and T chronic leukemias the LAK function is defective and, when inducible, does not appear directed against the leukemic population. The possibility of exploiting an immunotherapeutic approach with IL-2/LAK cells in the management of chronic lymphoproliferative disorders does not gain support by these findings.
19
Lee, Po-Shing, Ching-Nan Lin, Chientzu Liu, Chien-Tai Huang, and Wei-Shiou Hwang. "Acute Leukemia With Myeloid, B-, and Natural Killer Cell Differentiation." Archives of Pathology & Laboratory Medicine 127, no. 2 (February 1, 2003): e93-e95. http://dx.doi.org/10.5858/2003-127-e93-alwman.
Full textAbstract:
Abstract Biphenotypic acute leukemias account for 4% to 8% of all acute leukemias. Most of these leukemias are of myeloid–B-cell or myeloid–T-cell lineage. Acute myeloid–natural killer cell leukemia has been recognized recently. We report the first case, to our knowledge, of CD56+ acute leukemia showing unequivocal myeloid and B-cell differentiation in a 20-year-old woman, whose blast cells were positive for myeloperoxidase, CD13, CD33, CD117, terminal deoxynucleotidyl transferase, CD19, CD20, CD22, CD34, HLA-DR, and CD56 but negative for CD3, CD5, CD7, and CD10. Rare Auer rods were identified in the blast cells. Polymerase chain reaction assays showed rearrangement of immunoglobulin heavy-chain gene and absence of Epstein-Barr virus DNA. We propose that this novel form of multilineage leukemia may represent the neoplastic counterpart of a progenitor that can give rise to myeloid, B, and natural killer cells.
20
Duhrsen, U., and D. Metcalf. "Effects of irradiation of recipient mice on the behavior and leukemogenic potential of factor-dependent hematopoietic cell lines." Blood 75, no. 1 (January 1, 1990): 190–97. http://dx.doi.org/10.1182/blood.v75.1.190.190.
Full textAbstract:
Abstract After intravenous (IV) injection with factor-dependent FDC-P1 cells, irradiated DBA/2 and BALB/c mice developed transplantable leukemias owing to neoplastic transformation of the injected cells in vivo. Increasing the radiation dose shortened the preleukemic latent period, and in female mice the frequency of leukemia development was higher and the latent period shorter than in male mice. In the preleukemic period, the injected FDC-P1 cells rapidly increased in number in hematopoietic organs of irradiated animals, reaching peak levels 3 to 5 weeks after injection; factor-independent transformed cells were not detected before day 45. In unirradiated animals, these events were delayed by several weeks, and long-term survivors did not harbor detectable FDC-P1 cells. FDC-P1 cells sampled from preleukemic mice frequently showed atypical colony formation and reduced cloning efficiency in vitro, suggesting the occurrence of a distinct preleukemic change. U16.6 cells produced leukemia only in irradiated recipients, and the leukemic cells usually remained factor dependent. The two contrasting models should be of value in further analyzing the mechanisms underlying radiation- induced leukemias.
21
Duhrsen, U., and D. Metcalf. "Effects of irradiation of recipient mice on the behavior and leukemogenic potential of factor-dependent hematopoietic cell lines." Blood 75, no. 1 (January 1, 1990): 190–97. http://dx.doi.org/10.1182/blood.v75.1.190.bloodjournal751190.
Full textAbstract:
After intravenous (IV) injection with factor-dependent FDC-P1 cells, irradiated DBA/2 and BALB/c mice developed transplantable leukemias owing to neoplastic transformation of the injected cells in vivo. Increasing the radiation dose shortened the preleukemic latent period, and in female mice the frequency of leukemia development was higher and the latent period shorter than in male mice. In the preleukemic period, the injected FDC-P1 cells rapidly increased in number in hematopoietic organs of irradiated animals, reaching peak levels 3 to 5 weeks after injection; factor-independent transformed cells were not detected before day 45. In unirradiated animals, these events were delayed by several weeks, and long-term survivors did not harbor detectable FDC-P1 cells. FDC-P1 cells sampled from preleukemic mice frequently showed atypical colony formation and reduced cloning efficiency in vitro, suggesting the occurrence of a distinct preleukemic change. U16.6 cells produced leukemia only in irradiated recipients, and the leukemic cells usually remained factor dependent. The two contrasting models should be of value in further analyzing the mechanisms underlying radiation- induced leukemias.
22
Eisenwort, Gregor, Barbara Peter, Katharina Blatt, Sabine Cerny-Reiterer, Gregor Hoermann, Irina Sadovnik, Martin Bilban, et al. "Identification of a Neoplastic Stem Cell in Human Mast Cell Leukemia." Blood 124, no. 21 (December 6, 2014): 817. http://dx.doi.org/10.1182/blood.v124.21.817.817.
Full textAbstract:
Abstract Leukemic stem cells (LSCs) have recently been identified as an important target of therapy in various human leukemias and related blood cell disorders. Systemic mastocytosis (SM) is a rare hematologic neoplasm characterized by abnormal growth and accumulation of mast cells (MCs) in various organ systems, including the bone marrow (BM). Whereas patients with indolent SM (ISM) have a normal life-expectancy, patients with more advanced forms of SM have a poor prognosis. In these patients, neoplastic MCs are usually resistant against conventional drugs and various targeted drugs. MC leukemia (MCL) is the rare leukemic variant of advanced SM, defined by a rapidly devastating expansion of immature MCs in various hematopoietic organs and a poor prognosis with short survival times. Although MCL is considered a stem cell disease, little is known about the origin and phenotype of MCL-initiating LSCs. We examined the phenotypic and functional characteristics of putative LSCs in patients with aggressive SM (ASM, n=12) and MCL (n=6). Putative LSCs were identified and characterized phenotypically by flow cytometry. Highly enriched, sorted LSCs were injected into NOD-SCID-IL-2Rγ-/- mice exhibiting a 220 amino acid isoform of human membrane-bound hSCF (NSGSCF). We found that disease-initiating and propagating LSCs reside within a CD34+ fraction of the MCL clone. Whereas cell fractions containing CD34+ cells as well as highly enriched CD34+ cells produced engraftment in NSGSCF mice with a MCL-like disease (43-77% human MCL cells in mouse BM after 10-22 weeks), no substantial engraftment was produced by MC-rich but stem cell-depleted, KIT+/CD34─ cell fractions obtained from the same patients (<1% engraftment in mouse BM). In dilution experiments, engraftment of CD34+ cells was documented down to a minimum of 50 cells per mouse. The identity of engrafting MCL cells was confirmed by morphology, phenotyping and molecular studies demonstrating the presence of KIT mutations that were initially detected in the primary MCL samples used. Moreover, we were able to confirm long-term engraftment by successful serial transplantations into secondary recipient mice. In consecutive experiments, we were able to show that CD45+/CD34+/CD38─ cells also produce leukemic engraftment in NSGSCF mice. As assessed by flow cytometry, these CD34+/CD38─ MCL LSCs were found to express several stem cells markers, including aminopeptidase-N (CD13), leukosialin (CD43), Pgp-1 (CD44), the IL-3R alpha-chain (CD123), AC133 (CD133) and CXCR4 (CD184). In addition, in most patients examined, MCL LSCs were found to display IL-1RAP, a surface antigen that is otherwise expressed in CML LSCs but is not expressed in normal stem cells. In addition, MCL LSCs were found to express various cell surface targets, including CD33 and CD52. By contrast, MCL LSCs did not express CD2, CD25, CD26 and CLL-1. The more mature progenitor cell fractions (CD34+/CD38+) were found to stain positive for CD13, CD33, CD43, CD44, CD90, CD117, CD123, CD133 and CD184. Mature clonal MCs expressed a similar phenotype, including molecular markers and targets, such as CD13, CD30 CD33, CD52 and CD184. In patients with ISM and aggressive SM (ASM), the CD34+/CD38─ stem cells exhibited a similar surface marker profile compared to MCL, but expressed lower levels of CD133 and did not express IL-1RAP. In the validation phase of our study, we examined the effects of target-specific antibodies. As assessed by flow cytometry, the CD52-targeting antibody alemtuzumab was found to induce complement-dependent lysis of CD34+ and CD34+/CD38─ cells in all MCL samples analysed. Furthermore, pre-incubation of MCL cells with alemtuzumab prior to injection into NSGSCF mice resulted in a significantly reduced engraftment (2.7±4.1%) after 22 weeks. In conclusion, our data show that the MCL clone originates from a primitive hematopoietic stem cell that co-expresses CD34, CD123, CD133 and IL-1RAP but lacks CD25 and CD26. In addition, our data show that MCL LSC express a number of clinically relevant surface targets, including CD33, CD52 and CD117 (KIT). These observations may facilitate LSC detection and isolation in MCL and may lead to the development of novel LSC-eradicating treatment concepts in this highly aggressive and drug-resistant form of leukemia. Disclosures Valent: Novartis: Consultancy, Honoraria, Research Funding.
23
Brajuskovic, G., Milica Strnad, Snezana Cerovic, and Stanka Romac. "Programmed cell death proteins and chronic leukemia." Archives of Biological Sciences 63, no. 3 (2011): 527–35. http://dx.doi.org/10.2298/abs1103527b.
Full textAbstract:
Apoptosis or programmed cell death is a genetically regulated process of cellular suicide. Apoptosis has been implicated in a wide range of pathological conditions, and mutations in apoptotic genes play important roles in the process of malignant transformation. Chronic leukemia represents a neoplastic disorder caused primarily by defective programmed cell death, as opposed to increased cell proliferation. This paper presents the main results of our ten-year research on the apoptosis of leukemia cells. The research included the morphological aspects of the process, the effect of antineoplastic agents on the induction of apoptosis in leukemia cells and expression analysis of the proteins involved in programmed cell death. Special attention was paid to the expression and interaction of the Bcl-2 family of proteins in leukemia cells. The ultimate aim of the study of apoptosis of leukemic cells is the discovery of new biological agents that might be used in the treatment of chronic leukemia.
24
Barrell, Emily A., Midori Goto Asakawa, M. Julia B. Felippe, Thomas J. Divers, and Tracy Stokol. "Acute leukemia in six horses (1990–2012)." Journal of Veterinary Diagnostic Investigation 29, no. 4 (May 3, 2017): 529–35. http://dx.doi.org/10.1177/1040638717707724.
Full textAbstract:
Acute leukemia is rare in horses. Herein we describe historical, clinicopathologic, and postmortem findings in 6 horses with acute leukemia. Medical records of horses with >20% bone marrow blasts and cytochemical or immunophenotyping results were reviewed. Affected horses were 2–8 y of age and of different breeds and sex. Horses were presented acutely with nonspecific signs (e.g., fever, lethargy). Characteristic hemogram findings were bi- or pancytopenia with low blast numbers. Histologic examination revealed extramedullary infiltrates, especially in lymph nodes, spleen, kidney, liver, and lungs. Leukemias were classified as B-cell ( n = 3) and acute myeloid leukemia (AML) ( n = 3). Tumors in 4 cases expressed multiple lineage markers, which complicated classification. Acute leukemia should be suspected in horses with moderate-to-severe bi- or pancytopenia. Blood smears should be reviewed for neoplastic cells, and bone marrow examination is required for diagnosis. Leukemia classification is best achieved using combined morphologic, cytochemical, and immunophenotyping results.
25
Capobianco, A. J., P. Zagouras, C. M. Blaumueller, S. Artavanis-Tsakonas, and J. M. Bishop. "Neoplastic transformation by truncated alleles of human NOTCH1/TAN1 and NOTCH2." Molecular and Cellular Biology 17, no. 11 (November 1997): 6265–73. http://dx.doi.org/10.1128/mcb.17.11.6265.
Full textAbstract:
The Notch genes of Drosophila melanogaster and vertebrates encode transmembrane receptors that help determine cell fate during development. Although ligands for Notch proteins have been identified, the signaling cascade downstream of the receptors remains poorly understood. In human acute lymphoblastic T-cell leukemia, a chromosomal translocation damages the NOTCH1 gene. The damage apparently gives rise to a constitutively activated version of NOTCH protein. Here we show that a truncated version of NOTCH1 protein resembling that found in the leukemic cells can transform rat kidney cells in vitro. The transformation required cooperation with the E1A oncogene of adenovirus. The transforming version of NOTCH protein was located in the nucleus. In contrast, neither wild-type NOTCH protein nor a form of the truncated protein permanently anchored to the plasma membrane produced transformation in vitro. We conclude that constitutive activation of NOTCH similar to that found in human leukemia can contribute to neoplastic transformation. Transformation may require that the NOTCH protein be translocated to the nucleus. These results sustain a current view of how Notch transduces a signal from the surface of the cell to the nucleus.
26
Marchesini, M., R. Matocci, L. Tasselli, V. Cambiaghi, A. Orleth, L. Furia, C. Marinelli, et al. "PML is required for telomere stability in non-neoplastic human cells." Oncogene 35, no. 14 (June 29, 2015): 1811–21. http://dx.doi.org/10.1038/onc.2015.246.
Full textAbstract:
Abstract Telomeres interact with numerous proteins, including components of the shelterin complex, whose alteration, similarly to proliferation-induced telomere shortening, initiates cellular senescence. In tumors, telomere length is maintained by Telomerase activity or by the Alternative Lengthening of Telomeres mechanism, whose hallmark is the telomeric localization of the promyelocytic leukemia (PML) protein. Whether PML contributes to telomeres maintenance in normal cells is unknown. We show that in normal human fibroblasts the PML protein associates with few telomeres, preferentially when they are damaged. Proliferation-induced telomere attrition or their damage due to alteration of the shelterin complex enhances the telomeric localization of PML, which is increased in human T-lymphocytes derived from patients genetically deficient in telomerase. In normal fibroblasts, PML depletion induces telomere damage, nuclear and chromosomal abnormalities, and senescence. Expression of the leukemia protein PML/RARα in hematopoietic progenitors displaces PML from telomeres and induces telomere shortening in the bone marrow of pre-leukemic mice. Our work provides a novel view of the physiologic function of PML, which participates in telomeres surveillance in normal cells. Our data further imply that a diminished PML function may contribute to cell senescence, genomic instability, and tumorigenesis.
27
Schafernak, Kristian T., and Seth J. Corey. "Histiocytic clearance of neoplastic cells in acute promyelocytic leukemia." Blood 124, no. 19 (November 6, 2014): 3020. http://dx.doi.org/10.1182/blood-2014-08-596494.
Full text
28
Oki, Yasuhiro, Jaroslav Jelinek, Hagop M. Kantarjian, and Jean-Pierre J. Issa. "Hypomethylation Induction and Molecular Response after Decitabine Therapy in Chronic Myelomonocytic Leukemia (CMML)." Blood 108, no. 11 (November 1, 2006): 2322. http://dx.doi.org/10.1182/blood.v108.11.2322.2322.
Full textAbstract:
Abstract Decitabine has shown therapeutic activity in patients with MDS and CMML. The mechanisms of response to therapy remain incompletely understood. In particular, the relative contribution of this drug’s ability to induce hypomethylation and cytotoxicity remains unclear. To address this issue, we studied the dynamics of neoplastic cell clearance during decitabine treatment determined by quantitative monitoring of the mutant allele using pyrosequencing. DNA extracted from peripheral blood mononuclear cells from consented patients with CMML in a decitabine phase II study were first screened for JAK2 and NPM1 mutations as previously reported. We identified three patients with mutations (two with JAK2 mutation, one with NPM1 mutation) and samples at multiple points during therapy were available. All three carried normal karyotype. LINE repetitive element methylation and several other gene specific methylations were also assessed. In the three patients, LINE methylation decreased after each cycle of therapy, and recovered to near baseline after the drug was stopped (e.g. during the first cycle, average relative hypomethylation from baseline was 13.9% at day 12 and 6.5% at day 28). At the same time, the proportion of circulating neoplastic cells decreased slowly after the first cycle (decrease by 19.3% at day 12 and 13.5% at day 28). A substantial decrease in mutant allele percentage was observed after cycles 2, 3, and 2 in patients 1, 2, and 3, respectively. Clinical complete responses were achieved along with molecular responses at cycles 5, 4 and 2, respectively. Patients 1 and 2 showed complete disappearance of detectable neoplastic clones, and had sustained remissions (duration 1.5 and 2.5 years). In patient 3, the proportion of neoplastic cells was lower than baseline but still detectable at clinical remission, and the remission only lasted 8 months. We conclude that neoplastic cell clearance after decitabine therapy in CMML is observed after several courses of therapy, and is initially seen concurrently with hypomethylation. While LINE methylation returns to its steady state values after completion of decitabine infusion, the tumor elimination process slowly continues. Our data suggest a non-cytotoxic mechanism of action for the drug, whereby the biology of the neoplastic clone is altered by hypomethylation, leading to delayed clearances of unknown mechanism. Possibilities include an immune response and effects on the neoplastic (or normal) stem cells. Figure Figure
29
Talluri, V. S. S. L. Prasad, M. Bhavana, M. V. S. Mahesh Kumar, and S. V. Rajagopal. "L-Asparaginase: An Ultimate Anti-Neoplastic Enzyme." International Letters of Natural Sciences 15 (May 2014): 23–35. http://dx.doi.org/10.18052/www.scipress.com/ilns.15.23.
Full textAbstract:
The objective of the study described the importance of L-asparaginase and its importance in the field of medicine. Different types of enzymes are produced based on the adaptation to the environment where the living organisms live to tune the metabolic pathways according to their adapted changes. The enzymes present in various organs are produced by many cell types in multicellular organisms. Except ribosomes all other known enzymes are proteinaceous in nature. L-asparaginase is a potential therapeutic agent for acute lymphoblastic leukemia (ALL) and chronic myelogenous leukemia which is approved by FDA & WHO. L-asparaginase catalyzes the deamination of L-asparagine to L-aspartic acid & ammonia. Unlike normal cells, malignant cells require large amount of L-asparagine for protein synthesis and cell division. From this background the present review is an effort to gather the information on the mechanism, sources, molecular details and application of L-asparaginase enzyme.
30
Shah, Mithun Vinod, Karen S. Flatten, B. Douglas Smith, Allan D. Hess, and Scott H. Kaufmann. "MTH1 Inhibitor-Induced Cytotoxicity in Acute Myeloid Leukemia." Blood 126, no. 23 (December 3, 2015): 1273. http://dx.doi.org/10.1182/blood.v126.23.1273.1273.
Full textAbstract:
Abstract BACKGROUND: Acute myeloid leukemia (AML) is an aggressive leukemia with 5-year overall survival of 20-25%. The major reason for treatment failure in AML is resistance to chemotherapy. Thus, there is an urgent need for identification of novel therapeutic agents for AML. Neoplastic cells, including AML, have dysfunctional redox regulation that results in increased reactive oxygen species (ROS). Accumulation of ROS leads to oxidation of free and incorporated nucleotides, leading to DNA damage and cell death. MTH1 is a nudix family hydrolase that sanitizes the oxidized nucleotide pool to prevent incorporation of these damaged bases in the DNA. MTH1 is thought to be non-essential for normal cells but crucial for neoplastic cells in order to avoid incorporation of oxidized dNTPs into DNA, thereby evading DNA damage and cell death. Whether MTH1 inhibitors have any activity against AML is not known. METHODS: Neoplastic myeloid cell lines HL-60, HEL, K562, KG1A, ML1, MV-4-11, SET2, and U937 were treated with varying concentrations of TH588 for a total of 48 hours. In experiments using the pan-caspase inhibitor Q-VD-OPh (Qvd), cells were pre-treated with 5µM Qvd for 1 hour followed by TH588. Cells were washed and stained with annexin, propidium iodide (PI), or MitoTracker (Life Technologies, Carlsbad, CA) for flow cytometry. To evaluate the potential impact of MTH1 inhibition on chemorefractory AML, HL-60/VCR cells were treated with vehicle control or TH588 in culture medium with or without vincristine (1µg/ml). Percentage apoptosis was calculated by normalizing to vehicle only control. With IRB approval, bone marrow aspirate samples were obtained from patients with untreated AML or healthy controls. Mononuclear cells were analyzed using colony-forming unit (CFU) assays. The total number of erythroid (CFU-E) and myeloid (CFU-G, CFU-GM) colonies containing ≥50 cells were read on day 14 and reported as percentage colonies compared to vehicle control. RESULTS: TH588 induced dose-dependent cell death in each of the neoplastic cell lines tested except HEL. In particular, treatment with TH588 resulted in a dose-dependent increase in the number of cells undergoing apoptosis as indicated by annexin V and/or PI staining (IC50 3.1-21.3µM, Figure 1). Pre-treatment with Qvd significantly inhibited TH588-induced cell death in all the cell lines studied except KG1A and SET2, suggesting a caspase-dependent mechanism of cell death. In further studies, cells treated with TH588 exhibited decreased MitoTracker staining; and Qvd pretreatment increased the number of MitoTrackerLow cells at the same time apoptotic cells decreased, suggesting that mitochondrial damage is upstream of caspase activation in TH588-induced apoptosis. Treatment with TH588 not only induced apoptosis in HL-60/VCR cells, but also facilitated further apoptosis in cells co-treated with vincristine and TH588 (Figure 2). Treatment with TH588 also diminished colony formation in a primary AML sample (IC50 6µM, Figure 3). Analysis of additional primary AML samples is ongoing. DISCUSSION: Our results show that the MTH1 inhibitor TH588 induces apoptosis in most neoplastic myeloid cells. MTH1 causes mitochondrial damage that, in turn, leads to caspase-dependent apoptosis in these cells. In HL-60/VCR cells representing chemorefractory phenotype, TH588 induces apoptosis as a single agent and resensitizes cells to vincristine. Moreover, TH588 significantly diminished colony formation in primary AML ex vivo. Further preclinical and possible clinical study of this class of agent appears warranted. Figure 1. Induction of cell death by MTH1 inhibitor TH588 in neoplastic myeloid cell lines. Figure 1. Induction of cell death by MTH1 inhibitor TH588 in neoplastic myeloid cell lines. Figure 2. TH588 induces apoptosis in HL-60/VCR cells and resensitizes cells to vincristine. Figure 2. TH588 induces apoptosis in HL-60/VCR cells and resensitizes cells to vincristine. Figure 3. TH588 significantly diminished colony formation in primary AML ex vivo indose-dependent manner. Figure 3. TH588 significantly diminished colony formation in primary AML ex vivo indose-dependent manner. Disclosures No relevant conflicts of interest to declare.
31
Parkhideh, S., M. Mehdizadeh, A. Hajifathali, H. G. Nazari, E. Roshandel, and R. Mirfakhraie. "Exosomes derived from chronic myeloid leukemia cells: roles in disease progression, survival, and treatment." Pakistan Journal of Medical and Health Sciences 15, no. 5 (May 30, 2021): 1533–39. http://dx.doi.org/10.53350/pjmhs211551533.
Full textAbstract:
Exosomes, biologically active extracellular vesicles, are derived from normal and neoplastic cells. Emerging evidence revealed that exosomes modulate cell-cell communication and involve in hemostatic and pathologic processes. Recent studies have shown that exosomes released from cancer cells such as chronic myeloid leukemia cells could act as a key mediator in tumor induction and progression. Myeloid cells-derived exosomes affect different processes including angiogenesis, neoplastic proliferation, tumor cell survival, and imatinib resistance. These exosomes induce angiogenesis and tumor progression by IL-8 overexpression in both leukemic and bone marrow stromal cells. Exosomes cargo could alter the expression of different adhesion molecules, anti-and pro-apoptotic molecules, cytokines, and chemokines such as VCAM-1, ICAM-1, BCL, BAD, BAX, TGF-β, TNF-α, CXCL12 which affect tumor migration, homing, survival, and growth. CML-derived exosomes can also regulate signal transduction pathways, such as ERK/MAPK, ERK/Akt, EGFR/Ras, and Wnt. Furthermore, they can be applied as a vehicle for drug delivery or sensitization of drug-resistant cells. Here, we reviewed the role of chronic myeloid cell-derived exosomes in tumor growth, survival, and resistance to treatment. Keywords: Chronic myeloid leukemia, Exosome, Angiogenesis, Tyrosine kinase inhibitor, Drug resistance
32
Strik, Herwig Matthias, Christina Perske, Peter Proemmel, Ingelore Nagel, and Holger Nagel. "“Lymphomatous and Leukemic Meningitis – Patterns of Cytomorphology and Value of MRI and Protein Analysis”." Blood 114, no. 22 (November 20, 2009): 5011. http://dx.doi.org/10.1182/blood.v114.22.5011.5011.
Full textAbstract:
Abstract Abstract 5011 Introduction Lymphomatous and leukemic meningitis (LM), although a well known and relatively frequent complication of aggressive lymphoma and leukemia, are still difficult to detect. With cytomorphology, neoplastic lyphocytes are difficult to distinguish from inflammatory lymphocytes. We evaluated here if specific morphological criteria can improve this differentiation. Moreover, we assessed the sensitivity of MRI and protein analysis for the detection of LM in comparison with CSF-cytology. Patients and Methods To establish cytomorphological criteria, 42 cytospin preparations of CSF from patients with confirmed CSF involvement by aggressive lymphoma or acute leukemia were compared with 26 samples of inflammatory diseases. CSF cytology was analyzed morphologically for pre-selected parameters of cell, cytoplasm and nucleic appearance and the presence of mitoses or apoptoses. For the comparison of cytology and MRI, 38 patients with leukemic or lymphomatous meningitis were evaluated retrospectively for MRI-signs of neoplastic meningitis and for CSF-protein abnormalities (total protein, oligoclonal bands, lactate, ferritine). Results as expected, none of the cytomorphological parameters sharply discerns neoplastic and inflammatory transformation. However, neoplastic cells were significantly larger than inflammatory lymphocytes with a mean of 3.0 as opposed to 1.8 times the size of normal small lymphocytes (p=0.0001). Moreover, irregular shape, pointed borders of the cytoplasm, and deep notches in the nucleus were significantly more often found with neoplastic than with inflammatory lymphocytes. The total cell count was elevated in 68% of cases of lymphomatous meningitis. While cytomorphology could achieve approx. 90% sensitivity for the detection of LM, spinal and/or cranial MRI only detected 71% of cases with normal and 52% with elevated cell counts. Total protein was elevated in 77% of cases, lactate in 55% and ferritine in 48%. Oligoclonal IgG was found in 11% isolated in the CSF and in 18% in CSF and serum identically. Only 3/38 patients (8%) had completely normal CSF cell count and proteins. Conclusions CSF cytology is more sensitive than MRI for the detection of LM, but application of both methods clearly enhances the sensitivity by approx. 10%. No single cytomorphological parameter is sufficient to detect neoplastic lymphocytes. Considering a combination of cell size and irregular shape of cell and nucleus may improve the diagnostic accuracy of CSF dissemination by aggressive hematological malignancies. Disclosures Strik: Mundipharma : Consultancy, Honoraria, Research Funding, Speakers Bureau; Essex/Shering-Plough/Merck: Consultancy, Honoraria, Speakers Bureau; Medac: Research Funding.
33
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.
Full textAbstract:
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.
34
Campos-Cabrera, Gregorio, Salvador Campos-Cabrera, Virgina Campos-Cabrera, Maria Mora-Torres, Miguel-Angel Gomez-Guijosa, Maria-Luisa Pedraza-Colin, Alicia Rivera-Trujillo, Sonia Hernandez-Rodriguez, Luis Pita-Ramirez, and Jose-Luis Campos-Villagomez. "Prevalence of Immunophenotypes in Neoplastic Hematology At Laboratorios Fatima De Michoacan." Blood 120, no. 21 (November 16, 2012): 4829. http://dx.doi.org/10.1182/blood.v120.21.4829.4829.
Full textAbstract:
Abstract Abstract 4829 Introduction: Medical indication of flow cytometric immunophenotyping includes diagnosis, classification, prognosis and disease monitoring. This is an important tool that each time is more used in hematology. Third world countries could not stay away from this technology, effort should be made to get access to it and not only make diagnosis in morphology. Objective: To determinate the prevalence of immunophenotypes in neoplastic hematology in our region (Central-West Mexico). Material and Methods: Bone marrow samples referred to Laboratorios Fatima de Michoacan for flow cytometry immunophenotyping for neoplastic hematological disease. The protocol is based on the Report on the Second Latin American Consensus Conference for Flow Cytometric Immunophenotyping of Hematological Malignancies (Cytometry Part B (Clinical Cytometry) 2005;70B:39–44), and Immunophenotyping of acute leukemia and lymphoproliferative disorders: a consensus proposal of the European LeukemiaNet Work Package 10 (Leukemia 2011;25:567–574). Results: One hundred and seventy two cases were diagnosed. Fourteen myelodisplastic syndromes were detected. Forty five acute myeloid leukemia; M0-M1 twenty two cases, 5 with aberrant expression of CD7, one with CD19 and one CD20; M2 four cases, 1 with aberrant expression of CD 2 and 1 with CD7; M3 four cases; M4 one case; M5 twelve cases, 3 aberrant expression of CD7; M6 and M7 one case each. Sixty five B cell precursor acute lymphoblastic leukemia; BI twenty three cases, 2 with aberrant expression of CD7, and 2 aberrant expression of CD13 and one with aberrant expression of CD 33; BII twenty cases, 1 aberrant expression of CD2, 1 aberrant expression of CD5, and 4 aberrant expression of CD33; BIII twenty one cases, 1 aberrant expression of CD3; BIV one case. Five T cell precursor acute lymphoblastic leukemia. Thirty four chronic lymphoproliferative disorders; eighteen B cell chronic lymphocytic leukemia, two T cell chronic lymphocytic leukemia, seven follicular lymphoma, three mantle cell lymphoma, three splenic lymphoma with villous lymphocytes and one hairy cell leukemia One adult T cell leukemia/lymphoma. One natural killer cell leukemia (CD94+, perforin +, granzyme +) Seven monoclonal gammapathies. Conclusions: It is important to create the experience with new diagnostic tools based on the regional protocols. Low prevalence of AML M2 presumably because of classic morphologic features. Low prevalence of monoclonal gammapathies because for recent incorporation to diagnosis, treatment and response criteria; it is expected that in future this prevalence will arise. This data is complemented, whenever it is possible, with chromosomal analysis to determinate the risk and treatment. Disclosures: No relevant conflicts of interest to declare.
35
Gleixner, Karoline V., Katharina Blatt, Barbara Peter, Emir Hadzijusufovic, and Peter Valent. "Ponatinib Exerts Growth-Inhibitory Effects on Neoplastic Mast Cells and Synergizes with Midostaurin in Producing Growth Arrest and Apoptosis,." Blood 118, no. 21 (November 18, 2011): 3497. http://dx.doi.org/10.1182/blood.v118.21.3497.3497.
Full textAbstract:
Abstract Abstract 3497 Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) have a poor prognosis. In these patients, neoplastic mast cells (MC) usually harbor the D816V-mutated variant of KIT and are resistant to conventional cytoreductive drugs and to several tyrosine kinase inhibitors (TKI) such as imatinib. More recently, various KIT kinase blockers including midostaurin (PKC412), have been described to overcome KIT D816V-mediated resistance in neoplastic MC. However, despite encouraging first results observed in clinical trials, these novel kinase blockers are unable to induce long-lasting complete remissions in all patients with ASM and MCL. One reason for the poor response in these patients may be the expression and activation of additional KIT-independent pro-oncogenic signalling molecules and pathways that trigger survival of neoplastic MC. Therefore, current research is seeking novel broadly acting drugs and drug combinations directed against the pro-oncogenic signaling machinery of neoplastic MC. Ponatinib (AP24534) is a broadly acting novel multikinase inhibitor that has been shown to exert major anti-leukemic effects in chronic myeloid leukemia. The aim of our current study was to evaluate the effects of ponatinib on growth and survival of neoplastic MC. Ponatinib was applied as single agent or in combination with midostaurin (PKC412). As assessed by Western blotting, ponatinib was found to inhibit KIT-phosphorylation in both subclones of the human MC leukemia cell line HMC-1, namely HMC-1.1 harboring KIT G560V but not KIT D816V, and HMC-1.2 cells harboring KIT G560V and KIT D816V. Interestingly, the D816V mutation of KIT was found to induce relative resistance against ponatinib. Ponatinib was also found to counteract the phosphorylation of Lyn, a Src-kinase that serves as a major KIT-independent signalling molecule and survival factor in neoplastic MC. Activated STAT5 in MC was also blocked by ponatinib in a dose-dependent manner. In a next step, we examined the effects of ponatinib on proliferation of neoplastic MC by 3H-thymidine uptake experiments. Ponatinib was found to induce dose-dependent growth inhibition in both HMC-1 subclones, with higher IC50-values in HMC-1 cells harbouring KIT D816V (IC50: 100–500 nM) compared to cells lacking KIT D816V (IC50: 1–10 nM). Furthermore, ponatinib was found to inhibit the proliferation of primary neoplastic MC isolated from patients with indolent SM (ISM, n=2) and ASM (n=1), with IC50-values ranging between 50 nM and 500 nM. Growth inhibitory effects of ponatinib on neoplastic MC were accompanied by induction of apoptosis as assessed by light microscopy, flow cytometry, and TUNEL assay. Finally, we were able to demonstrate that ponatinib synergizes with midostaurin in producing growth-inhibition and apoptosis in HMC-1.1 cells and HMC-1.2 cells. Synergistic effects obtained with suboptimal concentrations of single agents were accompanied by a complete blockage of all relevant kinase targets tested including KIT, Lyn, and STAT5. In conclusion, ponatinib exerts major growth-inhibitory effects on neoplastic MC. KIT D816V-expressing MC are less sensitive to ponatinib. This relative resistance of MC against ponatinib can be overcome by combining ponatinib with midostaurin in an in vitro assay. Whether the drug-combination also exerts major anti-neoplastic effects in vivo in patients with ASM and MCL remains to be determined. Disclosures: Valent: Novartis: Consultancy, Honoraria, Research Funding.
36
Bauer, SR, H. Kubagawa, I. Maclennan, and F. Melchers. "VpreB gene expression in hematopoietic malignancies: a lineage- and stage-restricted marker for B-cell precursor leukemias." Blood 78, no. 6 (September 15, 1991): 1581–88. http://dx.doi.org/10.1182/blood.v78.6.1581.1581.
Full textAbstract:
Abstract We show here that analysis of VpreB gene transcription can be a specific way to identify acute leukemias of cells at very early stages of B-cell development. Northern blot analysis of RNAs from 63 leukemia samples showed that VpreB RNA was present in malignancies of precursor B cells, the expression being a feature of both common acute lymphoblastic leukemia (ALL) (CD10+) and null ALL (CD10-). It was absent from malignancies of mature B cells (surface Ig positive), from acute leukemias of the T-cell lineage and granulocyte-macrophage lineages, and from normal tonsil B and T lymphocytes. Chronic myeloid leukemia blast crises of the B-precursor-cell type expressed the VpreB gene while myeloid blast crises did not. VpreB RNA was also expressed in the neoplastic cells of one of three patients with acute undifferentiated leukemias. These data show that VpreB RNA expression is a marker of the malignant forms of precursor B cells, and that it appears at least as early as cytoplasmic CD22 and CD19 in tumors of the B-cell lineage.
37
Bauer, SR, H. Kubagawa, I. Maclennan, and F. Melchers. "VpreB gene expression in hematopoietic malignancies: a lineage- and stage-restricted marker for B-cell precursor leukemias." Blood 78, no. 6 (September 15, 1991): 1581–88. http://dx.doi.org/10.1182/blood.v78.6.1581.bloodjournal7861581.
Full textAbstract:
We show here that analysis of VpreB gene transcription can be a specific way to identify acute leukemias of cells at very early stages of B-cell development. Northern blot analysis of RNAs from 63 leukemia samples showed that VpreB RNA was present in malignancies of precursor B cells, the expression being a feature of both common acute lymphoblastic leukemia (ALL) (CD10+) and null ALL (CD10-). It was absent from malignancies of mature B cells (surface Ig positive), from acute leukemias of the T-cell lineage and granulocyte-macrophage lineages, and from normal tonsil B and T lymphocytes. Chronic myeloid leukemia blast crises of the B-precursor-cell type expressed the VpreB gene while myeloid blast crises did not. VpreB RNA was also expressed in the neoplastic cells of one of three patients with acute undifferentiated leukemias. These data show that VpreB RNA expression is a marker of the malignant forms of precursor B cells, and that it appears at least as early as cytoplasmic CD22 and CD19 in tumors of the B-cell lineage.
38
Samorapoompichit, Puchit, Hans P. Kiener, Gerit-Holger Schernthaner, John-Hendrik Jordan, Hermine Agis, Friedrich Wimazal, Mehrdad Baghestanian, et al. "Detection of tryptase in cytoplasmic granules of basophils in patients with chronic myeloid leukemia and other myeloid neoplasms." Blood 98, no. 8 (October 15, 2001): 2580–83. http://dx.doi.org/10.1182/blood.v98.8.2580.
Full textAbstract:
Abstract Tryptases are serine proteases primarily expressed in mast cells. Normal blood basophils express only trace amounts of the enzyme. However, recent immunohistochemical studies have raised the possibility that neoplastic basophils express significant amounts of tryptase. In this study, tryptase expression was analyzed in normal and neoplastic basophils by immunoelectron microscopy using antitryptase monoclonal antibody G3. Basophils were obtained from patients with chronic myeloid leukemia (CML), idiopathic myelofibrosis (IMF), and myelodysplastic syndrome (MDS), and from healthy donors. Tryptase-immunoreactive material was detected in cytoplasmic granules of basophils in CML, IMF, and MDS. By contrast, normal basophils did not contain significant amounts of tryptase by immunoelectron microscopy. As assessed by reverse transcription-polymerase chain reaction, neoplastic basophils contained messenger RNA (mRNA) for α-tryptase, but no β-tryptase mRNA. In summary, these data provide evidence that neoplastic basophils in CML, IMF, and MDS can express detectable amounts of tryptase. Therefore, tryptase should not be regarded as specific for mast cells when neoplastic myeloid cells are analyzed.
39
Carmichael, K. P., D. Bienzle, and J. J. Mcdonnell. "Feline Leukemia Virus-associated Myelopathy in Cats." Veterinary Pathology 39, no. 5 (September 2002): 536–45. http://dx.doi.org/10.1354/vp.39-5-536.
Full textAbstract:
Feline leukemia virus (FeLV) infection is associated with distinct neoplastic, hematologic, and immunosuppressive diseases. Here we report on a novel neurologic syndrome in 16 cats infected with FeLV for more than 2 years. Clinical signs consisted of abnormal vocalization, hyperesthesia, and paresis progressing to paralysis. The clinical course of affected cats involved gradually progressive neurologic dysfunction invariably resulting in euthanasia. Microscopically, white-matter degeneration with dilation of myelin sheaths and swollen axons was identified in the spinal cord and brain stem of affected animals. Neither neoplastic nor hematologic diseases commonly associated with FeLV infection were present. Fungal and protozoal infection in one animal was suggestive of impaired immune competence. Immunohistochemical staining of affected tissues revealed consistent expression of FeLV p27 antigens in neurons, endothelial cells, and glial cells. Furthermore, proviral DNA was amplified from multiple sections of spinal cord as well as intestine, spleen, and lymph nodes. These findings suggest that in a proportion of chronically FeLV-infected cats, a virus evolved with cytopathic potential for cells in the central nervous system.
40
Behfarnia, Parichehr, Parviz Deyhimi, Abbas Haghighat, Vahid Naemi, and Narges Naghsh. "Leukemia-induced Gingival Overgrowth as an Early Manifestation in Pregnancy: A Case Report." Journal of Periodontology & Implant Dentistry 6, no. 2 (October 8, 2014): 60–63. http://dx.doi.org/10.15171/jpid.2014.011.
Full textAbstract:
Leukemia is a neoplastic disease with early oral and periodontal manifestations such as ulceration, infection, bleeding and gingival hyperplasia. This paper describes a 39-year-old pregnant woman with a diagnosis of acute myelomonocytic leukemia (AML), with gingival enlargement in the upper and lower jaws. A gingival biopsy was performed, followed by a complete blood count and peripheral blood smear. From a histopathological view, infiltration of the neoplastic (myelomonocytoblastic) cells was observed and many immature lymphoid cells were revealed by the hematologic tests. The interesting clinical finding about this case was the absence of spontaneous bleeding and profuse bleeding on probing. This case is reported to emphasize the leukemia-induced gingival enlargement in pregnancy and the early diagnosis of AML by dentists, which results in immediate treatment and management of the patient.
41
Zhang, Ke, Hagop M. Kantarjian, Wanlong Ma, XI Zhang, Xiuqiang Wang, Zeev Estrov, Chen-Hsiung Yeh, et al. "Use of Ubiquitin-Proteasome System Profiling for Differentiating Between Various Leukemic Processes." Blood 114, no. 22 (November 20, 2009): 4712. http://dx.doi.org/10.1182/blood.v114.22.4712.4712.
Full textAbstract:
Abstract Abstract 4712 The ubiquitin-proteasome system (UPS) plays a major role in cell homeostasis in normal and neoplastic states. Expression and function of the UPS system vary with the specific characteristics of individual cell types, suggesting that determination of UPS “signatures” could be useful in identifying various cell populations. Since direct analysis of cancer cells is often problematic, even in hematologic diseases, we explored the potential of using UPS signatures in plasma to differentiate between various leukemias. We first analyzed plasma UPS profiles of patients with acute myeloid leukemia (AML; n=111), acute lymphoblastic leukemia (ALL; n=29), advanced myelodysplastic syndrome (MDS; n=20), chronic lymphocytic leukemia (CLL; n=118), or chronic myeloid leukemia (CML; n=128; 46 in accelerated/blast crisis [ACC/BL], 82 in chronic phase), and 85 healthy control subjects. Plasma levels of proteasome, ubiquitin (poly-ubiquitin), and the 3 proteasome enzymatic activities (chymotrypsin-like [Ch-L], caspase-like [Cas-L], trypsin-like [Tr-L]) were measured. Specific activities were calculated by normalizing each of the 3 enzyme activities to the levels of proteasome protein in plasma (Ch-L/p, Cas-L/p, and Tr-L/p). These 8 variables were used in multivariate logistic regression models to differentiate between leukemic processes. UPS signatures provided clear differentiation between patients with a leukemic process and normal controls (AUC=0.991), using 6 different variables (Tr-L/P, Ch-L, Ch-L/p, Cas-L, Cas-L/P, ubiquitin). Distinguishing between acute (AML, ALL, MDS) and chronic (CML, CLL) processes was less efficient (AUC=0.853 using Tr-L, Tr-L/P, Cas-L/P, Ch-L/P, proteasome, Ch-L), likely due to the high proportion (36%) of CML patients in ACC/BL phase. However, UPS signatures generally yielded powerful differentiation between individual leukemias (Table). MDS was not well differentiated from AML (AUC=0.791), reflecting the significant biological overlap of these diseases. These data support the potential usefulness of the UPS profile to aid in the differential diagnosis of various leukemias. Disclosures: No relevant conflicts of interest to declare.
42
Wen, T., H. Mellstedt, and M. Jondal. "Presence of clonal T cell populations in chronic B lymphocytic leukemia and smoldering myeloma." Journal of Experimental Medicine 171, no. 3 (March 1, 1990): 659–66. http://dx.doi.org/10.1084/jem.171.3.659.
Full textAbstract:
Clonality in the non-neoplastic T cell population was investigated in 21 patients with B cell chronic leukemic (B-CLL) or multiple myeloma (MM) by probing for TCR beta chain gene rearrangements using Southern blot analysis. In three patients with a benign form of B-CLL (stage 0), and in one patient with smoldering MM, evidence was found for predominant T cell clones. As cellular immunity against the malignant cells may be important in leukemia, the results are discussed in view of the potential role of T cell immunity in B-CLL and MM.
43
Dagher, Elie, Nicolas Soetart, Florian Chocteau, Bérengère Dequéant, Esther Piccirillo, Catherine Ibisch, Jérôme Abadie, and Laëtitia Jaillardon. "Plasma cell leukemia with plasmablastic morphology in a dog." Journal of Veterinary Diagnostic Investigation 31, no. 6 (October 14, 2019): 868–74. http://dx.doi.org/10.1177/1040638719882045.
Full textAbstract:
A 5-y-old female Golden Retriever was presented with a 2-wk history of hyporexia, vomiting, diarrhea, lethargy, weight loss, polyuria, and polydipsia. Clinical examination and ultrasonography revealed multiple organ enlargement with gallbladder and kidney nodules suggestive of disseminated neoplasia. Hematologic and biochemical analyses revealed pancytopenia, hypercalcemia, and monoclonal IgA gammopathy suspicious for a plasma cell neoplasm. Bone marrow and blood smear examination revealed neoplastic atypical cells highly suggestive of lymphoid origin. Autopsy confirmed the presence of homogeneous white masses and multifocal pale infiltrates in the spleen, kidney, small intestine, gallbladder, and urinary tract. Histologic features were consistent with a multicentric atypical plasma cell tumor. Tumor cells were negative for CD204, IBA-1, E-cadherin, CD3, CD5, CD79a, CD20, and PAX5, and positive for MUM1, consistent with plasma cell origin. The presence of > 20% of circulating blastic plasma cells was consistent with primary plasma cell leukemia with plasmablastic morphology, a disease rarely described in veterinary medicine.
44
Mathew, Paul. "Imatinib and the neoplastic bone microenvironment." Blood 111, no. 5 (March 1, 2008): 2495–96. http://dx.doi.org/10.1182/blood-2007-12-128306.
Full textAbstract:
The effects of aging, medical comorbidity, and systemic therapeutics interplay with the varied and distinctive capacities of neoplasms to usurp the physiological machinery regulating bone structure and function, thus determining skeletal morbidity and related mortality. In this issue of Blood, Fitter and colleagues report frequent increases in trabecular bone volume—a 2-fold increase over baseline in nearly half of patients with chronic myeloid leukemia (CML)—treated with the multi–tyrosine kinase receptor inhibitor, imatinib mesylate. Although the clinical significance of this anabolic and/or anticatabolic effect remains to be determined, these mechanistic studies offer a plausible explanation for the outcome.
45
D'Arena, Giovanni, Roberto Guariglia, Oreste Villani, Maria Carmen Martorelli, Giuseppe Pietrantuono, Giovanna Mansueto, Giuseppe Patitucci, et al. "An Urologic Face of Chronic Lymphocytic Leukemia:Sequential Prostatic and Penis Localization." Mediterranean Journal of Hematology and Infectious Diseases 5, no. 1 (January 2, 2013): e2013008. http://dx.doi.org/10.4084/mjhid.2013.008.
Full textAbstract:
We report a patient with chronic lymphocytic leukemia (CLL) in whom a leukemic involvement of prostate and penis occurred in the advanced phase of his disease. Obstructive urinary symptoms were indicative of prostatic CLL infiltration, followed by the occurrence of an ulcerative lesion on the glans. Histologic examination confirmed the neoplastic B-cell infiltration. Both localizations responded to conventional treatments. A review of the literature confirms that leukemic involvement of the genito-urinary system is uncommon in CLL patients. However, such an involvement should be considered in CLL patients with urologic symptoms and a long history of the disease.
46
Chen-Liang, Tzu-Hua, Andrés Jerez, Lourdes Florensa, and Francisco José Ortuño. "Neoplastic mastocytosis evolving from a poor prognosis acute myeloid leukemia." Medicina Clínica (English Edition) 144, no. 12 (June 2015): 571–72. http://dx.doi.org/10.1016/j.medcle.2015.12.026.
Full text
47
Wadleigh, Martha, Daniel J. DeAngelo, James D. Griffin, and Richard M. Stone. "After chronic myelogenous leukemia: tyrosine kinase inhibitors in other hematologic malignancies." Blood 105, no. 1 (January 1, 2005): 22–30. http://dx.doi.org/10.1182/blood-2003-11-3896.
Full textAbstract:
AbstractTyrosine kinases phosphorylate proteins on tyrosine residues, producing a biologic signal that influences many aspects of cellular function including cell growth, proliferation, differentiation, and death. Constitutive or unregulated activity through mutation or overexpression of these enzymes is a common pathologic feature in many acute and chronic leukemias. Inhibition of tyrosine kinases represents a strategy to disrupt signaling pathways that promote neoplastic growth and survival in hematologic malignancies and likely in other neoplasias as well. This review focuses on tyrosine kinases that have been implicated in the pathogenesis of hematologic diseases other than chronic myelogenous leukemia and discusses the evidence for the use of small molecules to target these kinases.
48
Imada, K., A. Takaori-Kondo, T. Akagi, K. Shimotohno, K. Sugamura, T. Hattori, H. Yamabe, M. Okuma, and T. Uchiyama. "Tumorigenicity of human T-cell leukemia virus type I-infected cell lines in severe combined immunodeficient mice and characterization of the cells proliferating in vivo." Blood 86, no. 6 (September 15, 1995): 2350–57. http://dx.doi.org/10.1182/blood.v86.6.2350.bloodjournal8662350.
Full textAbstract:
The mechanism involved in leukemogenesis and neoplastic cell growth of adult T-cell leukemia (ATL) still remains unclear. We examined the tumorigenicity of human T-cell leukemia virus type I (HTLV-I)-infected cell lines in an in vivo cell proliferation model using severe combined immunodeficient (SCID) mice. Eleven HTLV-I-infected cell lines were injected into SCID mice and we found that 4 of them were capable of proliferating in SCID mice. Three of four transplantable cell lines are derived from the leukemic cell clone and 6 of 6 HTLV-I-infected cell lines of nonleukemic cell origin could not engraft in SCID mice. Interestingly, it was shown that some HTLV-I-infected and interleukin-2 (IL-2)-dependent cell lines could successfully engraft in SCID mice. The expression of IL-2 mRNA was not detected in these cell lines growing either in vivo or in vitro. HTLV-I viral products were not detected in 3 of 4 transplantable cell lines proliferating in vivo. Peripheral blood T cells immortalized by introduction of tax gene of HTLV-I were found to have no tumorigenic potential in SCID mice. These data suggest that (1) HTLV-I-infected cell lines of nonleukemic cell origin do not have enough leukemogenic changes to acquire the tumorigenic potential in SCID mice; (2) the IL-2 autocrine mechanism is not directly involved in the tumor cell growth; (3) viral gene expression is not needed for the maintenance of neoplastic cell growth; and (4) the expression of tax gene is not sufficient for the neoplastic cell growth in vivo.
49
Alhaj Moustafa, Muhamad, Liuyan Jiang, Justin J. Kuhlman, Jeremy Jones, Yanyan Lou, Olayemi Sokumbi, and Han W. Tun. "BRAF p.V600E associated poly-neoplastic syndrome." Rare Tumors 13 (January 2021): 203636132110129. http://dx.doi.org/10.1177/20363613211012929.
Full textAbstract:
We report a male patient who developed eight different cancers between ages 57 and 64. BRAF p.V600E mutation was detected in Langerhans cell histiocytosis, chronic lymphocytic leukemia, histiocytic sarcoma, melanoma, and adenocarcinoma of the lung. It was not detected in multiple myeloma, basal cell carcinoma, and papillary thyroid cancer. BRAF p.V600E was not detected in normal skin tissue biopsy indicating that BRAF V600E was a somatic mutation affecting cancer cells. The presence of eight different cancers with five of them positive for BRAF p.V600E in a single patient is unprecedented. This type of BRAF p.V600E-associated poly-neoplastic syndrome has never been reported in the medical literature.
50
Panziera, Welden, Bianca Tessele, Ronaldo Bianchi, Camila Tochetto, Flávio De La Corte, Karin Brass, and Rafael Fighera. "Equine acute erythroid leukemia." Ciência Rural 45, no. 12 (August 25, 2015): 2214–17. http://dx.doi.org/10.1590/0103-8478cr20140876.
Full textAbstract:
Acute erythroid leukemia (AML M6) is a hematopoietic neoplasm frequently described in cats and mice, rarely in other animal species. This report describes a case of AML M6 in a yearling Thoroughbred filly. Clinically the horse presented marked pale mucous membranes and exercise intolerance. In addition, the owner and referring veterinarian reported a 30-day history of progressive weight loss. The CBC revealed severe anemia and leukopenia by neutropenia. Cytology evaluation obtained from bone marrow fine needle aspirates evidenced inversion of the myeloid: erythroid ratio (0.2), with 48% of the nucleated cells corresponding to rubriblasts. In addition to the gross evidence of anemia, necropsy findings consisted of splenomegaly and lymphadenomegaly. The diagnosis of AML M6B was confirmed histologically due to splenomegaly and lymphadenomegaly, secondary to neoplastic metastasization.