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Rabade, Nikhil, Goutham Raval, Shruti Chaudhary, PG Subramanian, Rohan Kodgule, Swapnali Joshi, Prashant Tembhare, et al. "MOLECULAR HETEROGENEITY IN ACUTE PROMYELOCYTIC LEUKEMIA - A SINGLE CENTRE EXPERIENCE FROM INDIA." Mediterranean Journal of Hematology and Infectious Diseases 10, no. 1 (January 1, 2018): 2018002. http://dx.doi.org/10.4084/mjhid.2018.002.
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Atypical breakpoints and variant APL cases involving alternative chromosomal aberrations are seen in a small subset of acute promyelocytic leukemia (APL) patients. Over 7 different partner genes for RARA have been described. Although rare, these variants prove to be a diagnostic challenge and require combination of advanced cytogenetic and molecular techniques for accurate characterization. Heterogeneity occurs not only at the molecular level but also at clinico-pathological level influencing treatment response and outcome. In this case series we describe the molecular heterogeneity of APL seen in a single tertiary referral centre with a focus on seven variant APL cases from a single tertiary cancer center in India over a period of two and a half years. We discuss five cases with PLZF-RARA fusion and two novel PML-RARA variants, including a Bcr3 variant involving fusion of PML exon4 and RARA exon3 with an additional 40 nucleotides originating from RARA intron2, another involving exon 6 of PML and exon 3 of RARA with addition of 126 nucleotides, which mapped to the central portion of RARA intron 2 To the best of our knowledge this is the first of kind case series from India
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Adams, Julia, and Mehdi Nassiri. "Acute Promyelocytic Leukemia: A Review and Discussion of Variant Translocations." Archives of Pathology & Laboratory Medicine 139, no. 10 (October 1, 2015): 1308–13. http://dx.doi.org/10.5858/arpa.2013-0345-rs.
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The majority of patients with acute promyelocytic leukemia (APL) manifest the t(15;17)(q24.1;q21.2) translocation; however, a minor but significant proportion of patients with APL harbor complex, cryptic, or variant translocations, which typically involve RARA. With the exception of ZBTB16/RARA, these variants have similar morphologic and immunophenotypic features as classic APL. Study of the variant forms of APL not only gives insight into the pathogenesis of APL but also allows us to understand the mechanism of retinoid therapy. It is important to identify these cryptic and variant translocations because certain variants, including ZBTB16/RARA and STAT5B/RARA, are resistant to treatment with all-trans retinoic acid, arsenic trioxide, and anthracyclines.
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Bajaj, Preeti, Rajyaguru Devangana, B. S. Shah, and Amrinder Kaur. "Hyperbasophilic Variant of Acute Promyelocytic Leukemia." MVP Journal of Medical Sciences 3, no. 2 (November 17, 2016): 125. http://dx.doi.org/10.18311/mvpjms/2016/v3/i2/7702.
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Acute Promyelocytic Leukemia (APL) is an extremely rare variant of acute myeloid leukemia. APL constitutes around 10-15 % of acute myeloid leukemia in adults. It is commonly diagnosed around 40 years age. Molecular/genetic studies exhibit chromosomal translocation between chromosome 15 and chromosome 17-t(15;17)(q22;q21) and PML-RARa rearrangement. Four variants of APL have been identified: The classic form M<sub>3</sub> hypergranular variant, the microgranular variant, the hyperbasophilic form and zinc-finger form-M<sub>3</sub>r, identified by a different chromosomal translocation, between chromosome 11 and chromosome 17:t(11,17) (q23, q11-12).
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Dowse, Robin T., and Robin M. Ireland. "Variant ZBTB16-RARA translocation: morphological changes predict cytogenetic variants of APL." Blood 129, no. 14 (April 6, 2017): 2038. http://dx.doi.org/10.1182/blood-2016-10-743856.
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Catalano, Alberto, Mark A. Dawson, Karthiga Somana, Stephen Opat, Anthony Schwarer, Lynda J. Campbell, and Harry Iland. "The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia." Blood 110, no. 12 (December 1, 2007): 4073–76. http://dx.doi.org/10.1182/blood-2007-06-095554.
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Abstract We report the molecular and cytogenetic characterization of a novel variant of acute promyelocytic leukemia (APL). The bone marrow showed 88% hypergranular promyelocytes, and the karyotype was 47,XY,+22 [5]/46,XY[30]. Fluorescence in situ hybridization (FISH) indicated disruption and deletion of the 5′-end of the RARA gene. Treatment with all-trans retinoic acid, idarubicin, and arsenic trioxide induced cytogenetic complete remission without morphologic evidence of residual leukemia. The diagnostic marrow was negative for PML-RARA transcripts by reverse transcription–polymerase chain reaction (RT-PCR), but an atypical product was observed. Sequencing showed partial homology to the PRKAR1A gene, encoding the regulatory subunit type I-α of cyclic adenosine monophosphate–dependent protein kinase. RT-PCR using specific primers for PRKAR1A and RARA amplified 2 transcript splice variants of a PRKAR1A-RARA fusion gene, and PRKAR1A and RARA FISH probes confirmed the fusion. This novel PRKAR1A-RARA gene rearrangement is the fifth variant APL in which the RARA partner gene has been identified and the second known rearrangement of PRKAR1A in a malignant disease. This trial was registered at www.actr.org.au with the Australian Clinical Trials Registry as number 12605000070639.
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Zhao, Jie, Liang Jian-Wei, Shuhong Shen, Jing Chen, Hui-Liang Xue, Ben-Shang LI, and Jing-Yan Tang. "The Genetics and Clinical Characteristics of Children Morphologically Diagnosed As Acute Promyelocytic Leukaemia." Blood 132, Supplement 1 (November 29, 2018): 2801. http://dx.doi.org/10.1182/blood-2018-99-112401.
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Abstract Acute promyelocytic leukaemia (APL) is characterized by t(15;17)(q22;q21), resulting in a PML-RARA fusion that is the master driver of APL. A few cases that can't be identified with PML-RARA by using routine methods (karyotype analysis, FISH, and RT-PCR) involve abnormal promyelocytes that are fully in accordance with APL in morphology, cytochemistry, and immunophenotype. To explore the mechanisms involved in pathogenesis and recurrence of morphologically diagnosed APL, we performed comprehensive variant analysis from structural variants (SVs) to single-nucleotide variants (SNVs) in paediatric patients mophologically diagnosed as APL by next generation sequencing. SV analysis using targeted gene sequencing(TGS) in 120 DNA samples from both diagnosis and relapse stage identified 95 samples with RARA rearrangement (including 94 with PML-RARA and one with NPM-RARA) and two samples with KMT2A rearrangement. In the cases failed to be identified with any RARA rearrangement, transcriptome sequencing was applied in the available 13 RNA samples at diagnosis. One case each with CPSF6-RARG, NPM1-CCDC28A, and TBC1D15-RAB21 and two cases with a TBL1XR1-RARB fusion were discovered, which strongly suggested their contributions to leukemogenesis as driver alternations and APL phenotype is inextricably linked to rearrangement of RARA gene. SNV analysis in 75 primary APL samples with RARA rearrangement showed recurrent alternations in FLT3(27%), WT1(13%), USP9X(9%), NRAS(7%), and ARID1A(4%), with a strong potential for involvement in pathogenesis, and WT1as the only gene recurrently mutated in 4/5 samples(3/4 cases) in relapsed APL. WT1 (17.6%), NPM1 (11.8%), NRAS (11.8%), FLT3 (11.8%), and NSD1 (11.8%) were identified as recurrently mutated in 17 primary samples without RARA rearrangement and WT1(44.4%), NPM1 (33.3%), TP53 (33.3%), and RARA (33.3%)as recurrently mutated in 9 relapsed samples. The retrospective study showed the survival rates of APL without RARA rearrangement(8y-EFS=38.7%±17.8%) were much worse than APL with RARA rearrangement(8y-EFS=90.9%±3.9%), which is similar to AML (non-M3) patients(8y-EFS=57.7%±3.0%). Thus,NGS is necessary in cases failed to be identified with RARA rearrangement by karyotype analysis, FISH, and RT-PCR, which can afford accurate diagnosis and treatment guidance. APL phenotype may arise by abnormities of other members of the nuclear receptor superfamily involved in retinoid signaling(RARB or RARG) or even by mechanisms distinct from the formation of aberrant retinoid receptors. Differences in genetic alternations and survival indicated that APL that cannot be identified as having a RARA rearrangement are more reasonably classified as a subclass of AML other than APL, and an AML treatment regimen or individualized treatment should be considered according to the genetic abnormalities. Figue1. (A)Mutational profile between APL with and without RARA rearrangement. (B)Comparison of estimated probability of EFS and OS among APL with and without RARA rearrangement and AML(non-M3) group . “Typical APL” means APL with RARA rearrangement and “Atypical APL” means APL without RARA rearrangement. Disclosures No relevant conflicts of interest to declare.
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Catalano, Alberto, Mark A. Dawson, Karthiga Somana, Stephen S. Opat, Lynda J. Campbell, Anthony P. Schwarer, and Harry J. Iland. "A Novel Fusion of RARA to the PRKAR1A Gene, Encoding the Regulatory Subunit Type-I α of Cyclic AMP Dependent Protein Kinase A, in a Variant Acute Promyelocytic Leukaemia." Blood 108, no. 11 (November 1, 2006): 2343. http://dx.doi.org/10.1182/blood.v108.11.2343.2343.
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Abstract The vast majority of acute promyelocytic leukemia (APL) cases are characterized by the formation of a PML/RARA fusion gene. Disruptions of retinoic acid receptor α (RARα) function have also been described in four types of variant APL in which an alternative partner gene (PLZF, NPM, NUMA, or STAT5B) is fused to RARA. We describe a novel variant APL with a RARA fusion formed by a complex gene rearrangement which is undetectable by conventional cytogenetics. A 66 yr old male with a history of mild thrombocytopenia was diagnosed with APL based on the blood and marrow morphology, the coagulopathy, and a microspeckled PML immunofluorescence pattern. The bone marrow immunophenotype was negative for CD2, CD19, CD34, CD56, CD117 and HLA-DR, and with weak expression of CD13, CD33 and CD11b, a pattern atypical for APL. The diagnostic bone marrow karyotype was 47,XY,+22[5]/46,XY[30] with no t(15;17)(q22;q21). FISH with the Vysis LSI PML/RARA dual fusion translocation probe did not show any fusion signals but there was splitting of an RARA signal on one 17q. A second probe, the Vysis LSI RARA break apart probe, showed deletion of the 5′ RARA probe and the 3′ RARA probe appeared to localize more distally than normal. The Cytocell PML/RARA ES probe also showed no fusion signals but one RARA signal appeared smaller. The diagnostic marrow was negative for PML/RARA transcripts by RT-PCR using PML and RARA specific primers, but an atypical product was observed. Sequencing of this product showed partial homology to the PRKAR1A gene that maps to 17q24 and encodes the regulatory subunit type I-alpha (RIα) of cyclic AMP-dependent protein kinase A. RT-PCR using PRKAR1A and RARA specific primers amplified two transcript splice variants of a PRKAR1A/RARA fusion gene. The shorter out-of-frame fusion transcript lacked PRKAR1A exon 3 and encoded a carboxy-truncated RIα protein. The longer in-frame fusion transcript resulted from cryptic splicing of the first 100 bases of PRKAR1A exon 3 to RARA exon 3, and encoded a chimeric RIα-RARα fusion protein that contained the dimerization domain of RIα and the same carboxy terminal domains of RARα that are found in all other known RARA rearrangements in APL. FISH using a BAC probe (RP11–120M18) encompassing the PRKAR1A gene identified signals on both copies of 17q; a strong signal on the normal 17 and a weaker signal on der(17). Before cytogenetic, FISH and molecular results were available, the patient was registered on the Australasian Leukaemia and Lymphoma Group’s APML4 treatment protocol which includes ATRA, age-adjusted idarubicin and arsenic trioxide. Arsenic was ceased on day 22 due to toxicity. Morphological and cytogenetic FISH complete remission was documented on day 35. A bone marrow biopsy eleven months from original diagnosis showed no evidence of leukemia and PRKAR1A/RARA RT-PCR was indicative of molecular remission. This novel PRKAR1A/RARA gene rearrangement identified in a variant APL is the fifth variant APL in which the RARA partner gene has been identified and the second known rearrangement of PRKAR1A in a malignant disease.
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Redner, Robert L., Lydia C. Contis, Carol Evans, Maureen E. Sherer, and Sofia Shekhter-Levin. "A Novel t(3;17) Variant of Acute Promyelocytic Leukemia with Rearrangement of the RARA Locus." Blood 104, no. 11 (November 16, 2004): 4428. http://dx.doi.org/10.1182/blood.v104.11.4428.4428.
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Abstract The vast majority of patients with Acute Promyelocytic Leukemia (APL, FAB M3) have the t(15;17)(q12;q21) chromosomal translocation. This introduces the gene for PML into the retinoic acid receptor alpha (RARA) locus, which leads to expression of a PML-RARA fusion. There is convincing evidence that expression of PML-RARA underlies the APL phenotype. Yet, there have been identified rare cases of APL that do not manifest t(15;17). Many of these cases exhibit cryptic rearrangements of PML and RARA. However, in a number of cases it has clearly been shown that a fusion protein different than PML-RARA is expressed. These include the t(11;17)(q23;q21) that expresses a PLZF-RARA fusion; t(5;17)(q35;q21) that encodes NPM-RARA; t(11;17)(q13;q21) that encodes NUMA-RARA; and der(17) with duplication of 17q21.3-q23 that fuses STAT5b to RARA. We report here a novel case of APL with t(3;17) with rearrangement of RARA, but not PML. A 72 year old man presented with leukocytosis, anemia, and thrombocytopenia: wbc 20.4 X10E+9/L; hgb 10.3 g/L; PLT 22 x10E+9/L. The wbc differential showed 20% polys, 4% bands, 15% lymphocytes, 19% monocytes, 34% blasts, 1% promyelocyte, 6% myelocyte, 1% metamyelocytes. Auer rods were seen. The bone marrow was hypercellular (approximately 80%), with 88% blasts, 1.7% promyelocytes, 0.3% myelocyte, 0.3% polys, 0.3% eosinophile, 3% monocytes, 0.3% pronormoblasts, 3.7% normoblasts, and 2.3% lymphocytes. The blasts demonstrated prominent cytoplasmic granulation, Flow cytometric analysis showed the blasts to be CD117 positive, myeloperoxidase positive, CD13/33 positive, but lacking CD34 or HLA-DR expression, consistent with a diagnosis of APL. Cytogenetic studies indicated a mosaic abnormal analysis with an apparent normal cell line and one that demonstrated a 47,XY,t(3;17)(p25;q12-21), +8 karyotype. Analysis for PML-RARA expression by RT-PCR was indeterminate, owing to poor quality of the extracted RNA. Fluorescence In Situ Hybridization (FISH) was therefore performed on two hundred unstimulated cells, primarily in interphase, using the Vysis t(15;17) dual color DNA probe. 98.5% of the cells were negative for PML-RARA rearrangement (the value of 1.5% positivity is within the laboratory’s control range for false positives). To confirm that the t(3;17) rearrangement involved the RARA locus, we scored 203 unstimulated cells using the LSI RARA dual color DNA probe. 100% were positive for the RARA gene rearrangement (split signal). Four metaphase cells each showed one fused red/green signal on the normal chromosome 17, one red signal on der (17), and one green signal on the distal arm of chromsome 3. The FISH analysis therefore indicated rearrangement of the RARA, but not the PML locus. The patient expired before treatment could begin. To determine whether the t(3;17) blasts could differentiate (a hallmark of t(15;17) APL), we cultured the bone marrow cells in RPMI 1640 with 10% FCS and 10E-6 M ATRA. At 10 days 58% of the cells resembled metamyelocytes, bands, or mature polys, compared with none in the control culture. This indicates that t(3;17) retains its ability to differentiate in the presence of ATRA, consistent with its classification as a novel variant of APL.
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Yamamoto, Yukiya, Sachiko Tsuzuki, Motohiro Tsuzuki, Kousuke Handa, Yoko Inaguma, and Nobuhiko Emi. "BCOR as a Novel Fusion Partner of Retinoic Acid Receptor Alpha In a t(X;17)(p11;q12) Variant of Acute Promyelocytic Leukemia." Blood 116, no. 21 (November 19, 2010): 1703. http://dx.doi.org/10.1182/blood.v116.21.1703.1703.
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Abstract Abstract 1703 The majority of acute promyelocytic leukemia (APL) cases are characterized by the presence of a PML-RARA fusion gene. In a small subset, RARA is fused to a different partner including PLZF, NPM1, NuMA, STAT5b, PRKAR1A and FIP1L1. Here we identified a novel RARA fusion transcript, BCOR-RARA in a t(X;17)(p11;q12) variant of APL. The patient was a 45-year-old man. Although the patient was clinically responsive to ATRA, repeated standard chemotherapy with ATRA did not effect a cure. The bone marrow promyelocytes had unique morphologic features, including rectangular and round cytoplasmic inclusion bodies. They were more granular than those of AML M2 but less granular than the classical t(15;17) APL. Flow cytometric analysis revealed strong expression of CD13, CD33, CD56, weak expression of CD11c and lack of HLA-DR and CD7. The karyotype analysis detected a novel chromosomal translocation described as 45,-Y, t(X;17)(p11.2;q12)[19]/ 46,XY[1]. FISH analysis indicated one intact and two split signals of RARA and two intact signals of PML. To amplify unknown chimeric fusion transcripts, we performed 5'-RACE. The sequence revealed that BCL6 co-repressor, BCOR cDNA from exons 9 to 12 to be fused to RARA exon 3. By RT-PCR, we confirmed full length chimeric fusion transcripts spanning from the start codon to 4,948 nt of BCOR cDNA (NM_001123384) fused to RARA cDNA from exon 3 to the stop codon. The chimeric cDNA had an in-frame codon from BCOR through RARA, creating a 1,931 amino acid fusion protein. One of the consistent features in all known RARA fusion partners is self-association. To determine whether BCOR-RARA self-associate, we performed co-immunoprecipitation assays. These results showed that BCOR-RARA is able to self-associate both through the region of BCOR-S and the ankyrin repeat domain of BCOR. In addition, BCOR-RARA associated with BCL6. RXR recruitment is a critical determinant of transforming potential of oligomeric RARA fusion proteins. To investigate how BCOR-RARA associates with RARE in vitro, we performed EMSA. These results showed that BCOR-RARA/RXRA complex associates with RARE in an alternative manner compared to RARA and PML-RARA. Deregulation of RARA transcriptional activations has a central role in pathogenesis of APL. Therefore, we evaluated ATRA-induced transcriptional activation of 4× RAREs with a reporter assay in HepG2 cells. Without ATRA, BCOR-RARA repressed the reporter activity. With addition of ATRA, BCOR-RARA induced transcriptional activation very weakly. Subsequently, we evaluated dominant-negative effects of the samples in the RARA/RXRA pathway. In contrast to BCOR, BCOR-RARA clearly inhibited ATRA-induced RARA transcriptional activation as well as PML-RARA. Furthermore, we asked which domains are sufficient for the dominant-negative effects with the deletion mutants. The results indicated that the region spanning from 999 to 1,409 aa of BCOR-RARA has pivotal roles in the dominant-negative effects. Correct protein function is highly dependent on intracellular localization. To investigate subcellular localization of BCOR-RARA, we performed immunofluorescence analysis in 293T cells. In BCOR-RARA-expressing cells, BCOR-RARA localized as two patterns; (I) diffusely in the nucleus as well as PML-RARA in 82% of the cells, (II) diffusely in the nucleus and aggregately in the cytoplasm in 18% of the cells. The subcellular localization of BCOR-RARA was clearly distinguishable from the punctuate pattern as shown in the nucleus of BCOR-expressing cells. Moreover, co-immunofluorescence analysis between BCOR-RARA and BCL6 indicated that the subcellular localization of BCOR-RARA/BCL6 is distinct from BCOR/BCL6. BCOR-RARA was found to possess common features with other RARA fusion proteins. These included: (I) the same break point in RARA cDNA; (II) self-association; (III) RXRA is necessary for BCOR-RARA to associate with the RARA responsive element; (IV) action in a dominant-negative manner on RARA transcriptional activation; (V) aberrant subcellular relocalization. It should be noted that there was no intact BCOR found in the 45,-Y,t(X;17)(p11;q12) APL cells because they featured only a rearranged × chromosome. These results highlight essential features of pathogenesis in APL in more detail. BCOR appears to be involved not only in human congenital diseases but also in a human cancer. Disclosures: No relevant conflicts of interest to declare.
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Redner, RL, EA Rush, S. Faas, WA Rudert, and SJ Corey. "The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion." Blood 87, no. 3 (February 1, 1996): 882–86. http://dx.doi.org/10.1182/blood.v87.3.882.bloodjournal873882.
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We have studied an acute promyelocytic leukemia (APL) patient with a variant t(5;17)(q32;q12). This translocation fuses the gene for the nucleolar phosphoprotein nucleophosmin (NPM) to the retinoic acid receptor alpha (RARA). Two alternatively spliced transcripts are expressed, which differ in 129 bases immediately upstream of the RARA sequence. The NPM sequences contained in the shorter NPM-RAR cDNA are identical to the NPM sequences contained in the NPM-ALK fusion gene expressed in t(2;5) lymphomas. The RARA sequences are the same as the RARA sequences found in the PML-RAR and PLZF-RAR fusion seen in t(15;17) and t(11;17) APL, respectively. Both NPM-RAR transcripts fuse NPM and RARA sequence in the same reading frame, to generate translation products of 57 kD and 62 kD. Both NPM-RAR proteins are expressed in the patient's leukemic cells, along with wild-type RARA derived from the uninvolved allele. In transcriptional assays using a retinoic acid response element reporter construct, both NPM-RAR fusion proteins act as retinoic acid-dependent transcriptional activators. This case defines a third class of APL rearrangements, all of which generate fusion proteins of RARA.
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Thomas, Mariam, Mahadeo A. Sukhai, Yali Xuan, Soheila A. Hamadanizadeh, Rashmi S. Goswami, Rikki R. Bharadwaj, Patricia P. Reis, and Suzanne Kamel-Reid. "Comparative Analysis of Downstream Genetic Targets of the Variant Acute Promyelocytic Leukemia Fusion Proteins NPM-RARA and NuMA-RARA." Blood 110, no. 11 (November 16, 2007): 3166. http://dx.doi.org/10.1182/blood.v110.11.3166.3166.
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Abstract Acute promyelocytic leukemia (APL) is characterized by accumulation of abnormal promyelocytes in the bone marrow and peripheral blood, and sensitivity to treatment with all-trans retinoic acid. APL cases have a balanced chromosomal translocation involving retinoic acid receptor alpha (RARA) on chromosome 17. The resulting fusion proteins (X-RARA) are aberrant transcription factors and block ATRA-induced neutrophil differentiation. Loss of RARA signalling impairs granulopoiesis, but is not sufficient to cause a leukemic phenotype. We elucidated the identities of additional signalling pathways, which can potentially cooperate with X-RARA in APL, that are commonly modulated by multiple X-RARA. We used the U-937 hematopoetic cell line retrovirally transduced with NPM-RARA (Kamel-Reid et al, 2003), and NuMA-RARA, in addition to NB4 cells (expressing PML-RARA) to determine the common genes and pathways deregulated in APL. Gene expression analysis was carried out on RNA harvested in triplicate from control and X-RARA expressing cell lines, using the Affymetrix U133Plus2 array platform. Gene expression and pathways analysis of array data was carried out using a suite of analysis tools. Array data were validated in an independent sample set by real-time quantitative PCR. We observed a total of 311 genes deregulated at least 2-fold by NuMA-RARA (192 up-regulated, 119 down-regulated), 393 genes deregulated by NPM-RARA (292 up-regulated, 101 down-regulated), and 2056 genes deregulated by PML-RARA (1097 up-regulated, 959 down-regulated). A total of 65 genes, in 5 major interaction networks, were commonly deregulated by all three X-RARA (42/65 up-regulated, 23/65 down-regulated). The majority of these genes are involved in cellular signalling (14 genes, p-value 1.57E-07–7.77E-3), transcription (13 genes, p-value 5.68E-7–3.91E-3), cell proliferation (25 genes, p-value 9.73E-7–7.77E-3), apoptosis (26 genes, p-value 9.96E-7–7.71E-3), and cell movement (17 genes, p-value 1.43E-6–7.60E-3). Genes involved in the CEBPA interaction network (GFI1, TRIB2, ELA2), as well as other genes that we anticipated to be deregulated in APL including ID1, MMP9, and JUN were found through this analysis. NF-kB (p-value 2.10E-3), AHR (p-value 2.12E-3), IL-6 (p-value 5.40E-3), and G-protein coupled receptor (p-value 7.45E-3) signalling were among the top canonical pathways determined to be altered by X-RARA. Over-expression of a number of NF-kB downstream transcriptional targets, including VEGF, IL8, MMP9, cIAP2, and TNFAIP3, were also observed in multiple X-RARA expressing cell lines. In addition, in vitro results were compared to NuMA-RARA gene targets identified in primary bone marrow cultures derived from the hCG-NuMA-RARA transgenic mouse model (Sukhai et al, 2004). We observed that pathways involved in cell signalling, cell death, gene expression, proliferation, and cell cycle were significantly deregulated in both mouse and human datasets, indicating that these pathways may be important cooperating events in APL. Our data represent the first comparison of the genetic profiles of the variant fusion proteins NPM-RARA and NuMA-RARA in a haematopoietic cell system. Our studies are a significant step in identifying key targets that cooperate with X-RARA in the development of APL.
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Won, Dahae, So Youn Shin, Chan-Jeoung Park, Seongsoo Jang, Hyun-Sook Chi, Kyoo-Hyung Lee, Jin-Ok Lee, and Eul-Ju Seo. "OBFC2A/RARA: a novel fusion gene in variant acute promyelocytic leukemia." Blood 121, no. 8 (February 21, 2013): 1432–35. http://dx.doi.org/10.1182/blood-2012-04-423129.
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Lopez, Pablo, Solange Simonet, Gerardo Romanelli, Daniela Infante, Analía Sanguinetti, Victoria V. Elizondo, Isabel Moro, et al. "PML/Rara and Rara/PML Chimeric Genes On Derivative Chromosome 17 In a Patient With Acute Promyelocytic Leukemia With Atypical t(15;17)(q11;q21)." Blood 122, no. 21 (November 15, 2013): 4960. http://dx.doi.org/10.1182/blood.v122.21.4960.4960.
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Abstract Introduction Acute promyelocytic leukemia (APL) of the WHO classification is genetically characterized by the t(15;17)(q22;q21) chromosomal translocation involving the retinoic acid receptor alpha (RARA) located on band 17q21 and the promyelocytic leukemia gene (PML) on band 15q24 , leading to the PML/RARA fusion transcript, and by sensitivity of blast cells to all-trans retinoic acid or arsenic trioxide (ATO) targeted therapy. Although the vast majority of APL cases present with t(15;17)(q24;q21), formerly (q22;q21), a few patients have either simple or complex variants of this translocation involving chromosome 15, 17 and one or more other chromosomes. Analysis of these variant translocations is of great interest because they may mask a cryptic t(15;17) leading to misdiagnose a true APL as non APL-AML with other translocations involving RARA but not PML do exist, as mentioned in the WHO classification, and generally these cases do not respond to ATRA or ATO therapy and require more intensive chemotherapy. In these cases, the PML/RARA fusion gene can be identified by molecular analyses such as reverse transcriptase-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH). Case report 29-year-old man presented with dizziness and tiredness. Physical examination: organomegaly was not observed. Peripheral blood: hemoglobin concentration, 71 g/L; platelet count, 10x109/L white blood cell count (WBC) 0.5x109/L. Bone marrow aspirate showed 56% blast cells with Auer rods. Coagulation tests were normal. Leukemic cells were CD13+, CD33+, CD34-, CD117+ and HLA-DR-. Cytogenetic analysis by G-banding performed in bone marrow metaphase cells afforded the following karyotype: 46,XY, t(15;17)(q11;q21) with derivative (der) (15) shorter and der(17) longer than in classical t(15;17)(q24;q21). PCR analysis of the PML/RAR fusion gene according to standard protocols disclosed the presence of the L isoform. FISH studies using dual color dual fusion probes (Vysis) covering the entire PML and RARA genes , showed a classical 2F1G1R (2 fusion, 1 green, 1 red) signal pattern on nuclei. However , on metaphases, we detected a normal PML (red) and RARA (green) signals on normal chromosome 15 and 17 respectively , but the two fusion signals were located on der(17). The patient was treated with IC-APL protocols (all-trans retinoic acid plus daunorubicin) and complete remission was achieved after induction therapy. Discussion To explain the origin of the observed karyotype and molecular results, especially the double fusion signal on der(17), we propose two hypotheses: a classical t(15;17)(q24;q21) initially occurred leading to one fusion gene located on each derivative accompanied or followed either by a second translocation event implicating both derivative chromosomes with breakpoints located centromeric to the former breakpoint on der(15) and telomeric to the former breakpoint on der(17), or by an insertion of part of the der(15) containing the PML/RARA fusion gene into the der(17). Results obtained through FISH analysis support our first hypotheses. No differences in the clinical outcome between APL cases with classical t(15;17) and those with variant translocations leading to PML-RARA fusion gene have been reported. These results highlight the utility of combined cytogenetic, FISH and RT-PCR analyses to unveil the cases with variant or cryptic t(15;17). To our knowledge, this is the first report of an APL patient showing a variant t(15;17) involving only chromosomes 15 and 17 with two fusion signals on der(17). Disclosures: No relevant conflicts of interest to declare.
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Kotian, Sushma R., and Kumar M. R. Bhat. "PECTORO-EPICONDYLARIS: A RARE EXTENSION OF THE PECTORALIS MAJOR MUSCLE. Pectoro-epicondilaris: Una rara extensión del músculo pectoral mayor." Revista Argentina de Anatomía Clínica 5, no. 1 (March 28, 2016): 29–32. http://dx.doi.org/10.31051/1852.8023.v5.n1.14049.
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El músculo pectoral mayor es propenso a varias incongruencias morfológicas. Diferentes deslizamien-tos musculares son comunes entre ellos. Sin embargo, durante la disección rutinaria de un cadáver masculino de 55 años por estudiantes de pregrado, se encontró una variante rara de la extensión tendinosa del músculo pectoral mayor. Surgía de la lámina profunda del tendón muscular bilaminar cerca de su inserción en el húmero. En su camino a unirse al tabique intermuscular medial del brazo y finalmente al epicóndilo medial del húmero, cruzó todas las estructuras en la parte delantera del brazo de lateral a medial. Considerando la extensión tendinosa de forma proximal, no se observó formación muscular separada. Esta variante de deslizamiento puede ser nombrada como músculo pectoral epicondilario. El conocimiento de esta variación particular puede ser de especial interés para los radiólogos y médicos en procedimien-tos tales como transformación de músculo, trasplante de tendón y uso en los colgajos miocutáneos durante cirugías reconstructivas. The pectoralis major muscle is prone to various morphological incongruities. Variant muscular slips are common among them. However during routine dissection for undergraduate students in a 55-year-old male cadaver, a rare variation of the tendinous extension of the pectoralis major muscle was found. It was arising from the deep lamina of the muscular bilaminar tendon close to its insertion to the humerus. On its way to be attached to the medial intermuscular septum of the arm and finally to the medial epicondyle of the humerus, it crossed all the structures in the front of the arm from lateral to medial. Tracing this tendinous extension slip proximally, no separate muscular extension was observed. this variant slip may be named as pectoro-epicondylaris muscle. The know-ledge of this particular variation could be of special interest to radiologists and clinicians in procedures such as muscle transformation, tendon transplantation and use of myo-cutaneous flaps during reconstructive surgeries.
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Yamamoto, Yukiya, Sachiko Tsuzuki, Motohiro Tsuzuki, Kousuke Handa, Yoko Inaguma, and Nobuhiko Emi. "BCOR as a novel fusion partner of retinoic acid receptor alpha in a t(X;17)(p11;q12) variant of acute promyelocytic leukemia." Blood 116, no. 20 (November 18, 2010): 4274–83. http://dx.doi.org/10.1182/blood-2010-01-264432.
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Abstract The majority of acute promyelocytic leukemia (APL) cases are characterized by the presence of a promyelocytic leukemia–retinoic acid receptor alpha(RARA) fusion gene. In a small subset, RARA is fused to a different partner, usually involved in regulating cell growth and differentiation. Here, we identified a novel RARA fusion transcript, BCOR-RARA, in a t(X;17)(p11;q12) variant of APL with unique morphologic features, including rectangular and round cytoplasmic inclusion bodies. Although the patient was clinically responsive to all-trans retinoic acid, several relapses occurred with standard chemotherapy and all-trans retinoic acid. BCOR is a transcriptional corepressor through the proto-oncoprotein, BCL6, recruiting histone deacetylases and polycomb repressive complex 1 components. BCOR-RARA was found to possess common features with other RARA fusion proteins. These included: (1) the same break point in RARA cDNA; (2) self-association; (3) retinoid X receptor alpha is necessary for BCOR-RARA to associate with the RARA responsive element; (4) action in a dominant-negative manner on RARA transcriptional activation; and (5) aberrant subcellular relocalization. It should be noted that there was no intact BCOR found in the 45,-Y,t(X;17)(p11;q12) APL cells because they featured only a rearranged X chromosome. These results highlight essential features of pathogenesis in APL in more detail. BCOR appears to be involved not only in human congenital diseases, but also in a human cancer.
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Singh, Manish Kumar, Mayur Parihar, Neeraj Arora, Deepak Kumar Mishra, Saurabh Jayant Bhave, and Mammen Chandy. "Diagnosis of variant RARA translocation using standard dual-color dual-fusion PML/RARA FISH probes: An illustrative report." Hematology/Oncology and Stem Cell Therapy 12, no. 1 (March 2019): 50–53. http://dx.doi.org/10.1016/j.hemonc.2016.12.003.
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Jezíšková, Ivana, Filip Rázga, Jana Gazdová, Michael Doubek, Tomáš Jurček, Zdeněk Kořístek, Jiří Mayer, and Dana Dvořáková. "A Case of a Novel PML/RARA Short Fusion Transcript with Truncated Transcription Variant 2 of the RARA Gene." Molecular Diagnosis & Therapy 14, no. 2 (April 2010): 113–17. http://dx.doi.org/10.1007/bf03256361.
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Zhu, Jiang, Shu-Hong Shen, Li-Juan Chen, Qiu-Hua Huang, Nan-Nan Zhang, Yi-Wu Sun, Stephen G. Emerson, Sai-Juan Chen, Zhu-Gang Wang, and Zhu Chen. "Deregulation of Retinoic Inducible Gene---Rig-I Underlies the Pathogenesis of Acute Promyelocytic Leukemia." Blood 106, no. 11 (November 16, 2005): 1606. http://dx.doi.org/10.1182/blood.v106.11.1606.1606.
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Abstract numerous chromosomal translocations, all of which involve the gene encoding retinoid acid receptor a (RARa), resulting in the generation of corresponding oncogenic fusion proteins including PML-RARa and PLZF- RARa (hereafter referred as to X- RARa). However, through deregulating which downstream genetic program(s) X- RARas perturb the hematopoiesis has remained unclear. Here we report that Rig-I, a putative RNA helicase, was identified in RA-induced granulocytic differentiation of APL cell line NB4 cells. Interestingly, the up-regulation of Rig-I was also realized in RA-treated freshly isolated primary APL blasts harboring PML-RARa and HL-60 cell line, but not in RA-treated NB4 variant NB4-R2 (RA refractory) and APL blasts carrying PLZF-RARa, suggesting that the induced Rig-I activity is one essential step underlying the granulocytic differentiation of myeloid leukemia cells. In line with this, the knockout mice of Rig-I produced a phenotype of profound granulocytosis with moderate differentiation blockage; and conversely the overexpression of Rig-I inhibited in vivo hematopoietic reconstitution of transduced normal primitive bone marrow cells. Most importantly, the Rig-I expression was found significantly repressed in myeloid compartment of X-RARa transgenic mice, and that the retroviral transduction of Rig-I cDNA into murine APL blasts carrying hMRP8-PML/RARa greatly decreased their leukemogenesis reconstitution ability in sublethally-irradiated syngeneic recipients. Moreover, we found that Rig-I integrity is required for the full expression of TRAIL, whose expression is critical factor in determining the pool size of myeloid cells. Such, we characterize Rig-I as a crucial negative regulator of granulopoiesis and a potential candidate for developing molecule-based target therapy of myeloid leukemia.
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Ramasamy, Chitra, and Shakthi Kumaran Ramasamy. "DOUBLE MIDDLE COLIC ARTERIES IN A FEMALE CADAVER OF ASIAN ORIGIN - A CASE REPORT. Doble arteria cólica media en un cadáver femenino de origen asiático – Presentación de un caso." Revista Argentina de Anatomía Clínica 7, no. 2 (March 28, 2016): 118–21. http://dx.doi.org/10.31051/1852.8023.v7.n2.14177.
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Tener conocimiento de las variantes en el suministro vascular del tracto gastrointestinal es esencial, sobre todo en procesos quirúrgicos de mínimamente invasivos. Se describe la rara variante de la arteria cólica media doble – arteria principal cólica media derecha de la arteria mesentérica superior y arteria accesoria cólica media izquierda del tronco celíaco en un cadáver femenino durante la disección ante estudiantes universitarios. Una arteriografía selectiva preoperatoria es importante para determinar tales anomalías antes de realizar resecciones pancreáticas electivas. Knowledge of variant vascular supply of the gastrointestinal tract is essential, especially in minimal access surgical procedures. We describe the rare variation of double middle colic arteries, the main right middle colic artery from the superior mesenteric artery and the accessory left middle colic artery from the celiac trunk in a female cadaver during dissection for undergraduate students. A pre-operative selective arteriogram is important to determine such anomalies prior to performing elective pancreatic resections
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Hiorns, LR, T. Min, GJ Swansbury, A. Zelent, MJ Dyer, and D. Catovsky. "Interstitial insertion of retinoic acid receptor-alpha gene in acute promyelocytic leukemia with normal chromosomes 15 and 17." Blood 83, no. 10 (May 15, 1994): 2946–51. http://dx.doi.org/10.1182/blood.v83.10.2946.2946.
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Abstract The translocation t(15;17)(q22;q21) is seen exclusively in patients with acute promyelocytic leukemia (APL) and in the promyelocytic blast crisis of chronic myeloid leukemia (CML). This translocation juxta- poses the promyelocytic leukemia (PML) gene on chromosome 15 and the retinoic acid receptor-alpha (RARA) gene on chromosome 17, resulting in the formation of a chimeric mRNA transcript. We describe a patient with the microgranular variant form of APL, with no detectable cytogenetic abnormality of either chromosomes 15 or 17, who nevertheless had juxtaposition of PML and RARA genes and expressed a chimeric transcript. Conventional cytogenetics showed the karyotype 46,XY,d- er(3)t(3;8)(p25;q12). Fluorescent in situ hybridization (FISH) with paints for chromosomes 8, 15, and 17 confirmed the presence of structurally intact chromosomes 15 and 17 and trisomy for chromosome 8q. Nevertheless, FISH using cosmid probes for PML and RARA showed their juxtaposition on one chromosome 15 homolog. Both genes were also present on their normal homologs; in addition, part of the RARA gene was still present on the remaining chromosome 17. DNA analysis by Southern blotting, performed with a variety of probes including PML, RARA and retinoic acid receptor-beta (RARB), showed a rearrangement in PML. Reverse transcriptase polymerase chain reaction (RT-PCR) confirmed the existence of hybrid transcripts of 276, 455 bp and 623 bp, from PML- RARA on the der(15) chromosome, consistent with alternate exon splicing of the long form of the transcript occurring in 50% to 60% of patients with APL. Our results show that APL patients with cytogenetically normal chromosomes 15 and 17 may, nevertheless, have involvement of both PML and RARA genes defining a subgroup of APL, t(15;17)- negative/PML-RARA-positive which is analogous to Philadelphia chromosome-negative/BCR-ABL-positive CML. In this case, the presence of chimeric transcripts suggests that treatment with all-trans RA may be warranted in APL, even in the absence of detectable cytogenetic change, showing the usefulness of RT-PCR or FISH to aid diagnosis.
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Lewis, Catherine, Vijay Patel, Sunil Abhyankar, Da Zhang, Rhett P. Ketterling, Rebecca F. McClure, and Diane L. Persons. "Microgranular variant of acute promyelocytic leukemia with normal conventional cytogenetics, negative PML/RARA FISH and positive PML/RARA transcripts by RT-PCR." Cancer Genetics 204, no. 9 (September 2011): 522–23. http://dx.doi.org/10.1016/j.cancergen.2011.09.001.
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Alotaibi, Ahmad S., Mustafa Abdulrazzaq, Keyur P. Patel, Farhad Ravandi, Sergej Konoplev, Carlos Bueso-Ramos, C. Cameron Yin, et al. "Acute promyelocytic leukemia (APL) with an IRF2BP2-RARA fusion transcript: an aggressive APL variant." Leukemia & Lymphoma 61, no. 12 (July 11, 2020): 3018–20. http://dx.doi.org/10.1080/10428194.2020.1791853.
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Tremblay, Mathieu, Nathalie Girard, Andre Haman, Benoit Grondin, Nathalie Bouchard, Jean Labrecque, Bing Chen, Zhu Chen, Sai-Juan Chen, and Trang Hoang. "The RARa-PLZF Oncogenic Protein Inhibits C/EBPa Function in Myeloid Cells." Blood 110, no. 11 (November 16, 2007): 1825. http://dx.doi.org/10.1182/blood.v110.11.1825.1825.
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Abstract In acute promyelocytic leukemia (APL), the variant t(15;17) translocation is responsive to differentiation therapy with retinoic acid (RA) while the t(11;17) APL is a more aggressive disease with poor prognosis. The latter produces two fusion proteins, PLZF-RARa and RARa-PLZF, and both proteins are required for leukemogenesis. To define the role of RARa-PLZF, we ectopically expressed the fusion gene in 32D cells and in primary bone marrow cells. First, our results show that RARa-PLZF inhibits myeloid gene expression, specifically CEBPa targets, which fulfill important function in cell survival and differentiation along the granulocytic lineage. Second, we found that repression by RARa-PLZF is dependent on the binding of C/EBPa to its cognate sequence in the promoter of CEBPa target gene, GCSFR. Third, we confirmed by chromatin immuprecipitation that RARa-PLZF associate with C/EBPa on DNA. Fourth, we showed that as PLZF, RARa-PLZF interact directly with HDAC1 and that this interaction causes a deacetylation of histone H3 at the promoter. This inhibition is reversed by treatment with histone deacetylase inhibitor (TSA) both in vitro and in vivo. Thus, this repression is dependent on direct interaction of RP with C/EBPa and recruitment of HDAC1, causing histone deacetylation at C/EBPa target loci. Finally, our data indicate that C/EBPa activity is severely impaired in leukemic cells from patients with t(11;17) APL, as compared to the t(15;17) APL, which is more amenable to therapy. In summary, our study indicates that the oncogene RARa-PLZF inhibits C/EBPa function through direct protein-protein interaction, and thus contributes to leukemogenesis in t(11;17) APL.
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Menezes, J., F. Acquadro, C. Perez-Pons de la Villa, F. Garcia-Sanchez, S. Alvarez, and J. C. Cigudosa. "FIP1L1/RARA with breakpoint at FIP1L1 intron 13: a variant translocation in acute promyelocytic leukemia." Haematologica 96, no. 10 (July 12, 2011): 1565–66. http://dx.doi.org/10.3324/haematol.2011.047134.
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Libura, Marta, Vahid Asnafi, Angela Tu, Eric Delabesse, Isabelle Tigaud, Florence Cymbalista, Annelise Bennaceur-Griscelli, et al. "FLT3 and MLL intragenic abnormalities in AML reflect a common category of genotoxic stress." Blood 102, no. 6 (September 15, 2003): 2198–204. http://dx.doi.org/10.1182/blood-2003-01-0162.
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Abstract MLL rearrangements in acute myeloid leukemia (AML) include translocations and intragenic abnormalities such as internal duplication and breakage induced by topoisomerase II inhibitors. In adult AML, FLT3 internal tandem duplications (ITDs) are more common in cases with MLL intragenic abnormalities (33%) than those with MLL translocation (8%). Mutation/deletion involving FLT3 D835 are found in more than 20% of cases with MLL intragenic abnormalities compared with 10% of AML with MLL translocation and 5% of adult AML with normal MLL status. Real-time quantification of FLT3 in 141 cases of AML showed that all cases with FLT3 D835 express high level transcripts, whereas FLT3-ITD AML can be divided into cases with high-level FLT3 expression, which belong essentially to the monocytic lineage, and those with relatively low-level expression, which predominantly demonstrate PML-RARA and DEK-CAN. FLT3 abnormalities in CBF leukemias with AML1-ETO or CBFβ-MYH11 were virtually restricted to cases with variant CBFβ-MYH11 fusion transcripts and/or atypical morphology. These data suggest that the FLT3 and MLL loci demonstrate similar susceptibility to agents that modify chromatin configuration, including topoisomerase II inhibitors and abnormalities involving PML and DEK, with consequent errors in DNA repair. Variant CBFβ-MYH11 fusions and bcr3 PML-RARA may also be initiated by similar mechanisms.
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Powers, Benjamin, Diane Persons, Deepthi Rao, Janet Woodroof, and Tara L. Lin. "High-Risk Microgranular Acute Promyelocytic Leukemia with a Five-Way Complex Translocation Involving PML-RARA." Case Reports in Hematology 2015 (2015): 1–3. http://dx.doi.org/10.1155/2015/343854.
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Acute promyelocytic leukemia (APL) is classically characterized by chromosomal translocation (15;17), resulting in the PML-RARA fusion protein leading to disease. Here, we present a case of a 50-year-old man who presented with signs and symptoms of acute leukemia with concern for APL. Therapy was immediately initiated with all-transretinoic acid. The morphology of his leukemic blasts was consistent with the hypogranular variant of APL. Subsequent FISH and cytogenetic analysis revealed a unique translocation involving five chromosomal regions: 9q34, 17q21, 15q24, 12q13, and 15q26.1. Molecular testing demonstrated PML/RARA fusion transcripts. Treatment with conventional chemotherapy was added and he went into a complete remission. Given his elevated white blood cell count at presentation, intrathecal chemotherapy for central nervous system prophylaxis was also given. The patient remains on maintenance therapy and remains in remission. This is the first such report of a 5-way chromosomal translocation leading to APL. Similar to APL with chromosomal translocations other than classical t(15;17) which result in the typical PML-RARA fusion, our patient responded promptly to an ATRA-containing regimen and remains in complete remission.
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Mori, Shahram, Cai Yuan, Wesam B. Ahmed, and Rushang D. Patel. "Acute Promyelocytic Leukemia with FLT3/ITD and RUNX1 Mutation Presenting As Extramedullary Soft Tissue Mass." Blood 128, no. 22 (December 2, 2016): 5185. http://dx.doi.org/10.1182/blood.v128.22.5185.5185.
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Abstract Background: APL formerly known as AML M3 is a variant of myeloid malignancies characterized by recurrent cytogenetic abnormality of PML/RARA translocation, t(15;17). Myeloid sarcoma, also called granulocytic sarcoma or chloroma, is a very rare presentation of extramedullary APL. In rare cases seen, it presents mainly as CNS disease in relapsed or refractory patients. Extramedullary APL on initial presentation is even rarer. As a result no significant information exists on the prognosis of such patients. Case report: A 50-year-old Caucasian female with no past medical history, presented with 6-month duration of chest pain, which was treated as costochondritis without any improvement. Three months later, a soft tissue mass was identified on her sternum. Complete blood count revealed pancytopenia with white blood cell 3.24 x 103/uL, hemoglobin 10.0 g/dL, platelets 58x 103/uL, absolute neutrophil count 1.13 x103/uL, and monocytes 0.13 x103/uL which indicated "low risk disease". A PET/CT scan revealed a 4.6 cm x 4 cm sternal soft tissue mass. The biopsy of the mass confirmed myeloid sarcoma. Bone marrow biopsy showed acute promyelocytic leukemia, approximately 20% blasts in a hypercellular marrow with 70-80% cellularity. Cytogenesis test was negative. FISH analysis subsequently showed a partial RARA transcript inserted at the PML locus suggestive of a cryptic PML/RARA. This was confirmed by PCR for the fusion transcript PML/RARA from the bone marrow. Next generation genome sequencing identified FLT3/ITD and RUNX1 mutation. The patient was treated as a high risk disease due to the presence of chloroma and immediately started on treatment with Daunorubicin, Arsenic Trioxide (ATO), and All-Trans-Retinoic Acid (ATRA). Conclusion: We present an extremely rare case of APL initially presenting with concomitant extramedullary sternal soft tissue mass with cryptic t(15;17) and somatic mutations in FLT/ITD as well as RUNX1 mutations. To our knowledge this is the first reported case of extramedullary APL with FLT/ITD and RUNX1 mutations. Early recognition of this rare presentation with timely chemotherapy may improve the outcomes of these patients. Disclosures No relevant conflicts of interest to declare.
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Park, Tae Sung, Seung Tae Lee, Jin Seok Kim, Jaewoo Song, Kyung-A. Lee, Sue Jung Kim, Yoon-Mi Seok, et al. "Acute promyelocytic leukemia in early pregnancy with translocation t(15;17) and variant PML/RARA fusion transcripts." Cancer Genetics and Cytogenetics 188, no. 1 (January 2009): 48–51. http://dx.doi.org/10.1016/j.cancergencyto.2008.08.012.
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Redner, R. L., L. C. Contis, F. Craig, C. Evans, M. E. Sherer, and S. Shekhter-Levin. "A novel t(3;17)(p25;q21) variant translocation of acute promyelocytic leukemia with rearrangement of the RARA locus." Leukemia 20, no. 2 (December 8, 2005): 376–79. http://dx.doi.org/10.1038/sj.leu.2404062.
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Chapiro, Elise, Eric Delabesse, Vahid Asnafi, Corinne Millien, Frederic Davi, Elizabeth Nugent, Kheira Beldjord, Torsten Haferlach, David Grimwade, and Elizabeth A. Macintyre. "Expression of T-lineage-affiliated transcripts and TCR rearrangements in acute promyelocytic leukemia: implications for the cellular target of t(15;17)." Blood 108, no. 10 (November 15, 2006): 3484–93. http://dx.doi.org/10.1182/blood-2005-09-009977.
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Abstract Acute promyelocytic leukemia (APL) is the most differentiated form of acute myeloid leukemia (AML) and has generally been considered to result from transformation of a committed myeloid progenitor. Paradoxically, APL has long been known to express the T-cell lymphoid marker, CD2. We searched for other parameters indicative of T-cell lymphoid specification in a cohort of 36 APL cases, revealing a frequent but asynchronous T-cell lymphoid program most marked in the hypogranular variant (M3v) subtype, with expression of PTCRA, sterile TCRA, and TCRG transcripts and TCRG rearrangement in association with sporadic cytoplasmic expression of CD3 or TdT proteins. Gene-expression profiling identified differentially expressed transcription factors that have been implicated in lymphopoiesis. These data carry implications for the hematopoietic progenitor targeted by the PML-RARA oncoprotein in APL and are suggestive of a different cellular origin for classic hypergranular (M3) and variant forms of the disease. They are also consistent with the existence and subsequent transformation of progenitor populations with lymphoid/myeloid potential.
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Geoffroy, Marie-Claude, and Hugues de Thé. "Classic and Variants APLs, as Viewed from a Therapy Response." Cancers 12, no. 4 (April 14, 2020): 967. http://dx.doi.org/10.3390/cancers12040967.
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Most acute promyelocytic leukemia (APL) are caused by PML-RARA, a translocation-driven fusion oncoprotein discovered three decades ago. Over the years, several other types of rare X-RARA fusions have been described, while recently, oncogenic fusion proteins involving other retinoic acid receptors (RARB or RARG) have been associated to very rare cases of acute promyelocytic leukemia. PML-RARA driven pathogenesis and the molecular basis for therapy response have been the focus of many studies, which have now converged into an integrated physio-pathological model. The latter is well supported by clinical and molecular studies on patients, making APL one of the rare hematological disorder cured by targeted therapies. Here we review recent data on APL-like diseases not driven by the PML-RARA fusion and discuss these in view of current understanding of “classic” APL pathogenesis and therapy response.
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Cheng, Chi Keung, Angela Z. Wang, Terry H. Y. Wong, Thomas S. K. Wan, Joyce S. Cheung, Radha Raghupathy, Natalie P. H. Chan, and Margaret H. L. Ng. "FNDC3B is another novel partner fused to RARA in the t(3;17)(q26;q21) variant of acute promyelocytic leukemia." Blood 129, no. 19 (May 11, 2017): 2705–9. http://dx.doi.org/10.1182/blood-2017-02-767707.
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Strehl, S., M. König, H. Boztug, B. W. Cooper, K. Suzukawa, S.-J. Zhang, H.-Y. Chen, A. Attarbaschi, and M. N. Dworzak. "All-trans retinoic acid and arsenic trioxide resistance of acute promyelocytic leukemia with the variant STAT5B-RARA fusion gene." Leukemia 27, no. 7 (December 28, 2012): 1606–10. http://dx.doi.org/10.1038/leu.2012.371.
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Kikuma, Tomoe, Yuji Nakamachi, Yoriko Noguchi, Yoko Okazaki, Daisuke Shimomura, Kimikazu Yakushijin, Katsuya Yamamoto, et al. "A new transcriptional variant and small azurophilic granules in an acute promyelocytic leukemia case with NPM1/RARA fusion gene." International Journal of Hematology 102, no. 6 (September 5, 2015): 713–18. http://dx.doi.org/10.1007/s12185-015-1857-2.
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Efiom-Ekaha, Daniel N., Jasotha Sanmugarajah, and William B. Solomon. "A Case of Relapsed Variant Acute Promyelcytic Leukemia with t(11;17)(q23q21), PLZF/RARa Fusion Gene, with Durable Molecular Remission Following an Induction and Consolidation Regimen That Included ATRA with Low Dose G-CSF and Valproic Acid as a Histone Deacetylase Inhibitor." Blood 108, no. 11 (November 16, 2006): 4584. http://dx.doi.org/10.1182/blood.v108.11.4584.4584.
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Abstract Background: Acute promyelocytic leukemia (APL) accounts for 10% of acute myeloid leukemias. Greater than 95% of cases are associated with the t(15;17)(q22;q21) translocation with the PML-RARa fusion product which is associated with increased affinity for nuclear co-repressor protein complex and recruitment of histone deacetylase. This leads to an alteration in chromatin conformation and inhibition of transcription and differentiation in promyelocytes in the presence of physiologic levels of retinoic acid. Pharmacologic doses of retinoic acid however are usually required to overcome this repression of transcription and leads to promyelocyte differentiaton and improvement in clinical outcomes in classic APL. A variant translocation in APL, t(11;17) (q23;q21) where the 3′ end of the RARa gene is fused to the 5′ end of a gene called PLZF (promyelocytic leukemia zinc finger), accounts for about 1% of cases. This disease phenotype is associated with refractoriness to pharmacologic doses of retinoic acid. Case Report; 52 year-old male presented with fever and rapidly progressive leukocytosis. His HCT was 24%, WBC count was 75,000/mcl and platelet count was 109,000/mcl. He required endotracheal intubation and mechanical ventilation with leukapharesis on his second day of admission due to leukostasis. He had been diagnosed with APL variant with t(11;17) (q23;q21) two years prior to this admission and had induction with Ara-c + daunorubicin (7+3), with an additional cycle for consolidation. He was then placed on maintenance with 6-MP + MTX for 24 months. Bone marrow and peripheral blood analysis confirmed disease relapse. Flow cytometric analysis revealed immature myeloid population CD34−, CD15−, CD13+, CD56+, HLA-DR-, with partial expression of CD33. FISH analyses on peripheral blood was negative for t(15;17) and positive for the variant t(11;17)(q23q21). He was started on induction therapy with Idarubicin 12mg/m2/day for three consecutive days with ATRA 45mg/m2/day (via NGT) + G-CSF 5mcg/kg/day. His Day 21 bone marrow examination revealed complete hematologic response. Consolidation/ maintanance with sodium valproate 500mg po BID (to maintain serum levels of 50–100mcg/ml), ATRA 45mg/m2/day (via NGT) + G-CSF 5mcg/kg/day (with G-CSF dose reductions for leukocytosis with a final stable dose of 30mcg/day). He subsequently achieved a complete cytogenetic remission and relapsed after 18 months on this regimen. Conclusion: Induction of promyelocyte differentiation and reversal of retinoic acid refractoriness in variant APL with t(11;17) (q23;q21) can be achieved with G-CSF priming and the addition of valproic acid s a HDAC inhibitor.
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Goto, Emi, Akihiro Tomita, Akihide Atsumi, Hitoshi Kiyoi, and Tomoki Naoe. "Double Genetic Mutations in PML-Rara Fusion Gene Confirmed in a Patient Showing Resistance to All-Trans Retinoic Acid and Arsenic-Trioxide Therapy." Blood 114, no. 22 (November 20, 2009): 1743. http://dx.doi.org/10.1182/blood.v114.22.1743.1743.
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Abstract Abstract 1743 Poster Board I-769 Background Molecular targeting drugs, all-trans retinoic acid (ATRA)and arsenic trioxide (ATO), have major advances in the treatment of acute promyelocytic leukemia (APL). However, resistance to these drugs has been also observed in clinical practice. ATRA acts as a ligand for retinoic acid receptor alpha (RAR) and restores the aberrant transcription repression by PML-RARA fusion protein in APL cells. Previous reports demonstrate that amino-acids substitution, resulting from genetic mutations, in ligand binding domain (LBD) of RARA region of PML-RARA were closely related to drug resistance to ATRA therapy. In contrast, for ATO therapy, the molecular mechanisms of the effectiveness and also the resistance are still unclear. Here we identified a PML-RARA that holds double genetic missense mutations in RARA and PML regions, respectively, from an APL patient, who showed clinically resistance to ATRA and ATO therapy. These mutations were observed as his disease progression, and we are interested in the relationship between these mutations with drug resistance to ATRA and/or ATO. Aims Analyses of the molecular and clinical significance of the double missense mutations of PML-RARA for disease progression and resistance to ATRA and ATO therapy. Results Eight APL patients were treated with ATO in Nagoya University Hospital, Japan, during ∼5 years from Apr. 1, 2000 to Dec. 31, 2004. One out of 8 patients showed clinically ATO resistance. The patient showing ATO resistance firstly diagnosed as APL (M3 variant) from cytogenetic and chromosomal analyses, and complete remission was obtained after combination chemotherapy with ATRA. Molecular CR was confirmed by RT-PCR analysis, but after 3 month from the induction therapy, ATRA-resistant relapse was observed. After treatment with ATO therapy, response was observed, but the effectiveness was gradually decreased, resulting finally into the resistance. The patient died of disease progression. During his 7 years clinical course, leukemia cells were harvested repeatedly from his bone marrow and peripheral blood. RT-PCR using the total RNA from his tumor cells followed by DNA sequencing was performed, with the result of PML-RARA fusion gene with the bcr3 breakpoint in the intron 3 of PML. When using the tumor cells that were harvested at his terminal stage, a missense point mutation in the LBD of the RARA region of PML-RARA was confirmed. Furthermore, missense point mutation in the PML-B2 domain was also confirmed in the same cDNA clones. Interestingly, these mutations were not observed in the leukemia cells obtained at the onset. These mutations were analyzed in each sample that was obtained as his disease progressed, and some correlation between disease progression and/or the drug resistance and the timing of appearance of these two mutations were suggested. These mutated fusion transcripts were cloned into expression vectors, and we are now analyzing the function relating to the drug resistance and disease progression. Conclusions Double genetic missense mutations in the RARA-LBD and PML-B2 of PML-RARA were confirmed in ATRA and ATO resistant patient. These genetic mutations were confirmed in the leukemia cells during his disease progression, and the relationship between those mutations and drug resistances were suggested from the clinical features. Mutations in the PML-B2 domain has not been reported previously, thus, it may be important to show whether this type of mutations are related to the drug resistance, especially to ATO therapy. Disclosures Kiyoi: Novartis Pharma Co. Ltd.: Research Funding; Kyowa Hakko Kirin Co. Ltd.: Consultancy. Naoe:Kyowa Hakko Kirin Co., Ltd. : Research Funding; Chugai Pharmaceutical Co.,Ltd.: Research Funding; Wyeth K.K.: Research Funding.
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Chauffaille, Maria de Lourdes L. F., Ana C. Ameida, Rosana M. Martinez, and Aline S. G. Silva. "Frequency and Diversity of Variant Philadelphia Chromosome In Chronic Myeloid Leukemia Patients." Blood 118, no. 21 (November 18, 2011): 4903. http://dx.doi.org/10.1182/blood.v118.21.4903.4903.
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Abstract Abstract 4903 The Philadelphia chromosome (Ph), t(9;22), is detected in around 90% of the chronic myeloid leukemia (CML) patients, but in the remaining 5–10% cases a variant type may be present. Variant Ph-chromosome is characterized by the involvement of another chromosome in addition to the 9 and 22. It can be a simple type of variant when one more chromosome is involved, or complex, in which two or more chromosomes take part in the translocation. The aim of this report is to relate the diversity of variants Ph found in CML patients at the Cytogenetic service of Fleury Lab (São Paulo, Brazil) during the past 12 years. All Ph-positive CML patients (ALL&AML were excluded) were surveyed and the variant Ph ones were listed. All the karyotype analysis were from non-stimulated short term cultures of bone marrow or peripheral blood and classified according to ISCN (1999-2009). Of the 1,071 Ph-positive cases, 967 were classic Ph, while 50 (5.17%) were variants. Regarding the variant form, 44 (88%) were simple type and 6 (12%) complex type (table 1), similar to Marzocchi et al (2011), who found 93% and 7% of each type, respectively. Some of the variant Ph translocations we detected are listed in table 1. In agreement with what Marzocchi et al reported, the most involved chromosome was the 17 (eleven times in the present report and four cases in theirs), followed in frequency by the chromosome 1 (six times), 20 (five times), 6, 11 (four times each), and 2, 10, 12 and 15 (three times each). The chromosomes not involved in the Ph translocation were: 8, 9, 18, 21, 22, X and Y (Figure 1). Among all breakpoints seen in this survey, six were repeated: 11p15, 14q32, 15q11.2, 16p13.1, 17p13 e 17q21, differing from Marzocchi et al who denied finding any recurrent breakpoint. Reid et al. (2003) listed nine recurring breakpoints in variant Ph translocations most reported by other authors, who also assert that most of breakpoints related to variant Ph occur in regions of known oncogenes or typical secondary breakpoints in other cancers. Indeed we endorse this statement, since we also found some breakpoints related to other cancers. Of the list Reid et al reported, three were found in this study as well: 12p13, 17p13 and 17q21. Some of the genes located in these regions are related to other cancers (i.e. ETV6, CD9, RARA, GAS7). However, the gene TP53, located in the region 17p13 was the only one previously reported as related to CML. Oliver M. (2007) states that this gene is involved in 20–30% of cases of blast crisis CML. Regarding the prognosis, evolution of the disease and response to the treatment, it seems that variant type of Ph translocation has no implication for survival (Marzocchi et al 2011 and Maha et al 2004. In conclusion, as we presented a large variety of variant Ph translocations, it becomes clear that there are lots of possible interactions to form variant type and most of them occur in regions already reported as oncogenes or related to cancers, indicating that there must be local phenomena favoring the predisposition to these breakpoints involvement.Table 1–Examples of variant Ph karyotypes found in this survey, showing a little of the diversity of interaction.Karyotype46,XY,t(1;9;22;16)(q32;q34.1;q11.2;p13)[2]/46,XY46,XX,t(9;22;1;13)(q34.1;q11.2;p12;q34)[17]/46,XX[3]46,XY,t(9;22;1;?3)(q34.1;q11.2;q36.3;?q26)[20]46,XX,t(1;9;22;14)(p21;q34.1;q11.2;q32)[20]46,XY,t(9;22;2)(q34.1;q11.2;q24)[8]/46,XY[12]46,XY,t(9;22;4)(q34.1;q11.2;p16)[20]46,XY,t(9;22;5)(q34.1;q11.2;p13)[20]46,XY,t(9;22;6)(q34.1;q11.2;q22)46,XX,t(9;22;7)(q34.1;q11.2;p22)[20]46,XY,t?(9;22;10;11)(q34.1;q11.2;q22;q25)[20]46,XY,t(9;22;12)(q34.1;q11.2;p13)[20]46,XY,t(9;22;14)(q34.1;q11.2;q32)[19]/46,XY[1]46,XY,t(9;22;15)(q34.1;q11.2;q11.2)[20]46,XX,t?(9;22;16)(q34.1;q11.2;p13.3)[20]46,XY,t(9;22;17)(q34.1;q11.2;p13)[20]46,XY,t(9;22;19)(q34.1;q11.2;q11.2)[20]46,XY,t(1;7)(p22;q22),t(9;22;20)(q34.1;q11;q11.2)[2]/46,XY[18]Figure 1– Distribution of chromosomes involved in variant Ph translocation, according to the chromosome region (p arm or q arm).Figure 1. – Distribution of chromosomes involved in variant Ph translocation, according to the chromosome region (p arm or q arm). Disclosures: No relevant conflicts of interest to declare.
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Gruver, Aaron M., Heesun J. Rogers, James R. Cook, Blake C. Ballif, Roger A. Schultz, Jacqueline R. Batanian, Mark J. Fesler, and Raymond R. Tubbs. "Modified Array-based Comparative Genomic Hybridization Detects Cryptic and Variant PML-RARA Rearrangements in Acute Promyelocytic Leukemia Lacking Classic Translocations." Diagnostic Molecular Pathology 22, no. 1 (March 2013): 10–21. http://dx.doi.org/10.1097/pdm.0b013e31825b8326.
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Bally, Cecile, Jacqueline Lehmann-Che, Bruno Cassinat, Lionel Ades, Eric Letouze, Pierre Hirsch, Marie-Joelle Mozziconacci, et al. "Whole Exome Analysis of Relapsing Patients with Acute Promyelocytic Leukemia." Blood 128, no. 22 (December 2, 2016): 2892. http://dx.doi.org/10.1182/blood.v128.22.2892.2892.
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Abstract Background : APL is, in the vast majority of cases, driven by t(15 ;17) translocation, which leads to PML/RARA rearrangement. Remarkably, APL is an uncommon genetically simple disease and only few additional alterations, cooperating with PML/RAR, have been described at diagnostic (Welch et al, Cell 2012). Most APL can be cured with targeted therapy combining all-trans retinoic acid (ATRA) and chemotherapy (CT). However, genetic mechanisms underlying the 10-15% relapses observed with this regimen remain unclear. The goal of the present study was to identify mutations that cooperate with PML/RAR and those responsible for acquired resistance to ATRA-CT treatment in APL patients by whole-exome sequencing of diagnostic/ remission/relapse trios. Methods: Newly diagnosed APL patients included in clinical trials of the French Swiss Belgian APL group between 1994 and 2008, treated with ATRA-CT, before the introduction of first-line ATO, who experienced at least one relapse and had adequate material, were studied. We collected retrospectively 64 samples from 23 patients, including 23 diagnostic samples, 18 at first complete remission (CR) and 23 at relapse (22 first relapse and 1 second relapse). Whole exome-sequencing was performed on all samples. DNA libraries were prepared with the SureSelect human v5 kit (Agilent) and sequenced on Hiseq1000 (Illumina). The bioinformatic analysis was performed by GECO/integragen using CASAVA variant calling (Illumina) and dedicated pipeline. 18 trios and 5 duos passed the stringent quality control and were analyzed for somatic variants and copy number variations (CNV). Results : After elimination of polymorphisms, the median number of somatic variants corresponding to de novo mutation at diagnosis was 14, while only 3 new somatic variants appeared at relapse (figure 1). Notably, we failed to detect oncogene alterations other than PML/RARA in 7/23 (30%) patients. At diagnostic, 39% of patients (9/23) presented the common FLT3 alterations and at relapse 22% (5/23) of patients presented the known RARA mutations. Moreover, recurrent alterations were observed in activators of the MAPK signaling (22%): NRAS (2 patients), BRAF (1 patient), KRAS (1 patient), SPRY1 (1 patient). Mutations in the NT5C2 gene (3 patients), coding a 5'nucleotidase implicated in resistance to nucleoside-analog therapy, were solely observed at relapse, as in acute lymphoblastic leukemia (ALL). Abnormalities of epigenetic regulators were also detected at diagnostic and/or relapse: WT1 (7 patients, 30%), NSD1 (2 patients), TET2 (1 patient), ASXL1 (1 patient) and MED12 (2 patients). Homozygote WT1 inactivation by mutation plus neutral copy LOH occurred in 3 patients at relapse. The genetic markers identified allowed us to construct several evolution models. In 8 patients (35%), the diagnostic and relapse clones were clearly distinct, supporting the fact that they independently derived from pre-leukemic cells that survived ATRA/chemotherapy. In contrast, other relapses appeared to derive from the diagnostic clone. Conclusion: Our data highlight the genetic simplicity of APL with very few alterations detected and 30% patients without identified mutations in addition to PML/RARa. Our results support the existence of two prototypic mechanisms of relapse: re-emergence of a new APL from persisting pre-leukemic cells and relapse from APLs often expressing strong oncogenes at diagnosis, impeding therapy response and favoring the acquisition of resistance mutations at relapse, including PML/RARA or NT5C2. It will be interesting to assess the prevalence of those two mechanisms in the exceptional cases of relapse in patients treated with more recent frontline regimens that combine ATRA and arsenic in APL. Disclosures Ades: Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding.
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Stavropoulou, Chryssa, Vasileios N. Georgakakos, Kalliopi N. Manola, Maria Pagoni, Maria Garofalaki, Gabriel E. Pantelias, and Constantina Sambani. "5′ RARA submicroscopic deletion from new variant translocation involving chromosomes 15, 17, and 18, in a case of acute promyelocytic leukemia." Cancer Genetics and Cytogenetics 182, no. 1 (April 2008): 50–55. http://dx.doi.org/10.1016/j.cancergencyto.2007.12.011.
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Kikuma, Tomoe, Yuji Nakamachi, Yoriko Noguchi, Yoko Okazaki, Daiki Shimomura, Kimikazu Yakushijin, Katsuya Yamamoto, et al. "Erratum to: A new transcriptional variant and small azurophilic granules in an acute promyelocytic leukemia case with NPM1/RARA fusion gene." International Journal of Hematology 102, no. 5 (September 29, 2015): 643. http://dx.doi.org/10.1007/s12185-015-1868-z.
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Redner, Robert L., Anuja Chattopadhyay, Brian L. Hood, and Thomas P. Conrads. "NPM-RAR Binds to Tradd and Impedes the Extrinsic Apoptotic Pathway." Blood 120, no. 21 (November 16, 2012): 5126. http://dx.doi.org/10.1182/blood.v120.21.5126.5126.
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Abstract Abstract 5126 The t(5;17)(q35;q21) variant of Acute Promyelocytic Leukemia fuses nucleophosmin (NPM) to the retinoic acid receptor alpha (RARA). The resultant NPM-RAR fusion protein blocks myeloid differentiation, and leads to a leukemic phenotype similar to that caused by the t(15;17)(q22;q21) PML-RAR fusion. The contribution of the N-terminal 117 amino acids of NPM contained within NPM-RAR has not been well studied. NPM is a molecular chaperone, and binds to a variety of proteins implicated in leukemogenesis. We performed a proteomic analysis to identify NPM-RAR interacting proteins. Vectors encoding NPM-RAR or RARA (as control) fused in frame to calmodulin binding peptide and Protein A were expressed in HEK293 cells, and interacting proteins subjected to tryptic digest. Peptides were analyzed by nanoflow reversed-phase liquid chromatography-mass spectrometry. Amongst other targets, we identified tumor necrosis factor receptor type 1-associated DEATH domain protein (TRADD) as a distinct binding partner for NPM-RAR. TRADD did not bind to wild-type RARA or NPM, suggesting that the interaction was unique to the fusion protein. The NPM-RAR/TRADD interaction was verified by reciprocal co-precipitation. Though NPM-RAR localizes primarily in the nucleoplasm, we also found a low level of NPM-RAR/TRADD dimer in the cytoplasm utilizing confocal microscopy. Expression of NPM-RAR in U937 cells impaired TNF activation of caspase 8 and caspase 3. TNF-induced acquisition of Annexin V, generation of sub-G0/G1 nuclear content, and cleavage of PARP were all blunted, indicating that NPM-RAR blocks TNF-induced apoptosis. Our studies identify a novel mechanism through which NPM-RAR impacts leukemogenesis. Disclosures: No relevant conflicts of interest to declare.
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Arteaga, Maria Francisca, Jan-Henrik Mikesch, and Chi Wai Eric So. "Discovery of Critical Functions of Histone Demethylase, PHF8, in Mediating ATRA Response in APL." Blood 118, no. 21 (November 18, 2011): 226. http://dx.doi.org/10.1182/blood.v118.21.226.226.
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Abstract Abstract 226 Introduction: Transcription deregulation plays a key role in acute leukemogenesis, which is mostly initiated by chimeric transcription factors such as PML–RARa that accounts for almost 100% of acute promyelocytic leukemia (APL). While APL is uniquely sensitive to all trans retinoic acid (ATRA) treatment and has been the paradigm of differentiation/epigenetic therapies, the underlying mechanisms remain largely unknown and are major interests in the field with a potential of extending the success to other hematological malignancies. Previously, others and we have shown that aberrant recruitment of histone deacetylases and polycomb repressive complexes by oligomeric PML-RARa are key for suppression of its downstream targets and promote cellular transformation. ATRA treatment disrupts their bindings and results in de-repression of target genes. However, the identification of the co-activator complex responsible for gene activation upon ATRA treatment remains a major hurdle that significantly hinders the progress of understanding mechanisms underlying the epigenetic therapy. Results and Discussion: Given the critical functions of JmjC-domains containing histone demethylases in mediating transcriptional regulation, we performed a systematic screening for differential interaction between JmjC-histone demethylases and PML–RARa upon ATRA treatment. We identified a highly specific interaction between PML–RARa and Plant Homeodomain Finger 8 (PHF8). To assess its effect on histone methylation, we detected specific reduction of H3K9me2 and enhancement of H3K4me3 in PHF8 transfected cells, consistent with its function as a transcriptional activator. This was further supported by results from chromatin immuno-precipitation (ChIP) assays in human APL cell line (NB4) showing that PHF8 differentially bound and mediated the same histone modifications in RARb promoter and activated its expression. To investigate the functional significance of this interaction, PHF8 was expressed in human NB4 cells harboring PML-RARa or murine primary bone marrow cells transformed by APL fusion proteins. Induction of PHF8 expression significantly decreased their in vitro transformation capacity in the presence of physiological concentrations of ATRA. Conversely, specific down-modulation of PHF8 expression by shRNAs reduced ATRA sensitivity of these cells, suggesting a critical function of PHF8 in mediating ATRA response. We hypothesized that PHF8 may be able to sensitize ATRA resistant cells to the treatment. Hence, we induced expression of PHF8 in the ATRA resistant variant of NB4 line, NB4-MR2. We were able to demonstrate that PHF8 sensitized NB4-MR2 cells to ATRA treatment in vitro. In contrast, NB4-MR2 cells expressing PHF8-F279S, a catalytically inactive mutant could not be sensitized to ATRA treatment, indicating that the enzymatic activity is critical for mediating the ATRA response. Most importantly, NB4-MR2 cells expressing wild type PHF8 were also sensitive to ATRA treatment in vivo and failed to induce leukemia in NOD/SCID mice, which would otherwise succumb to leukemia in a very brief latency. To gain further insights into the molecular regulation of PHF8 in ATRA response, we characterized the potential functions of CDK1-mediated phosphorylation of PHF8. It is known that in ATRA treated leukemic cells Cyclin A translocates into the nucleus where it interacts with CDK1. Activated CDK1 induces phosphorylation of PHF8 at two serine (S33)/ threonine (T84) phosphorylation sites. Our results showed that PHF8 in its phosphorylated form had a much higher binding affinity to PML-RARa. Consistently, ChIP analyses revealed that the binding of PHF8 to the RARb promoter and the resultant activation were significantly augmented when PHF8 was constitutively phosphorylated. Moreover, inhibition of PHF8 dephosphorylation by Okadaic Acid, sensitized NB4-MR2 cells to ATRA treatment. Conclusions: We discovered a novel function of the histone demethylase PHF8 in mediating therapeutic response in both ATRA sensitive and ATRA resistant cells. This function of PHF8 is critically dependent on two phosphorylation sites as well as its histone modification activity. Thus, therapeutic interventions such as phosphatase inhibitors that enhance the PHF8 activity might become useful tools for development of new epigenetic therapies sensitizing leukemic cells to ATRA treatment. Disclosures: No relevant conflicts of interest to declare.
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Fujishima, Masumi, Naoto Takahashi, Ikuo Miura, Yoshimi Kobayashi, Masaaki Kume, Tamio Nishinari, and Akira B. Miura. "A PML/RARA Chimeric Gene on Chromosome 2 in a Patient with Acute Promyelocytic Leukemia (M3) Associated with a New Variant Translocation." Cancer Genetics and Cytogenetics 120, no. 1 (July 2000): 80–82. http://dx.doi.org/10.1016/s0165-4608(99)00238-1.
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Pamidi, Narendra, Srinivasa Rao Sirasanagandla, Satheesha Nayak B, and Raghu Jetti. "VARIANT POSITION OF THE GALLBLADDER ASSOCIATED WITH ABNORMAL PERITONEAL FOLD AROUND IT. Variantes en la posición de la vesícula biliar asociada con un pliegue peritoneal anormal a su alrededor." Revista Argentina de Anatomía Clínica 4, no. 2 (March 28, 2016): 70–73. http://dx.doi.org/10.31051/1852.8023.v4.n2.14024.
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Los pliegues peritoneales anómalos alrededor de la vesícula biliar son muy raros y pocos fueron reportados en el pasado. La presencia de tales pliegues peritoneales son probablemente debidos a la extensión del mesenterio ventral que forma el omento menor. En el caso presente, reportamos un pliegue peritoneal anómalo suspendiendo la vesícula biliar desde la superficie inferior del hígado, a lo largo de la margen izquierda de la fosa para la vesícula biliar. Este pliegue, cuando se trazó cuidadosamente, se continuaba con el colon transverso, mesocolon transverso y también se encontró fusionado con la segunda porción del duodeno. La vesícula biliar con inusuales pliegues peritoneales tiene tendencia a vólvulo, una rara enfermedad que exige la intervención quirúrgica inmediata. El conocimiento de la posibilidad de tal anomalía peritoneal alrededor de la vesícula biliar facilita la interpretación de los hallazgos de la imagen para el diagnostico apropiado. Anomalous peritoneal folds around the gallbladder are very rare and a few were reported in the past. The presence of such peritoneal folds is probably due to extension of the ventral mesentery which forms the lesser omentum. In the present case we report anomalous peritoneal fold suspending the gall bladder from the undersurface of the liver, along the left margin of the fossa for gallbladder. This fold, when traced carefully, became continuous with transverse colon, transverse mesocolon and also found to be merged with the second part of duodenum. The gallbladder with unusual peritoneal folds has a tendency to volvulus, a rare surgical disease which demands the immediate surgical intervention. Awareness of the possibility of such peritoneal anomaly around gallbladder facilitates the interpretation of image findings for proper diagnosis.
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Schnittger, Susanne, Claudia Haferlach, Tamara Alpermann, Wolfgang Kern, and Torsten Haferlach. "Impact of FLT3 Mutation Status and Other Genetic Parameters In Acute Promyelocytic Leukemia (APL) with t(15;17)(q22;q12)/PML-RARA." Blood 116, no. 21 (November 19, 2010): 1685. http://dx.doi.org/10.1182/blood.v116.21.1685.1685.
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Abstract Abstract 1685 Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12)/PML-RARA displays the most favourable entity among the different subtypes of acute myeloid leukemia with a five year overall survival (OS) of more than 80%. However, around 10–20% still experience relapse. In order to find pretreatment parameters that may be predictive for outcome in APL, we have comprehensively analyzed 147 PML-RARA-positive patients (pts) at diagnosis. All pts were treated with ATRA in addition to standard chemotherapy. Patients were selected according to availability of cytogenetics, FLT3-ITD mutational status and FLT3-TKD mutational status. The cohort was comprized of 85 males and 62 females. Median white blood cell count (WBC) was 1,8×109/L (range: 0.2–183.4 × 109/L), median platelet count was 30.0 (range: 1.0–228.0 × 109/L) and median hemoglobin level (Hb) was 9.7 (range: 3.6–16.4 g/dL). In 115 pts bone marrow smears were available: 68 were classified as M3 and 47 as M3v (FAB criteria). According to PML-RARA fusion type 89 pts had a bcr1 (long variant), 52 a bcr3 (short variant) and 6 a bcr2 (exon6) breakpoint. Diagnostic %PML-RARA/ABL1 transcript levels were heterogeneously distributed ranging from 0.6 to 96.7 (median: 18.5). In 57/147 pts (38.8%) additional cytogenetic aberrations (ACA) were detected (+8/+8q: n=26, i(17q): n=11, 9q-: n=3, complex: n=2, all others: n=15). A FLT3-ITD was detected in 47 pts (32.0%) and a FLT3-TKD mutation in 19 pts (12.9%). Thus, a total of 65 pts (44.2%) had a mutated FLT3 status (one case revealed both ITD and TKD mutations). FLT3-ITD was highly associated with bcr3 breakpoints (32 FLT3-ITD vs. 20 FLT3wt compared to 14 FLT3-ITD vs 75 FLT3wt in bcr1 and 1 FLT3-ITD vs. 5 FLT3wt in bcr2; p<0.001). Furthermore, FLT3-ITD was associated with higher WBC (mean: 33,153 compared to 5,170 × 109/L in FLT3wt pts, p<0.001) and a lower platelet count (mean: 30,351 vs. 63,324 × 109/L in FLT3wt pts, p=0.001). All parameters mentioned above were analyzed for a possible impact on OS and EFS. Median follow up time of this cohort was 16 months. OS was significantly better in males (2 year OS: 94.2% vs. 78.5% in females; p=0.038). Age as a continuous variable was found significantly related to both OS and EFS (p=0.002, each). Overall, the presence of ACAs had no impact on OS or EFS. In a next step the different ACAs as defined above were evaluated separately. The only group with significantly shorter OS and EFS was the one including the non recurrent “other” ACAs (2 years OS/EFS: 63.6% each, compared to 87.5%/81.4% in the remaining 5 cytogenetic groups, p=0.014/p=0.040). Importantly, these differences exclusively are due to four early deaths in this “other non recurrent” group. No significant effect on OS or EFS was found for WBC, Hb, platelet count, M3/M3v, PML-RARA breakpoint, diagnostic %PML-RARA/ABL1 transcript levels as well as FLT3-ITD, FLT3-TKD or combined FLT3-ITD/TKD status. However, when the FLT3-ITD/wildtype ratio was taken into account a significantly worse EFS was found for those with a FLT3-ITD/wildtype ratio >0.5 (n=21; 2 years EFS: 61.2% vs. 83.5% in the combined group with FLT3wt or FLT3-ITD/wildtype ratio < 0.5, p=0.009). Parameters with significant impact in univariate analysis were included into the multivariate analyses. For OS this was performed for gender, age and “other non recurrent ACA”. All three parameters were proven independent prognostic factors (p=0.026, RR: 0.24; p=0.004, RR: 1.44/decade; and p=0.013, RR: 4.32, respectively). For EFS age, FLT3-ITD/wildtype ratio >0.5, and “other non recurrent ACA” were analyzed (p=0.003, RR: 1.41/decade; p=0.077, RR: 2.73, and p=0.049, RR: 2.46, respectively). In conclusion, specific treatment in APL is extremely efficient what results in minor prognostic impact of otherwise established pretreatment parameters like WBC count, additional cytogenetic aberrations and mutated FLT3 status. Age is the strongest prognostic factor for OS and EFS. Non-recurrent ACAs are associated with an inferior OS. Most importantly, FLT3-ITD mutations with high allelic burden of more than 0.5 are associated with a shorter EFS. This data should be confirmed in controlled prospective studies to draw final conclusions for clinical decision making. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership, Research Funding. Alpermann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
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Chapiro, Elise, Vahid Asnafi, Eric Delabesse, Frédéric Davi, Elizabeth Nugent, Françoise Valensi, Khiera Beldjord, David Grimwade, and Elizabeth A. Macintyre. "Expression of T-Lineage Affiliated Transcripts and TCR Rearrangements in Hypogranular Variant Acute Promyelocytic Leukemia (APL): Implications for the Cellular Target of the t(15;17)." Blood 104, no. 11 (November 16, 2004): 574. http://dx.doi.org/10.1182/blood.v104.11.574.574.
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Abstract APL is generally considered to be the most differentiated subtype of acute myeloid leukemia (AML) and to derive from late myeloid-restricted progenitors. This is, however, difficult to reconcile with the observation that approximately 25% of APL cases, particularly those with the hypogranular variant (M3v) form, express the T-lineage affiliated marker, CD2. To gain further insight into the extent of T-lineage deregulation in primary APL blasts and its implications for the likely target progenitor for the t(15;17), we quantified the expression of pre-Tα(pTα), T earlyα(TEA) and RAG1 transcripts by RQ-PCR (expressed as ΔCt ABL-target, whereby ΔCt =−2 is approximately 3 log higher than ΔCt =−12) and determined TCRδ and γ status in 36 cases of PML-RARA positive APL, including 21 classical hypergranular (M3) and 15 M3v forms. pTαforms part of the pre-TCR necessary for TCRαβ lineage differentiation and TEA represents a sterile transcript involved in the early stages of TCRαrearrangement. 107 T-ALLs 15 M3v 21 M3 14 M0/1/2 12 M4/5 Mean ΔCt pTα −2.1 −2.38 −4.64 −5.7 −12.23 Mean ΔCt TEA −3.21 (34 pt) −3.55 −6.58 −5.23 −6.95 TCR rearrangement NA 4/15 (27%) 1/17 (6%) 0/12 1/8 Both classical and M3v APL expressed pTαat higher levels compared to 26 non-APL AML (p<0.001), with the levels in M3v being similar to those found in T-ALL. Amongst control AMLs, pTαlevels were lower (p<0.001) in FAB M4/5 AML compared to FAB M0/1/2 AML, which were not different from pTαlevels in classical APL (p=0.31). Unlike T-ALL, in which pTαand RAG1 expression cosegregate, M3v and classical APL did not express RAG1 transcripts. However, TEA was expressed at significantly higher levels in M3v APL compared to classical APL (p<0.001) and non-APL AML (p=0.002). TCR γ and δ rearrangements tended to be more common in M3v as compared with classical APL (p=0.11); moreover, expression of cytoplasmic CD3 (2/12) and TdT (3/13) were also restricted to these cases (0/3 and 0/5 in classical APL). Only M3v morphology and CD34 expression correlated with higher levels of pTαexpression amongst APL. Notably, CD2 expression, known to correlate with M3v APL, including in this series, did not. These data demonstrate that M3v APL blasts exhibit several features suggestive of early T-lymphoid orientation which may reflect the progenitor subject to leukemic transformation. They suggest that the PML-RARA fusion gene may arise in more primitive hematopoietic stem cells in M3v than previously thought to be the case and that the biological differences between classical and hypogranular variant forms of the disease may in part reflect differing cellular origins. Moreover these data are consistent with the existence of bipotent myeloid/T-lymphoid progenitors recently proposed by Katsura and colleagues and which could be the progenitor population subject to leukemic transformation in the hypogranular variant form of APL.
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Bahr Ulloa, Sandra, and Katia Guisado Zamora. "TRIPLICIDAD DE ARTERIAS RENALES DERECHAS CON DUPLICIDAD DE IZQUIERDAS: REPORTE DE CASO. Triplicity of right renal arteries and duplicity of left ones: Case report." Revista Argentina de Anatomía Clínica 11, no. 1 (March 24, 2019): 30–36. http://dx.doi.org/10.31051/1852.8023.v11.n1.22011.
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Durante la embriogénesis renal, ocurren fenómenos en su desarrollo que, de persistir en el adulto, se describen como variantes anatómicas. La presencia de arterias renales supernumerarias es una de variantes más frecuentes, pero la triplicidad de estas es rara. Este trabajo tiene como objetivo reportar un caso de arterias renales supernumerarias derechas e izquierdas. El hallazgo se produjo durante una sesión de disección en los laboratorios docentes de anatomía humana de la universidad. El caso consiste en un bloque anatómico de cadáver femenino del cual se aisló el segmento urogenital. El mismo fue disecado en fresco por el método macroscópico directo y luego conservado en formol por el método de Thiel durante 10 días, para luego ser examinado y fotografiado. El bloque consta de dos riñones, derecho e izquierdo, con sus vasos arteriales y venosos unidos a la arteria aorta abdominal y vena cava inferior respectivamente. Las arterias renales halladas fueron cinco, mostrando una triplicidad de arterias renales derechas con duplicidad de izquierdas. Las arterias renales derechas presentan similar calibre y dos de sus ramas son arterias polares superiores, en el caso de las arterias izquierdas la superior presentó mayor calibre. Asociada a esta variante se encontró la vena renal izquierda en posición posterior a la arteria renal inferior izquierda. Es importante para la práctica médica conocer las posibles variantes vasculares renales que pueden presentarse, para efectuar correctos procedimientos diagnósticos radiológicos, así como las planificaciones preoperatorias adecuadas de intervenciones quirúrgicas. During renal embryogenesis, phenomena occur in its development that, if persist in adult age, will be described as anatomical variant. The presence of supernumerary renal arteries is one of the most frequent variants, but the triplicity of these is rare. The objective of this work is to report a case of right and left supernumerary renal arteries. This finding appeared during a dissection session at the university's laboratory of human anatomy. The report case consists on an anatomical block of a female cadaver from which the urogenital piece was isolated. It was dissected fresh by the direct macroscopic method and then preserved in formaldehyde by the Thiel’s method for 10 days, to be examined and photographed. The block consisted on two kidneys, right and left, with their arterial and venous vessels attached to the abdominal aorta and inferior vena cava respectively. After the initial examination, five renal arteries were found, including a triplicity of right renal arteries and duplicity of left one. The right renal arteries have a similar caliber, with two branches as superior polar arteries. In regard to the left arteries, the superior artery presented greater caliber. Associated to these variants, left renal vein was in a posterior position in relation to the artery. It is important for medical practice to know the possible renal vascular variants that may occur, to carry out correct radiological diagnostic procedures and to adequately plan preoperative surgical interventions.
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Schnittger, Susanne, Tobias M. Kohl, Nina Leopold, Claudia Schoch, Wolfgang Kern, Peter Lohse, Wolfgang Hiddemann, Torsten Haferlach, and Karsten Spiekermann. "The FLT3-D324N Variant Is a Functionally Silent Polymorphism in the FLT3 Gene and May Be Associated with a Higher Risk for AML." Blood 104, no. 11 (November 16, 2004): 3373. http://dx.doi.org/10.1182/blood.v104.11.3373.3373.
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Abstract Mutations within the FLT3-gene are of growing importance for classification, risk assessment and therapeutic targeting in acute myeloid leukemia (AML). An increasing number of activating mutations have been reported during the last few years. A D324N variant located in the extracellular region of the FLT3 protein has been described recently in 4/94 (4.3%) of AML patients (Ley TJ et al., PNAS 2003). We have analyzed 705 de novo AML for D324N using a LightCycler based screening assay and found a gac to aac change in codon 324 in 43 cases (6.1%). This is approximately the same frequency that has been described for tyrosine kinase domain mutations in FLT3. However, in contrast to other FLT3 mutations the D324N was associated with a low leucocyte count (6.700/μl) and had no association to any AML subtype nor a prognostic impact regarding overall survival and event free survival (235 D324N- cases vs. 13 D324+ cases with normal karyotype analyzed). To analyze whether this FLT3 variant might be a polymorphism we analyzed peripheral blood of 329 healthy donors with a similar ethnic background. In this population we could also detect the D324N variant, but only in 4 cases (1.2%). This difference between AML and healthy donors was statistically significant (p=.0001). Three of the cases were heterozygous and one was homozygous for the D324N variant. Of one of the heterozygous cases a buccal smear was evaluated and the same heterozygous pattern could be detected in this material. In addition, of three D324N positive AML at diagnosis a sample from any time point in CCR was available that was negative for the leukemia clone with a sensitivity of 10−4 to 10−6 as assessed by quantitative PML-RARA- (1 case) or CBFB-MYH11- (1 case) specific PCR or by immunophenotyping (1 case). In these remission samples again a 50% ratio of the normal and the D324N variant was detectable. To functionally characterize the FLT3-D324N in vitro, FLT3-WT, FLT3-D324N, and FLT3-ITD cDNA were retrovirally transduced into IL-3 dependent Ba/F3 cells. Stably expressing cell lines were grown for 72h in the absence of IL-3 with varying doses of human FLT3 ligand (FL) and the number of viable cells was assessed by trypan blue exclusion. In contrast to FLT3-ITD expressing cells, FLT3-D324N transduced cells were not able to grow in the absence of IL-3. The growth of FLT3-WT and FLT3-D324N, but not vector expressing cell lines could be stimulated by exogenous FL in a dose-dependent manner. No significant difference could be demonstrated between FLT3-WT and FLT3-D324N cells. In apoptosis assays using annexin-V-PE and 7-AAD staining FL stimulation protected both D324N mutant and FLT3-WT expressing Ba/F3 cells from apoptotic cell death to a similar degree. These results strongly support the hypothesis that the D324N variant in the FLT3 gene represents a functionally silent polymorphism. The fivefold higher frequency in patients with AML compared to healthy donors raises the question whether this FLT3 variant is associated with a higher risk for AML.
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Castelli, Roberto, Valentina Rossi, Matteo Giovanni della Porta, Riccardo Schiavon, Marco Barchiesi, Laura Cicconi, and Francesco Lo Coco. "Clinical characteristics and treatment outcome of an 86-year-old patient with acute myeloid leukaemia with acute promyelocytic-like morphology and uncommon RARA fusion variant." Annals of Hematology 97, no. 12 (June 5, 2018): 2523–25. http://dx.doi.org/10.1007/s00277-018-3377-7.
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