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Acute Myeloid Leukemia Milan, Italy, June 12 – 15, 2014 were associated with overexpression by RQ-PCR. High levels of PRDM16 Acute myeloid leukemia - Biology 3 expression (greater that three standard deviations above the mean 2- ΔΔ Ct of 10 normal bone marrow controls) were observed in a significant subset of AML with normal karyotype (AML-NK) (12/25;48%) and with adverse cytogenetic P779 prognostic group (3/11;27.3%) but they were also associated with isolated rare translocations (4/10;40%). In 3 cases with a complex karyotype FISH analysis DECREASE EXPRESSION OF MIR-20A PROMOTES CANCER CELL detected an extra copy of PRDM16. Cases with gene amplification were PROLIFERATION AND PREDICTS POOR SURVIVAL OF ACUTE MYELOID associated with older age, complex karyotype involving chromosome 5 and 7 LEUKEMIA 1 1 1 1,* 1 1 1 1 abnormalities, higher WBC and AML compared to cases with PRDM16 P Li , D Ning , X Dahai , Z Nan , L Xiaoliang , W Yang , Z Xiuxian , C Hongli translocations. 1Emergency Department, First Hospital of Jilin University, changchun, China Summary and Conclusion: PRDM16 gene is a frequent target of 1p36 abnormalities in AML. Copy number gain of PRDM16 is a recurrent genetic Background: MicroRNAs (miRNAs) are a family of 19- to 25-nucleotides non- abnormality in AML with 1p36 abnormalities and, although less common, in coding small RNAs that primarily function as gene regulators. Growing AML with complex karyotype but undetectable 1p36 abnormalities. Copy evidences indicate miRNAs play important roles in cancer development, number gain of chromosome 1p36 has not been previously associated with progression, metastasis and may constitute robust biomarkers for cancer PRDM16 overexpression in patients with myeloid malignancies. We also prognosis. To date, although certain miRNAs have been established a clear demonstrated overexpression of PRDM16 in different subgroups of AML without oncogenic role in hematological malignancies, other individual miRNAs PRDM16 rearrangements or amplification, especially in AML-NK subset. Since potentially involved in human leukemogenesis still remain elusive. the poor prognosis associated to PRDM16, the role and prevalence of PRDM16 Aims: This study aimed to determine the clinical characteristics and prognostic expression should be addressed further in a larger cohort of patient. Although significance of microRNA-20a (miR-20a) in adult de novo acute myeloid the limited case series, amplification seems to be associated with distinct leukemia (AML) patients. cytogenetic and clinical features and could reflect a different pathway or role of Methods: The expression levels of miR-20a in bone marrow mononuclear cells PRDM16 in the pathogenesis of these AML patients. Supported by University were measured in 98 newly diagnosed AML patients and 20 cases of normal of Bologna RFO, BolognAil and Coop Reno. healthy donors by real-time quantitative polymerase chain reaction. Kaplan- Meier and Cox proportional regression analyses were utilized to determine the association of miR-20a with survival of patients. The potential functions of miR- P781 20a on proliferation were evaluated by proliferation and flow cytometry analysis. The direct target gene of miR-20a was also identified by luciferase reporter CHARACTERIZATION OF THE RARE TRANSLOCATION T(3;10)(Q26;Q21) assays. IN AN ACUTE MYELOID LEUKEMIA PATIENT Results: miR-20a was expressed at significantly lower levels in the bone T Jancuskova 1,* , R Plachy 1, J Stika 1, D W Hardekopf 1, L Zejskova 1, I Praulich 2, marrow of AML patients compared with normal controls. Patients with lower KA Kreuzer 2, N Kosyakova 3, T Liehr 3, S Pekova 1 miR-20a expression had significantly poorer complete remission (CR) rates 1Laboratory for Molecular Diagnostics, synlab genetics s.r.o., Prague, Czech (Log rank p<0.001), relapse-free survival (RFS, Log rank p<0.001) and overall Republic, 2Department I of Internal Medicine, University at Cologne, Cologne, survival (OS, Log rank p<0.001). Low miR-20a expressers had lower CR rates 3Institute of Human Genetics, Jena University Hospital, Jena, Germany and OS within the Southwest Oncology Group classification. Multivariate analysis revealed that lower miR-20a was an independent predictor of poor Background: Recently, we introduced a flexible strategy for mapping prognosis. MiR-20a restoration could result in low levels of cAMP and weak cytogenetically identified unique abnormalities down to the single nucleotide activity of PKA, thus relieving the inhibitory effect of PKA on mononuclear- level. This strategy has enabled us to design clone-specific assays for sensitive leukemic cell proliferation. Subsequent investigations revealed that miR-20a minimal residual disease (MRD) monitoring in acute leukemia patients directly reduced the endogenous protein level of myeloid cell leukemia (Jancuskova et al . Leuk Res. 2013) as well as to elucidate regions/genes sequence 1 (Mcl-1) in mononuclear-leukemic cell. involved in congenital chromosomal aberrations (unpublished data). Here we Summary and Conclusion: MiR-20a is decreased in AML and correlates with characterize the rare chromosomal translocation t(3;10)(q26;q21), involving AML prognosis. Down-regulation of miR-20a increases the proliferation abilities the MECOM gene (MDS and EVI1 complex locus located in band 3q26), of AML cells. Our findings suggest miR-20a may represent a novel potential identified in an acute myeloid leukemia (AML) patient. therapeutic target and biomarker for survival of AML patients. Aims: Our aim was to use our strategy to identify the fusion partner on chromosome 10q21 and to characterize the precise nucleotide sequence of the chromosomal breakpoint. P780 Methods: The chromosomal translocation was revealed by standard cytogenetic techniques (G-banding, mFISH), and involvement of the MECOM COPY NUMBER GAINS OF CHROMOSOME 1P36 LEAD TO PRDM16 gene was confirmed by FISH with the use of a commercially available probe OVEREXPRESSION IN AML PATIENTS 1,* 1 1 1 1 1 set. The derivative chromosome 10 was isolated using fine-needle C Baldazzi , E Ottaviani , S Luatti , G Marzocchi , G Ameli , C Papayannidis , microdissection followed by whole genome amplification (WGA). Ten dissected C Gamberini 1, E Franchini 1, M Cavo 1, G Martinelli 1, N Testoni 1 1 fragments were sequenced on the GS-Junior next-generation sequencing Institute of Hematology and Medical Oncology “L. e A. Seràgnoli”, S.Orsola- platform. The reads obtained were aligned to reference sequences of Malpighi Hospital, Bologna, Italy chromosomes 3 and 10 using in-house developed software. The last mapped reads from both chromosomes were used as docking sites for primers for long- Background: PRDM16 gene (1p36) is rearranged in AML/MDS with range PCR to amplify the putative breakpoint. The long-range PCR products t(1;3)(p36;q21), t(1;21)(p36;q22) and t(1;12)(p36;p13). These translocation were directly sequenced using Sanger sequencing to reveal the precise resulted in PRDM16 overexpression through juxtaposition to the enhancer of nucleotide sequence of the breakpoint. RPN1 at 3q21 or through fusion transcript formation with RUNX1at 21q22 or Results: Using a combination of cytogenetic and molecular approaches, we ETV6 at 12p13, respectively. AML/MDS with t(1;3)(p36;q21) showed similar mapped the t(3;10)(q26;q21) to the single nucleotide level, revealing a fusion clinical and prognostic characteristics with AML/MDS with inv(3)/t(3;3) and EVI1 of the MECOM gene (3q26.2) and C10orf107 (10q21.2). rearrangements. PRDM16 overexpression has been reported in AML in Summary and Conclusion: In AML patients, the MECOM gene can be absence of 1p36 rearrangements, but the mechanisms are still unknown and rearranged with a variety of other partner chromosomes and partner genes. the studies not conclusive. According to the Mitelman database, only one case with a t(3;10)(q26;q21) Aims: To characterize PRDM16 in cases with 1p36 abnormalities and to assess translocation has been reported, but neither the fusion partner of the MECOM PRDM16 expression in a cohort of AML without 1p36 involvement. gene nor DNA sequence were identified. The approach described here opens Methods: The study group was composed of 14 AML and MDS cases with 1p36 up new possibilities in characterizing acquired as well as congenital abnormalities and a cohort of 80 AML without 1p36 involvement by conventional chromosomal aberrations. In addition, DNA sequences of chromosomal cytogenetic (CC) and were analysed by relative RQ-PCR and FISH using 3 BAC breakpoints may be a useful tool for unique molecular MRD target identification probes covering PRDM16 and its flanking regions (BlueGnome Ltd. Cambridge, UK). in acute leukemia patients. Results: We identified 14 cases with 1p36 abnormalities: FISH analysis of 13 available samples identified 4 cases with PRDM16 rearrangement. Two cases showed a t(1;3)(p36;q21), one a t(1;21)(p36;q22) and the last one an add(1)(p36) in CC. In 3 cases the breakpoint was at 5’ of PRDM16, whereas in t(1;21) it was at 3’ of PRDM16, which is a rare event. We were not able to identify the chromosome partner involved in the case with add(1)(p36). Other 3 cases showed copy number gains of PRDM16 identified as the presence from 3 to 5 signals with all the three probes used in interphase FISH. To exclude the amplification of the whole p arm we used a control probe on 1p32 that did not show amplification. Metaphases FISH localized the site of amplification on the der(1)(p36) in two cases, whereas it was localized on unidentified chromosome in the last one. Rearrangements and amplification of PRDM16 haematologica | 2014; 99(s1) | 283 19 th Congress of the European Hematology Association although in myeloid malignancies with a t(3;17) translocation over-expressed EVI1 rearranged with MSI2 7. Interestingly, haematological features of all the available cases suggest that GSX2 ectopic expression delineates a genetic subgroup among CD7+ AML. Although the fine mechanisms of GSX2 de- regulation remain to be understood, in our cases we hypothesize that they are related to inactivation of silencers located close to GSX2, at 5’ in patient 1 and at 3’ in patient 2.
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