Functional screen of genes on chromosome 7q that contribute to the pathogenesis of myelodysplastic syndrome (MDS) / acute myeloid leukemia (AML) and to the response to hypomethylating agents

骨髓增生异常综合征(MDS)包括一组以无效造血为特征的克隆性白血病前期疾病。MDS的一个临床特征是经常进展为急性髓系白血病(AML)，这是这些患者的主要死亡原因。这些所谓的继发性急性髓细胞白血病(SAML)的特点是对标准化疗相对耐药，预后不良。最近对氮胞苷的研究表明，7q(7q-)长臂缺失的MDS患者似乎比其他MDS患者从去甲基化药物治疗中受益更大。7q-在MDS和AML中是一种反复出现的异常，但导致受影响细胞克隆性显性的相应缺失基因仍不清楚。在拟议的项目中，我们的目标是通过使用RNA干扰筛选来识别负责基因。为了确定低甲基化药物的特定细胞毒性的分子基础，在本项目的第二部分，我们将在地西他滨存在的情况下对7q基因进行RNA干扰筛选。最后，MDS/SAML中的已知突变将通过慢病毒转导shRNA或突变的cDNA来表征其功能。

The myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal, pre-leukemic disorders characterized by ineffective hematopoiesis. One clinical feature of MDS is the frequent progression to acute myeloid leukemia (AML), which is a leading cause of death in these patients. These so-called secondary AML (sAML) are characterized by relative resistance to standard chemotherapy and an adverse prognosis. Recent studies with azacytidine revealed that MDS patients with deletions on the long arm of 7q (7q-) seem to benefit from treatment with hypomethylating agents to a greater degree than other MDS patients. 7q- is a recurrent aberration in MDS and AML but the corresponding deleted gene or genes that lead to a clonal dominance of the affected cells remain unknown. In the proposed project we aim to identify the responsible genes by using an RNA interference screen. To determine the molecular basis for the specific cell toxicity from hypomethylating agents we will perform an RNA interference screen of 7q genes in the presence of decitabine in the second part of this project. Finally, known mutations in MDS/ sAML will be characterized functionally by lentiviral transduction of shRNAs or mutated cDNAs.