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

对 7q 染色体上与骨髓增生异常综合征 (MDS)/急性髓性白血病 (AML) 发病机制以及对低甲基化药物反应有关的基因进行功能筛选

• 批准号: 188485988
• 负责人: Professor Dr. Jan Krönke
• 金额: --
• 依托单位: Brigham and Womens Hospital
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/188485988?language=en
• 关键词: Functional; screen; genes; chromosome; 7q

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.

骨髓增生异常综合征（MDS）包括一组异质性克隆性白血病前期疾病，其特征在于无效的造血。MDS的一个临床特征是频繁进展为急性髓性白血病（AML），这是这些患者死亡的主要原因。这些所谓的继发性AML（sAML）的特征在于对标准化疗的相对抗性和不良预后。最近的氮杂胞苷研究显示，与其他MDS患者相比，7 q长臂缺失（7 q-）的MDS患者似乎从低甲基化药物治疗中获益更大。7 q-是MDS和AML中的复发性畸变，但导致受影响细胞的克隆优势的相应缺失基因或基因仍然未知。在拟议的项目中，我们的目标是通过使用RNA干扰筛选来确定负责的基因。为了确定来自低甲基化剂的特异性细胞毒性的分子基础，我们将在本项目的第二部分中在地西他滨的存在下对7 q基因进行RNA干扰筛选。最后，MDS/ sAML中的已知突变将通过shRNA或突变cDNA的慢病毒转导在功能上表征。