Analysis of Initiating Events in Inv(16) Associated Acute Myeloid Leukemia

描述(由申请人提供)：这项K99/R00赠款申请的总体目标是过渡到一个独立的研究人员职位，并识别和描述与INV(16)相关的急性髓系白血病(AML)的早期事件。我的长期目标是在髓系白血病领域确立自己的独立研究员地位，专注于与inv(16)相关的AML。 Inv(16)在转录因子Cbfb和编码肌球蛋白重链的基因MYH11之间创建了一个融合基因。由此产生的融合基因Cbfb-MYH11编码CBF2-SMMHC蛋白。根据我以前的研究，我假设Cbfb-MYH11的表达通过基因表达的明显变化诱导了白血病起始细胞(LIC)的异常群体。了解这些LIC的产生机制可能为inv(16)AML的治疗提供新的药物靶点。因此，我建议(特定目标1)鉴定和分离Cbfb-MYH11+白血病起始群体；(特定目标2)使用生物信息学方法分析Cbfb-MYH11诱导的基因表达变化。完成这些特定目标将提供：(I)更好地理解Cbfb-MYH11 LIC，(Ii)Cbfb-MYH11诱发白血病的潜在机制，(Iii)分析基因表达数据和全基因组测序数据的计算方法方面的培训。

DESCRIPTION (provided by applicant): The overall goals of this K99/R00 grant application are to transition to an independent investigator position and to identify and characterize the early events in inv(16) associated acute myeloid leukemia (AML). My long-term goal is to establish myself as an independent investigator in the field of myeloid leukemia, with a focus on inv(16) associated AML. Inv(16) creates a fusion gene between the transcription factor CBFB, and the gene encoding smooth muscle myosin heavy chain, MYH11. The resulting fusion gene, CBFB-MYH11 encodes the protein CBF2- SMMHC. Based on my previous research, I hypothesize that expression of CBFB-MYH11 induces an abnormal population of leukemia initiating cells (LIC) through distinct changes in gene expression. Understanding the mechanism that generates these LICs may provide new drug targets for the treatment of inv(16) AML. Thus, I propose to (Specific Aim 1) characterize and isolate the Cbfb-MYH11+ leukemia initiating population; (Specific Aim 2) use bioinformatic approaches to analyze Cbfb-MYH11 induced changes in gene expression. Completing these Specific Aims will provide: (i) an improved understanding of CBFB-MYH11 LICs, (ii) potential mechanisms of CBFB-MYH11 induced leukemogenesis, (iii) training in computational methods for analysis of gene expression data and genome wide sequencing data.