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

描述（由申请人提供）：本K99/R 00资助申请的总体目标是过渡到独立的研究者职位，并确定和表征inv（16）相关急性髓性白血病（AML）的早期事件。我的长期目标是使自己成为髓系白血病领域的独立研究者，重点关注inv（16）相关的AML。 Inv（16）在转录因子CBFB和编码平滑肌肌球蛋白重链的基因MYH 11之间产生融合基因。所得到的融合基因CBFB-MYH 11编码蛋白CBF 2- SMMHC。基于我以前的研究，我假设CBFB-MYH 11的表达通过基因表达的不同变化诱导白血病起始细胞（LIC）的异常群体。了解产生这些LIC的机制可能为治疗inv（16）AML提供新的药物靶点。因此，我建议（具体目标1）表征和分离Cbfb-MYH 11+白血病起始人群;（具体目标2）使用生物信息学方法分析Cbfb-MYH 11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-MYH 11 LIC，（ii）CBFB-MYH 11诱导白血病发生的潜在机制，（iii）用于分析基因表达数据和全基因组测序数据的计算方法培训。

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.