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

Inv(16) 相关急性髓系白血病起始事件分析

• 批准号: 8895273
• 负责人: Ricia Katherine Hyde
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8895273
• 关键词: Acute Myelocytic Leukemia; Address; Affect; Animals; Applications Grants; Binding; Bioinformatics; CBFB gene; Cell Cycle; Cell surface; Cells; Cellular biology; Chromosome abnormality; Chromosomes, Human, Pair 16; Computing Methodologies; DNA Methylation; Data; Development; Disease; Drug Targeting; Event; Future; Gene Expression; Gene Expression Profiling; Genes; Goals; MYH11 gene; Mediating; Modeling; Mutation; Myeloid Leukemia; Myosin Heavy Chains; Patients; Pharmaceutical Preparations; Population; Positioning Attribute; Proteins; Recurrence; Research; Research Personnel; Resources; Role; Smooth Muscle Myosins; Solid; Testing; Training; Work; base; cell type; drug sensitivity; fusion gene; genome-wide; human MYH11 protein; improved; inhibitor/antagonist; insight; leukemia; leukemogenesis; mouse model; transcription factor; treatment strategy

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.

描述（由申请人提供）：该K99/R00赠款应用程序的总体目标是过渡到独立研究者职位，并确定和表征INV（16）相关的急性髓样白血病（AML）中的早期事件。我的长期目标是确立自己是髓样白血病领域的独立研究者，重点是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MYH11之间创建了融合基因。所得的融合基因CBFB-MYH11编码蛋白质CBF2-SMMHC。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引起了白血病启动细胞（LIC）异常的人群。了解产生这些LIC的机制可能会为治疗INV（16）AML的新药物提供新的靶标。因此，我建议（特定目标1）表征和隔离CBFB-MYH11+白血病启动人群； （特定目的2）使用生物信息学方法分析CBFB-MYH11诱导基因表达的变化。完成这些具体目标将提供：（i）对CBFB-MYH11 LIC的了解，（ii）CBFB-MYH11的潜在机制诱导的白血病发生，（III）计算方法中的培训，用于分析基因表达数据和基因组广泛测序数据。

项目成果

Targeting binding partners of the CBFβ-SMMHC fusion protein for the treatment of inversion 16 acute myeloid leukemia.

• DOI: 10.18632/oncotarget.11357
• 发表时间: 2016-10-04
• 期刊: Oncotarget
• 作者: Richter L;Wang Y;Hyde RK
• 通讯作者: Hyde RK

Runx1 is required for hematopoietic defects and leukemogenesis in Cbfb-MYH11 knock-in mice.

• DOI: 10.1038/leu.2015.58
• 发表时间: 2015-08
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: Hyde RK;Zhao L;Alemu L;Liu PP
• 通讯作者: Liu PP