The Role of CHAF1B in Maintaining Malignant Leukemia Stem Cells

CHAF1B 在维持恶性白血病干细胞中的作用

基本信息

  • 批准号:
    10076236
  • 负责人:
  • 金额:
    $ 24.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-06-01 至 2023-05-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Children with Down syndrome (DS) are at substantial risk of developing acute leukemia, which suggests that there are leukemia promoting genes on chromosome 21. Chromatin Assembly Factor 1B (CHAF1B), which resides in the DS critical region, is a member of the heterotrimeric CAF1 chromatin assembly complex that is responsible for depositing H3/H4 heterodimers at the replication fork during S-phase. CHAF1B levels are elevated in DS-AML patient samples, as well as non-DS AML cell lines and primary AML samples when compared to healthy samples. While elevated expression is associated with poor prognosis in most tumors, the mechanism by which CHAF1B promotes leukemogenesis is unknown. My preliminary data show that CHAF1B directly binds discrete regions of chromatin associated with promoters and enhancers of myeloid differentiation genes. Deletion of Chaf1b in myeloid leukemia cells results in replacement of CHAF1B on the chromatin with the pro-differentiation transcription factors including CEBPA and the subsequent activation of a myeloid differentiation transcriptional program. Therefore, I propose that CHAF1B is required to maintain the undifferentiated state of MLL-AF9 leukemic cells through a role as a transcriptional regulator. In this proposal, I will study the mechanism of CHAF1B-dependent maintenance of leukemic stem cells. The central hypothesis is CHAF1B maintains the undifferentiated state of myeloid leukemic cells by competing for chromatin occupancy with transcription factors at the promoters and enhancers of differentiation genes. This competition leads to reduced expression of these genes and the resulting maintenance of the leukemic blast phenotype. In Aim 1, I will explore the mechanism of how the different domains of the CHAF1B protein contribute to maintaining the undifferentiated state of myeloid leukemic cells. Then, in Aim 2, I will establish CHAF1B as a therapeutic target in AML (including DS-AML) by determining its contribution to the progression of hematologic tumors in vivo and primary human patient samples in vitro. My ultimate goal is to use the information gained during the K99/R00 award to develop novel small molecule compounds that can block CHAF1B function and control AML tumors in vivo by differentiation. My career goal is to become an independent investigator and leader in the field of chromatin assembly and its effects on hematopoietic malignancies with the ultimate goal of developing new therapeutic strategies to treat leukemia. During the mentored K99 phase, my main technical goal is to become proficient at analysis of large-scale NGS data sets and basic proteomics. The impact of the K99 phase will be enhanced by my collaborations with Dr. Scott Armstrong at Dana Farber Cancer Center at Harvard University and Dr. Yubin Ge at Wayne State University, by allowing me to expand my training outside my home institution of Northwestern University. Dr. John Crispino and my advisory team will guide me through the completion of my postdoctoral training and assist me with my transition to independence.
项目总结 患有唐氏综合症(DS)的儿童有患急性白血病的巨大风险,这表明 在21号染色体上有促进白血病的基因。染色质组装因子1B(CHAF1B), 位于DS关键区,是异三聚体CAF1染色质组装复合体的成员 负责在S阶段在复制叉处沉积H3/H4异二聚体。CHAF1B水平为 在DS-AML患者样本以及非DS AML细胞系和原发AML样本中 与健康样本相比。虽然在大多数肿瘤中,高表达与预后不良有关,但 CHAF1B促进白血病发生的机制尚不清楚。我的初步数据显示CHAF1B 直接结合与髓系分化启动子和促进剂相关的染色质离散区域 基因。髓系白血病细胞中CHAF1B的缺失导致染色质上的CHAF1B被 促分化转录因子包括CEBPA和随后的髓系激活 分化转录程序。因此,我建议要求CHAF1B保持 作为转录调节因子的MLL-AF9白血病细胞未分化状态。在这项建议中,我 将研究CHAF1B依赖维持白血病干细胞的机制。中心假设是 CHAF1B通过争夺染色质占有率维持髓系白血病细胞的未分化状态 转录因子位于分化基因的启动子和增强子。这场比赛导致了 这些基因的表达减少,从而维持白血病原始细胞表型。 在目标1中,我将探索CHAF1B蛋白的不同结构域如何参与 维持髓系白血病细胞的未分化状态。然后,在目标2中,我将把CHAF1B确立为 急性髓系白血病(包括DS-AML)的治疗靶点确定其在血液学进展中的作用 体内肿瘤和体外原发人类患者样本。我的最终目标是利用所获得的信息 在K99/R00奖期间,开发能够阻断CHAF1B功能和 通过分化控制体内AML肿瘤。我的职业目标是成为一名独立调查员和领导者 在染色质组装及其对血液系统恶性肿瘤的影响领域,最终目标是 开发治疗白血病的新治疗策略。在指导K99阶段,我的主要技术 目标是精通大规模NGS数据集的分析和基础蛋白质组学。经济衰退带来的影响 K99期将通过我与达纳·法伯癌症中心的斯科特·阿姆斯特朗博士的合作而得到加强 哈佛大学和韦恩州立大学的葛宇斌博士,允许我在外面扩展我的培训 我的家乡西北大学。约翰·克里斯皮诺博士和我的顾问团队将指导我完成 完成我的博士后培训,并帮助我过渡到独立。

项目成果

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Andrew Volk其他文献

Andrew Volk的其他文献

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{{ truncateString('Andrew Volk', 18)}}的其他基金

How CHAF1B maintains cell state by repressing transcription of fate genes
CHAF1B 如何通过抑制命运基因的转录来维持细胞状态
  • 批准号:
    10693278
  • 财政年份:
    2021
  • 资助金额:
    $ 24.9万
  • 项目类别:
How CHAF1B maintains cell state by repressing transcription of fate genes
CHAF1B 如何通过抑制命运基因的转录来维持细胞状态
  • 批准号:
    10271523
  • 财政年份:
    2021
  • 资助金额:
    $ 24.9万
  • 项目类别:
The Role of CHAF1B in Maintaining Malignant Leukemia Stem Cells
CHAF1B 在维持恶性白血病干细胞中的作用
  • 批准号:
    10406265
  • 财政年份:
    2020
  • 资助金额:
    $ 24.9万
  • 项目类别:
The Role of CHAF1B in Maintaining Malignant Leukemia Stem Cells
CHAF1B 在维持恶性白血病干细胞中的作用
  • 批准号:
    10163137
  • 财政年份:
    2020
  • 资助金额:
    $ 24.9万
  • 项目类别:
Sensitizing Leukemia Stem Cells to NF-kB Inhibition by Blocking TNF Signaling
通过阻断 TNF 信号传导使白血病干细胞对 NF-kB 抑制敏感
  • 批准号:
    8456470
  • 财政年份:
    2013
  • 资助金额:
    $ 24.9万
  • 项目类别:
Sensitizing Leukemia Stem Cells to NF-kB Inhibition by Blocking TNF Signaling
通过阻断 TNF 信号传导使白血病干细胞对 NF-kB 抑制敏感
  • 批准号:
    8641557
  • 财政年份:
    2013
  • 资助金额:
    $ 24.9万
  • 项目类别:

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    1980
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DETERMINANTS OF RESPONSE OF ACUTE MYELOCYTIC LEUKEMIA
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    3556968
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