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
• 负责人: Andrew Volk
• 金额: $ 24.9万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10406265
• 关键词: Acute Megakaryocytic Leukemias; Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Acute leukemia; Advisory Committees; Affect; Automobile Driving; Award; Binding; CEBPA gene; Cancer Center; Cell Line; Cells; ChIP-seq; Child; Chromatin; Chromatin Modeling; Chromosome 21; Collaborations; Complex; DNA replication fork; Data; Data Set; Deposition; Diagnosis; Differentiated Gene; Differentiation Therapy; Down Syndrome; Enhancers; Gene Expression; Genes; Genetic Transcription; Goals; Growth; Hematologic Neoplasms; Hematopoietic; Hematopoietic Neoplasms; Home; Human; In Vitro; Institution; Leukemic Cell; MLL-AF9; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Mentors; Modeling; Mus; Mutation; Myelogenous; Myeloid Leukemia; Myeloproliferative disease; Nature; Nucleosomes; Outcome; Patients; Phase; Phenotype; Predisposition; Process; Prognosis; Proteins; Proteomics; Reagent; Reporting; Research; Research Personnel; Risk; Role; S phase; Sampling; TP53 gene; The Cancer Genome Atlas; Therapeutic; Training; Transcription Coactivator; Undifferentiated; Universities; WD Repeat; acute myeloid leukemia cell; base; cancer cell; career; effective therapy; experience; experimental study; genetic signature; genomic locus; in vivo; knock-down; leukemia; leukemic stem cell; leukemogenesis; member; myeloid leukemia cell; next generation sequence data; novel; novel therapeutic intervention; overexpression; post-doctoral training; programs; promoter; small molecule; therapeutic target; therapy design; tool; transcription factor; transient myeloproliferative disorder; tumor

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.

项目概要 患有唐氏综合症（DS）的儿童患急性白血病的风险很高，这表明 21 号染色体上存在促进白血病的基因。染色质组装因子 1B (CHAF1B)， 位于 DS 关键区域，是异源三聚体 CAF1 染色质组装复合体的成员，该复合体是 负责在 S 期期间在复制叉处沉积 H3/H4 异二聚体。 CHAF1B 水平为 DS-AML 患者样本以及非 DS AML 细胞系和原发性 AML 样本中的 与健康样本相比。虽然在大多数肿瘤中表达升高与不良预后相关， CHAF1B 促进白血病发生的机制尚不清楚。我的初步数据显示 CHAF1B 直接结合与骨髓分化启动子和增强子相关的染色质离散区域 基因。髓性白血病细胞中 Chaf1b 的缺失会导致染色质上的 CHAF1B 被替换为 包括 CEBPA 在内的促分化转录因子以及随后的骨髓细胞激活 分化转录程序。因此，我建议需要 CHAF1B 来维持 通过作为转录调节因子来调节 MLL-AF9 白血病细胞的未分化状态。在这个提案中，我 将研究白血病干细胞依赖CHAF1B维持的机制。中心假设是 CHAF1B通过竞争染色质占据维持髓系白血病细胞的未分化状态 在分化基因的启动子和增强子处具有转录因子。此次竞赛导致 这些基因的表达减少以及由此导致的白血病原始细胞表型的维持。 在目标 1 中，我将探讨 CHAF1B 蛋白的不同结构域如何促进 维持髓系白血病细胞的未分化状态。然后，在目标 2 中，我将建立 CHAF1B 作为 通过确定 AML（包括 DS-AML）的治疗靶标对血液学进展的贡献 体内肿瘤和体外原始人类患者样本。我的最终目标是利用获得的信息 在 K99/R00 奖期间开发可以阻断 CHAF1B 功能的新型小分子化合物 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造血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 数据集和基础蛋白质组学的分析。的影响 我与 Dana Farber 癌症中心的 Scott Armstrong 博士的合作将增强 K99 阶段 哈佛大学和韦恩州立大学的 Yubin Ge 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

NOTCH-ing up nucleotide metabolism in T-cell acute lymphoblastic leukemia.

NOTCH 增强 T 细胞急性淋巴细胞白血病的核苷酸代谢。

• 发表时间: 2021
• 影响因子: 5.9
• 作者: Volk; Andrew
• 通讯作者: Andrew

Repression of TRIM13 by chromatin assembly factor CHAF1B is critical for AML development.

染色质组装因子 CHAF1B 对 TRIM13 的抑制对于 AML 的发展至关重要。

• 发表时间: 2023-09-12
• 影响因子: 7.5
• 作者: Dean, Sarai T;Ishikawa, Chiharu;Zhu, Xiaoqin;Walulik, Sean;Nixon, Timothy;Jordan, Jessica K;Henderson, Samantha;Wyder, Michael;Salomonis, Nathan;Wunderlich, Mark;Greis, Kenneth D;Starczynowski, Daniel T;Volk, Andrew G
• 通讯作者: Volk, Andrew G

Paralog-specific signaling by IRAK1/4 maintains MyD88-independent functions in MDS/AML.

IRAK1/4 的旁系同源特异性信号传导在 MDS/AML 中维持 MyD88 独立的功能。

• 发表时间: 2023-09-14
• 影响因子: 20.3
• 作者: Bennett, Joshua;Ishikawa, Chiharu;Agarwal, Puneet;Yeung, Jennifer;Sampson, Avery;Uible, Emma;Vick, Eric;Bolanos, Lyndsey C;Hueneman, Kathleen;Wunderlich, Mark;Kolt, Amal;Choi, Kwangmin;Volk, Andrew;Greis, Kenneth D;Rosenbaum, Jan;Hoyt, Scot
• 通讯作者: Hoyt, Scot

LKB1/STK11 Is a Tumor Suppressor in the Progression of Myeloproliferative Neoplasms.

LKB1/STK11 是骨髓增生性肿瘤进展中的肿瘤抑制因子。

• 发表时间: 2021-06
• 影响因子: 28.2
• 作者: Marinaccio, Christian;Suraneni, Praveen;Celik, Hamza;Volk, Andrew;Wen, Qiang Jeremy;Ling, Te;Bulic, Marinka;Lasho, Terra;Koche, Richard P;Famulare, Christopher A;Farnoud, Noushin;Stein, Brady;Schieber, Michael;Gurbuxani, Sandeep;Root, David
• 通讯作者: Root, David