The role of Sin3B in coordinating cell cycle exit and differentiation in hematopoiesis

Sin3B 在协调造血细胞周期退出和分化中的作用

• 批准号: 10005263
• 负责人: Alexander Calderon
• 金额: $ 4.55万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-11 至 2022-01-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005263
• 关键词: Acute; Acute Myelocytic Leukemia; Adult; Blood Cells; Bone Marrow; Cell Compartmentation; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell physiology; Cells; Chromatin; Chromatin Remodeling Factor; Clone Cells; Complex; DNA biosynthesis; Defect; Engraftment; Gene Expression; Genes; Genetic Transcription; Genomics; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic System; Hematopoietic stem cells; Hemorrhage; Histone Deacetylase; Home environment; Homeostasis; Impairment; Individual; Label; Lead; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Modeling; Mus; Myelosuppression; Nature; Pancytopenia; Pathway Analysis; Phenotype; Play; Population; Production; Proliferating; Property; Proteins; Recording of previous events; Refractory; Regenerative response; Regulation; Relapse; Repression; Resistance; Role; Scaffolding Protein; Sepsis; Stress; System; Techniques; Testing; Transgenes; Translating; Transplantation; base; cell type; chemotherapy; conditional knockout; differential expression; exhaustion; experimental study; genomic locus; hematopoietic differentiation; hematopoietic stem cell differentiation; hematopoietic stem cell quiescence; hematopoietic stem cell self-renewal; leukemia treatment; leukemic stem cell; new therapeutic target; novel; novel therapeutics; programs; recruit; relapse patients; response; self-renewal; stem cell biology; stem cells; stemness; success; transcription factor; transcriptome sequencing

PROJECT SUMMARY Hematopoietic stem cells (HSCs) in the bone marrow must maintain a constant production of effector blood cells to maintain homeostasis. Key to this is the ability for HSCs, at a population level, to self-renew and maintain quiescence. Central to the maintenance of quiescence and to a functional stem cell pool is regulation of cell cycle entry and exit. Many repressive chromatin-modifying complexes exist that target genes related to proliferation and DNA replication. Perturbations in the maintenance of quiescence or differentiation can lead to bone marrow failure or malignant transformation. We have recently demonstrated that the chromatin scaffolding protein Sin3B is essential for the maintenance of functional HSCs in mice. Sin3B recruits histone deacetylases and through interaction with sequence specific transcription factors modulates local chromatin at discrete genomic loci and represses transcription. Loss of Sin3B diminishes HSCs ability to maintain quiescence and properly differentiate in a competitive transplantation setting. This proposal seeks to understand the Sin3B- dependent transcriptional network necessary for maintenance of HSC function. Additionally, we seek to translate these studies to Acute Myeloid Leukemia, a malignancy characterized by rapid proliferation of blasts that are blocked in differentiation. Specifically, it is thought that patients relapse due to the presence of chemotherapy- resistant Leukemic Stem Cells (LSCs). These LSCs have many similarities to HSCs including quiescence and self-renewal properties, which is hypothesized to be responsible for their resistance to conventional chemotherapy. We propose to understand the role Sin3B plays in maintaining AML LSCs and to determine if targeting of Sin3B presents a novel therapeutic strategy to sensitize LSCs to treatment. This proposal aims to couple acute deletion of Sin3B with chemotherapy treatment to assess if relapse in AML can be abrogated through selective targeting of LSCs.

项目概要 骨髓中的造血干细胞 (HSC) 必须维持效应血液的持续产生 细胞维持稳态。其关键在于 HSC 在群体水平上自我更新和维持的能力 静止。维持静止和功能性干细胞库的核心是细胞的调节 循环进入和退出。存在许多抑制性染色质修饰复合物，其目标基因与 增殖和DNA复制。维持静止或分化的扰动可能导致 骨髓衰竭或恶变。我们最近证明了染色质支架 Sin3B 蛋白对于小鼠 HSC 功能的维持至关重要。 Sin3B 招募组蛋白脱乙酰酶 并通过与序列特异性转录因子的相互作用，以离散的方式调节局部染色质 基因组位点并抑制转录。 Sin3B 的缺失会降低 HSC 维持静止和 在竞争性移植环境中正确区分。该提案旨在了解 Sin3B- 维持 HSC 功能所必需的依赖转录网络。此外，我们寻求翻译 这些研究针对急性髓系白血病，这是一种以原始细胞快速增殖为特征的恶性肿瘤， 分化受阻。具体来说，人们认为患者复发是由于化疗的存在—— 耐药性白血病干细胞（LSC）。这些 LSC 与 HSC 有许多相似之处，包括静止和 自我更新的特性，被认为是它们对传统的抵抗力的原因 化疗。我们建议了解 Sin3B 在维持 AML LSC 中所扮演的角色，并确定是否 Sin3B 的靶向提供了一种使 LSC 对治疗敏感的新治疗策略。该提案旨在 将 Sin3B 急性缺失与化疗结合起来，以评估是否可以消除 AML 的复发 通过选择性靶向LSC。