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

项目总结 骨髓中的造血干细胞(HSCs)必须维持效应血的持续生产。 维持体内平衡的细胞。关键是造血干细胞在种群水平上自我更新和维持的能力 宁静。维持静止状态和功能干细胞库的中心是对细胞的调节 循环进入和退出。存在许多抑制染色质修饰复合体，其靶基因与 增殖和DNA复制。在保持静止或分化过程中的干扰会导致 骨髓衰竭或恶性转化。我们最近证明了染色质支架 蛋白Sin3B是维持小鼠肝星状细胞功能所必需的。SIN3B招募组蛋白脱乙酰酶 通过与序列的相互作用，特定的转录因子在离散的 基因组定位并抑制转录。SIN3B的丢失降低了HSCs维持静止和 在竞争激烈的移植环境中正确区分。这项建议旨在理解SIN3B- 维持HSC功能所必需的依赖转录网络。此外，我们还寻求翻译 这些研究针对的是急性髓系白血病，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。具体地说，人们认为患者复发是由于存在化疗- 耐药白血病干细胞(LSC)。这些LSC与HSC有许多相似之处，包括静止和 自我更新的属性，这被认为是他们抵抗传统的 化疗。我们建议了解Sin3B在维护AML LSC中所起的作用，并确定 靶向Sin3B提供了一种新的治疗策略，使LSCs对治疗敏感。这项建议旨在 将Sin3B基因急性缺失与化疗相结合评估急性髓系白血病是否可以消除复发 通过选择性地瞄准LSC。

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.