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

项目摘要 骨髓中的造血干细胞（HSC）必须维持效应血的恒定产生 细胞来维持体内平衡。关键是HSC在群体水平上自我更新和维持 安静维持静止和功能性干细胞库的核心是调节细胞周期， 循环进出。存在许多抑制性染色质修饰复合物，其靶向与以下相关的基因： 增殖和DNA复制。在维持静止或分化方面的扰动可导致 骨髓衰竭或恶性转化。我们最近证明了染色质支架 蛋白Sin 3B对于维持小鼠中的功能性HSC是必需的。Sin 3B募集组蛋白去乙酰化酶 通过与序列特异性转录因子的相互作用， 基因座并抑制转录。Sin 3B的缺失降低了HSC维持静止的能力， 在竞争性移植环境中正确区分。本文旨在了解Sin 3B- 维持HSC功能所必需的依赖性转录网络。此外，我们致力于翻译 急性髓系白血病是一种恶性肿瘤，其特征是原始细胞的快速增殖， 分化受阻。具体地说，人们认为患者复发是由于化疗的存在- 耐药白血病干细胞（LSC）。这些LSC与HSC有许多相似之处，包括静止和静止。 自我更新的属性，这是假设是负责他们的阻力，传统的 化疗我们建议了解Sin 3B在维持AML LSC中的作用，并确定是否 靶向Sin 3B提供了使LSC对治疗敏感的新的治疗策略。这项建议旨在 将Sin 3B的急性缺失与化疗治疗相结合，以评估AML的复发是否可以消除 通过选择性靶向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.