CUX1 pioneer factor activity is required to prevent myeloid leukemogenesis

项目摘要/摘要 髓系恶性肿瘤包括一组异质性的危及生命的克隆性骨髓 仅在美国就影响了超过15万人的肿瘤。目前的治疗方法 治疗急性髓系白血病和骨髓增生异常综合征的选择有限，只有 为高危患者提供适度的福利。7号染色体[-7/del(7q)]的部分或全部缺失是一种 与不良风险预后和抗药性相关的常见细胞遗传学改变 传统疗法。[-7/del(7q)]中导致高密度脂蛋白的遗传机制(S) 风险髓系疾病在该领域仍然是一个关键但尚未解决的问题。然而，我们的实验室 已经发现了一种肿瘤抑制基因CUX1，它编码在7q上，在 髓系疾病。CUX1功能丧失突变与临床不良相关 独立于7号染色体细胞遗传学异常的预后。尽管有这些发现，但 CUX1在造血过程中的内源性作用及其抑制机制 白血病转化，目前仍不清楚，这是理解白血病转化的主要障碍 CUX1单倍体不足会导致高危疾病。我的初步数据显示，CUX1 人类造血干细胞和祖细胞(HSPC)抑制增殖所需 促进红系发育。此外，我的数据表明CUX1与 HSPC中SWI/SNF核小体重塑复合体调节染色体可及性 并促进红系基因的表达。这项提议将利用创新的功能基因组 方法，结合对原代人类HSPC的发育分析，以确定 CUX1调控HSPC生物学和分化的分子和细胞机制。 填补这一知识差距将对帮助开发新的治疗方法至关重要 高危髓系恶性肿瘤的治疗策略。这项提议还将为我提供 实现我成为一名独立科学家的长期目标所需的专业知识 癌症基因组学领域。为了监督我的项目和职业发展，我聘请了一名 一支在髓系肿瘤方面有丰富经验的高素质导师团队， 造血学、基因组学、生物信息学和生物统计学。我们共同制定了一项 健全的培训计划，包括个人和小组会议、授课课程、 机构资源和研讨会，以及参加国际会议为我做好准备 在学术科学方面的职业生涯。

PROJECT SUMMARY/ABSTRACT Myeloid malignancies comprise a heterogenous group of life-threatening clonal bone marrow neoplasms that affect over 150,000 people in the United States alone. Current treatment options for acute myeloid leukemia and myelodysplastic syndrome are limited, and have only modest benefits for high-risk patients. Deletion of part or all of chromosome 7 [-7/del(7q)] is a common cytogenetic change associated with adverse-risk prognosis and resistance to conventional therapies. The underlying genetic mechanism(s) in [-7/del(7q)] that leads to high- risk myeloid disease has remained a critical but unsolved question in the field. However, our lab has identified a tumor suppressor gene, CUX1, encoded on 7q that is recurrently mutated in myeloid disorders. CUX1 loss-of-function mutations are associated with a poor clinical prognosis independent of chromosome 7 cytogenetic abnormalities. Despite these findings, the endogenous role of CUX1 during hematopoiesis, and the mechanism by which it suppresses leukemia transformation, remain unclear, presenting a major barrier to understanding how CUX1 haploinsufficiency leads to high-risk disorders. My preliminary data suggest that CUX1 is required in human hematopoietic stem and progenitor cells (HSPCs) to suppress proliferation and promote erythroid development. Furthermore, my data indicate that CUX1 cooperates with the SWI/SNF nucleosome remodeling complex in HSPCs to regulate chromosome accessibility and promote erythroid gene expression. This proposal will utilize innovative functional genomic approaches, coupled with developmental assays with primary human HSPCs, to define the molecular and cellular mechanisms by which CUX1 regulates HSPC biology and differentiation. Fulfilling this gap in knowledge will be critical to aiding the development of new therapeutic strategies for high-risk myeloid malignancies. This proposal will also provide me with the expertise necessary to achieve my long-term goal of becoming an independent scientist in the field of cancer genomics. To oversee my project and career development, I have enlisted a team of highly qualified mentors with a breadth of experience in myeloid neoplasia, hematopoiesis, genomics, bioinformatics, and biostatistics. Together we have developed a robust training plan that incorporates individual and group meetings, didactic coursework, institutional resources and seminars, and attendance at international conferences to prepare me for a career in academic science.