Regulation of hematopoietic stem cell differentiation

描述(申请人提供)：所有成熟的血细胞都来自一种罕见的特殊群体，即造血干细胞(HSCs)，它们大多处于静止状态。HSCs的细胞分裂导致它们的增殖和逐渐分化为越来越受血统限制的成熟血细胞，以及维持一小部分不分化的HSCs，而是在生物体的整个生命中进行造血。由于HSC功能的重要性，阐明控制HSC自我更新和分化之间平衡的信号是一项至关重要的任务。有趣的是，几项研究表明，生理性造血和诱导恶性血液病(白血病)之间存在密切的平衡，这是由能够转化HSC和祖细胞的异常信号控制的。与这一观点一致，我们最近发现E3泛素连接酶Fbw7在急性淋巴细胞白血病(ALL)中是一个重要的肿瘤抑制因子。Fbw7失活突变在很大一部分患者中被发现，并由于包括Notch1和c-Myc在内的几个重要癌基因的异常稳定性而诱导转化。我们利用一种新的条件性基因敲除小鼠模型研究了Fbw7在HSC功能中的作用。我们发现，Fbw7的缺失以一种细胞自主的方式特异性地、快速地影响HSC间隔室。Fbw7-/-HSC表现出维持静止的缺陷，导致自我更新受损和竞争性再生能力的严重丧失。此外，对Fbw7-/-HSC的全基因组转录组研究表明，Fbw7调节与静止的、自我更新的HSC表型相关的全球转录“签名”。在这一应用中，我们：a)确定Fbw7靶向的HSC特异性蛋白底物，在HSC分化和功能中发挥重要作用；b)通过研究Fbw7在胚胎干细胞功能中的作用，解决其在干细胞自我更新中的普遍功能；c)研究所有Fbw7错义突变在造血和HSC自我更新中的作用。 公共卫生相关性：所有血细胞都来自罕见的具有自我更新和分化能力的多能造血干细胞(HSC)。在这项资助中，我们详细研究了一种新的HSC调节因子E3泛素连接酶Fbw7的生物学功能。我们的研究具有直接的翻译影响，因为他们解决了HSC补充免疫系统的中央调节因子的功能，同时在白血病中发挥肿瘤抑制因子的功能。

DESCRIPTION (provided by applicant): All mature blood cells arise from a rare and specialized population, the hematopoietic stem cells (HSCs), which exist mostly in a quiescent state. Cell division of HSCs results in both their proliferation and progressive differentiation into increasingly lineage-restricted mature blood cells, as well as maintenance of a small pool of HSCs that do not differentiate, but rather carry out hematopoiesis throughout the life of an organism. Due to the significance of HSC function, the elucidation of the signals that govern the balance between HSC self-renewal and differentiation is a paramount task. Interestingly, several studies have suggested an intimate balance between physiological hematopoiesis and induction of hematopoietic malignancy (leukemia) controlled by aberrant signaling that is able to transform HSC and progenitor cells. In agreement with this notion, we have recently identified the E3 ubiquitin ligase Fbw7 as an important tumor suppressor in acute lymphocytic leukemia (ALL). Fbw7 inactivating mutations are found in a large fraction of ALL patients and induce transformation due to the aberrant stability of several important oncogenes, including Notch1 and c-Myc. We have addressed the role of Fbw7 in HSC function using a novel conditional knock-out mouse model. We have found that deletion of Fbw7 specifically and rapidly affected the HSC compartment in a cell-autonomous manner. Fbw7-/- HSCs showed defective maintenance of quiescence, leading to impaired self-renewal and a severe loss of competitive repopulating capacity. Furthermore, genome-wide transcriptome studies of Fbw7-/- HSC indicated that Fbw7 regulates a global transcriptional "signature" associated with the quiescent, self-renewing HSC phenotype. In this application we: a) Identify HSC-specific protein substrates targeted by Fbw7 and playing important roles in HSC differentiation and function, b) address the universal function of Fbw7 in stem cell self-renewal by studying its role in embryonic stem cell function and c) study the effects of ALL Fbw7 missense mutations in hematopoiesis and HSC self- renewal. PUBLIC HEALTH RELEVANCE: All blood cells originate from a rare population of pluripotent hematopoietic stem cells (HSC) that have the ability to both self-renew and differentiate. In this grant we study in detail the biological function of a novel HSC regulator the E3 ubiquitin ligase Fbw7. Our studies have direct translational impact as they address the function of a central regulator of HSC ability to replenish the immune system that at the same time functions as a tumor suppressor in leukemia.