Regulation of hematopoietic stem cell differentiation

描述（由申请人提供）：所有成熟血细胞都来自一种罕见的特化群体，即造血干细胞（HSC），其主要以静止状态存在。HSC的细胞分裂导致其增殖和逐渐分化成越来越受谱系限制的成熟血细胞，以及维持一小部分不分化的HSC，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，阐明调控HSC自我更新和分化之间平衡的信号是一项重要任务。有趣的是，几项研究表明，生理造血和诱导造血恶性肿瘤（白血病）之间的密切平衡控制的异常信号，能够转化HSC和祖细胞。与此观点一致，我们最近鉴定了E3泛素连接酶Fbw 7作为急性淋巴细胞白血病（ALL）的重要肿瘤抑制因子。Fbw 7失活突变在大部分ALL患者中发现，并由于几种重要癌基因（包括Notch 1和c-Myc）的异常稳定性而诱导转化。我们使用一种新的条件性基因敲除小鼠模型研究了Fbw 7在HSC功能中的作用。我们已经发现，Fbw 7的缺失特异性地和快速地以细胞自主的方式影响HSC区室。Fbw 7-/-HSC表现出有缺陷的静止维持，导致自我更新受损和竞争性再增殖能力的严重丧失。此外，Fbw 7-/- HSC的全基因组转录组研究表明，Fbw 7调节与静止、自我更新的HSC表型相关的全局转录“签名”。在本申请中，我们：a）鉴定由Fbw 7靶向并在HSC分化和功能中起重要作用的HSC特异性蛋白质底物，B）通过研究Fbw 7在胚胎干细胞功能中的作用来解决Fbw 7在干细胞自我更新中的通用功能，和c）研究ALL Fbw 7错义突变在造血和HSC自我更新中的作用。

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.