Regulation of hematopoietic stem cell differentiation

造血干细胞分化的调控

• 批准号: 8761288
• 负责人: Iannis Aifantis
• 金额: $ 14.01万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-11-27 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761288
• 关键词: Acute Lymphocytic Leukemia; Address; Adult; Affect; Agreement; Alleles; Animal Model; Binding; Biochemical Genetics; Biological Process; Blood Cells; Cell Cycle Regulation; Cell division; Cell physiology; Cells; Chromatin; Data; Dominant-Negative Mutation; Equilibrium; Gene Expression; Gene Expression Profile; Gene Targeting; Genetic; Genome; Genomics; Grant; Health; Hematopoiesis; Hematopoiesis Induction; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Immune system; Knock-in Mouse; Knock-out; Knockout Mice; Lead; Life; Maintenance; Malignant Neoplasms; Mediating; Missense Mutation; Modeling; Mutation; Oncogenes; Oncogenic; Organism; Patients; Phenotype; Physiological; Play; Point Mutation; Population; Post-Translational Protein Processing; Proliferating; Proteins; Proto-Oncogene Proteins c-myc; Protocols documentation; Regulation; Role; Signal Transduction; Stem cells; System; Testing; Time; Tissues; Tumor Suppressor Proteins; Ubiquitination; c-myc Genes; embryonic stem cell; fetal; genome-wide; leukemia; loss of function; mouse model; notch protein; novel; progenitor; self-renewal; stem cell differentiation; ubiquitin-protein ligase

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.

描述（由申请人提供）：所有成熟的血细胞都源自一种罕见且特殊的群体，即造血干细胞（HSC），它们大多以静止状态存在。 HSC 的细胞分裂导致其增殖并逐渐分化为谱系限制越来越多的成熟血细胞，并维持一小部分 HSC 不分化，而是在生物体的整个生命周期中进行造血作用。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首要任务。有趣的是，一些研究表明，生理性造血与造血系统恶性肿瘤（白血病）的诱导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 是急性淋巴细胞白血病 (ALL) 的重要肿瘤抑制因子。 Fbw7 失活突变存在于大部分 ALL 患者中，并且由于包括 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。我们使用新型条件敲除小鼠模型探讨了 Fbw7 在 HSC 功能中的作用。我们发现 Fbw7 的缺失以细胞自主的方式特异性且快速地影响 HSC 区室。 Fbw7-/- HSCs 表现出静态维持缺陷，导致自我更新受损和竞争性繁殖能力严重丧失。此外，Fbw7-/- HSC 的全基因组转录组研究表明，Fbw7 调节与静止、自我更新的 HSC 表型相关的全局转录“特征”。在此应用中，我们：a) 鉴定 Fbw7 靶向的 HSC 特异性蛋白底物，并在 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 Fbw7 在干细胞自我更新中的普遍功能，以及c) 研究 ALL Fbw7 错义突变对造血和 HSC 自我更新的影响。

项目成果

The controversial role of the Hedgehog pathway in normal and malignant hematopoiesis.

• DOI: 10.1038/leu.2011.143
• 发表时间: 2011-11
• 期刊: Leukemia
• 影响因子: 11.4

Prolyl-isomerase Pin1 controls normal and cancer stem cells of the breast.

• DOI: 10.1002/emmm.201302909
• 发表时间: 2014-01
• 期刊: EMBO MOLECULAR MEDICINE
• 影响因子: 11.1
• 作者: Rustighi, Alessandra;Zannini, Alessandro;Tiberi, Luca;Sommaggio, Roberta;Piazza, Silvano;Sorrentino, Giovanni;Nuzzo, Simona;Tuscano, Antonella;Eterno, Vincenzo;Benvenuti, Federica;Santarpia, Libero;Aifantis, Iannis;Rosato, Antonio;Bicciato, Silvio;Zambelli, Alberto;Del Sal, Giannino
• 通讯作者: Del Sal, Giannino

Regulation of hematopoietic stem cell fate by the ubiquitin proteasome system.

• DOI: 10.1016/j.it.2012.01.009
• 发表时间: 2012-07
• 期刊: Trends in immunology
• 影响因子: 16.8
• 作者: Moran-Crusio K;Reavie LB;Aifantis I
• 通讯作者: Aifantis I

Regulation of pluripotency and cellular reprogramming by the ubiquitin-proteasome system.

• DOI: 10.1016/j.stem.2012.09.011
• 发表时间: 2012-12-07
• 期刊: CELL STEM CELL
• 影响因子: 23.9
• 作者: Buckley, Shannon M.;Aranda-Orgilles, Beatriz;Strikoudis, Alexandros;Apostolou, Effie;Loizou, Evangelia;Moran-Crusio, Kelly;Farnsworth, Charles L.;Koller, Antonius A.;Dasgupta, Ramanuj;Silva, Jeffrey C.;Stadtfeld, Matthias;Hochedlinger, Konrad;Chen, Emily I.;Aifantis, Iannis
• 通讯作者: Aifantis, Iannis

Energy addiction and lymphocyte differentiation: a new role for the liver kinase B1 kinase.

能量成瘾和淋巴细胞分化：肝激酶 B1 激酶的新作用。

• DOI: 10.1002/eji.200940206
• 发表时间: 2010
• 期刊: European journal of immunology
• 影响因子: 5.4
• 作者: Aifantis,Iannis;Sawai,Catherine
• 通讯作者: Sawai,Catherine