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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA105129-07
Application #
8196726
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Mufson, R Allan
Project Start
2003-12-01
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
7
Fiscal Year
2012
Total Cost
$299,591
Indirect Cost
$122,318
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Ntziachristos, Panagiotis; Lim, Jing Shan; Sage, Julien et al. (2014) From fly wings to targeted cancer therapies: a centennial for notch signaling. Cancer Cell 25:318-34
Rustighi, Alessandra; Zannini, Alessandro; Tiberi, Luca et al. (2014) Prolyl-isomerase Pin1 controls normal and cancer stem cells of the breast. EMBO Mol Med 6:99-119
Gough, Daniel J; MariƩ, Isabelle J; Lobry, Camille et al. (2014) STAT3 supports experimental K-RasG12D-induced murine myeloproliferative neoplasms dependent on serine phosphorylation. Blood 124:2252-61
Trimarchi, Thomas; Bilal, Erhan; Ntziachristos, Panagiotis et al. (2014) Genome-wide mapping and characterization of Notch-regulated long noncoding RNAs in acute leukemia. Cell 158:593-606
Strikoudis, Alexandros; Guillamot, Maria; Aifantis, Iannis (2014) Regulation of stem cell function by protein ubiquitylation. EMBO Rep 15:365-82
Lobry, Camille; Oh, Philmo; Mansour, Marc R et al. (2014) Notch signaling: switching an oncogene to a tumor suppressor. Blood 123:2451-9
Ntziachristos, Panagiotis; Tsirigos, Aristotelis; Welstead, G Grant et al. (2014) Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature 514:513-7
Di Micco, Raffaella; Fontanals-Cirera, Barbara; Low, Vivien et al. (2014) Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes. Cell Rep 9:234-47
Ntziachristos, Panagiotis; Mullenders, Jasper; Trimarchi, Thomas et al. (2013) Mechanisms of epigenetic regulation of leukemia onset and progression. Adv Immunol 117:1-38
King, Bryan; Trimarchi, Thomas; Reavie, Linsey et al. (2013) The ubiquitin ligase FBXW7 modulates leukemia-initiating cell activity by regulating MYC stability. Cell 153:1552-66

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