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 #
5R01CA105129-08
Application #
8385544
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Mufson, R Allan
Project Start
2003-12-01
Project End
2015-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
8
Fiscal Year
2013
Total Cost
$281,616
Indirect Cost
$114,979
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Aranda-Orgilles, Beatriz; Saldaña-Meyer, Ricardo; Wang, Eric et al. (2016) MED12 Regulates HSC-Specific Enhancers Independently of Mediator Kinase Activity to Control Hematopoiesis. Cell Stem Cell 19:784-799
Ntziachristos, Panagiotis; Abdel-Wahab, Omar; Aifantis, Iannis (2016) Emerging concepts of epigenetic dysregulation in hematological malignancies. Nat Immunol 17:1016-24
King, Bryan; Boccalatte, Francesco; Moran-Crusio, Kelly et al. (2016) The ubiquitin ligase Huwe1 regulates the maintenance and lymphoid commitment of hematopoietic stem cells. Nat Immunol 17:1312-1321
Strikoudis, Alexandros; Lazaris, Charalampos; Trimarchi, Thomas et al. (2016) Regulation of transcriptional elongation in pluripotency and cell differentiation by the PHD-finger protein Phf5a. Nat Cell Biol 18:1127-1138
Guillamot, Maria; Cimmino, Luisa; Aifantis, Iannis (2016) The Impact of DNA Methylation in Hematopoietic Malignancies. Trends Cancer 2:70-83
Kourtis, Nikos; Moubarak, Rana S; Aranda-Orgilles, Beatriz et al. (2015) FBXW7 modulates cellular stress response and metastatic potential through ​HSF1 post-translational modification. Nat Cell Biol 17:322-32
Cimmino, Luisa; Dawlaty, Meelad M; Ndiaye-Lobry, Delphine et al. (2015) TET1 is a tumor suppressor of hematopoietic malignancy. Nat Immunol 16:653-62
Gao, Jie; Buckley, Shannon M; Cimmino, Luisa et al. (2015) The CUL4-DDB1 ubiquitin ligase complex controls adult and embryonic stem cell differentiation and homeostasis. Elife 4:
Kourtis, Nikos; Strikoudis, Alexandros; Aifantis, Iannis (2015) Emerging roles for the FBXW7 ubiquitin ligase in leukemia and beyond. Curr Opin Cell Biol 37:28-34
Witkowski, M T; Cimmino, L; Hu, Y et al. (2015) Activated Notch counteracts Ikaros tumor suppression in mouse and human T-cell acute lymphoblastic leukemia. Leukemia 29:1301-11

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