Cancer, Cell Transformation, Cellular Differentiation, Hematopoiesis, Leukemia, Oncogenes, Oxidative Stress, Signal Transduction, Stem Cells, Transcription Factors
Cancer Biology [CAB], Developmental and Stem Cell Biology [DSCB]
MD, Universite de Paris XII, Paris, France
Clinical Scientist, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology
MSc, Universite de Paris XII, Paris, France
PhD, University of British Columbia, Vancouver, B.C., Canada
Bridge Grant Award
American Society of Hematology
Myeloproliferative Neoplam (MPN) Foundation
Research Foundation New Investigator Award
New York State Stem Cell Science (NYSTEM) Award
Irma Hirschl/Weill-Caulier Trust Research Award
Roche Foundation for Anemia Research (RoFAR) Award
Black Family Stem Cell Institute Exploratory Research Award
NIH Clinician Scientist Career Award
National Cancer Institute
American Cancer Society
National Cancer Institute of Canada
Terry Fox Physician-Scientist Fellowship
Blood and Blood Disorders
The Ghaffari laboratory investigates mechanisms that regulate blood stem and progenitor cell formation that are implicated in the pathophysiology of blood disorders. We have been addressing these questions by focusing on FOXO family of transcription factors, which are key regulators of stress resistance and implicated in enhancing human longevity (FOXO3). In our studies we apply genetic tools and biochemistry to investigate the biology of mouse and human cells and the pathophysiology of various mouse models of human blood disorders.
In carrying this work forward we have set up multiple collaborations with investigators at Mount Sinai and elsewhere. Several projects deriving from the line of work described here are available to PhD and MD/PhD students at Mount Sinai.
Hematopoiesis, Hematopoietic Stem Cells and Erythropoiesis
Blood-forming stem cells have unique properties that enable them to live a long life and regenerate blood constantly. The well-being of blood-forming stem cells throughout life is essential for maintaining a healthy life by producing billions of red and white blood cells every day in humans. With aging this regenerative capacity declines which compromises optimum blood production and might also lead to blood malignancies whose incidence increases with age. The primary goal of our laboratory is to dissect the regulatory pathways that maintain the health of blood-forming stem and progenitor cells throughout life. We hope this knowledge will eventually lead to the identification of specific targets and/or development of novel tools that could be used in the clinic to improve therapy and/or to produce healthy blood-forming stem cells in a dish for bone marrow transplantation. In these efforts, we have identified the transcription factor FOXO3 and its regulatory network as critical regulators of blood-forming stem cells and their production of red blood cells.
Erythropoiesis, Red Blood Cells and FOXO3
Erythropoiesis is the process of making red blood cells (RBCs) from hematopoietic progenitor cells. RBCs carry oxygen and travel throughout the body to oxygenate all tissues. Anemia or reduced capacity of RBCs to carry oxygen constitutes a major health problem associated with many disorders. In response to loss or reduced production of RBCs, blood-forming stem and progenitor cells are activated to produce RBCs. RBC production is dependent mainly on erythropoietin, a hormone that is produced when oxygen levels are low. We found FOXO3, a protein that regulates a response to oxygen levels and whose function is partly controlled by erythropoietin, as key to physiologicalregulation of red blood cell maturation and production and the regulation of harmful consequences of oxygen metabolism (oxidative stress) during this process. Our work suggests that enhancing FOXO3 function might increase RBC production in a dish. We are currently evaluating whether some of FOXO3 targets might recapitulate its function and also increase RBC formation in a dish.
Hematopoietic Stem Cells, Leukemic Stem Cells, Aging Stem Cells, Mitochondria and FOXO3
Dormancy is a fundamental property of most adult stem cells. The regeneration capacity of adult blood-forming stem cells is tightly linked to their dormancy, a property that requires the transcription factor FOXO3. The maintenance of stem cell dormancy requires balanced metabolism and mitochondrial function. Our work indicates that FOXO3 is required for mitochondrial metabolism in blood-forming stem cells. We have devised a new approach to investigate stem cell functions. Using this novel approach and other tools we have acquired or developed, we are delving deep into mitochondrial metabolism, its regulation of blood-forming stem cells, and the role of FOXO3. We are also using these tools to dissect the generation of leukemic stem cells and the potential contribution of FOXO3 to this process. Our hope is that these combined approaches will enhance our ability to identify molecules that interfere with abnormal mitochondrial metabolism that might eventually be used therapeutically to modulate stem cell function.
Pauline Rimmelé Ph.D., Post-doctoral Fellow
Carolina Bigarella Ph.D., Post-doctoral Fellow
Raymond Liang, Ph.D. Student
Liang R, Campreciós G, Kou Y, McGrath K, Nowak R, Catherman S, Bigarella CL, Rimmelé P, Zhang X, Gnanapragasam MN, Bieker JJ, Papatsenko D, Ma'ayan A, Bresnick E, Fowler V, Palis J, Ghaffari S. A Systems Approach Identifies Essential FOXO3 Functions at Key Steps of Terminal Erythropoiesis. PLoS genetics 2015 Oct; 11(10).
Rimmelé P, Liang R, Bigarella CL, Kocabas F, Xie J, Serasinghe MN, Chipuk J, Sadek H, Zhang CC, Ghaffari S. Mitochondrial metabolism in hematopoietic stem cells requires functional FOXO3. EMBO reports 2015 Sep; 16(9).
Rimmelé P, Bigarella CL, Liang R, Izac B, Dieguez-Gonzalez R, Barbet G, Donovan M, Brugnara C, Blander JM, Sinclair DA, Ghaffari S. Aging-like phenotype and defective lineage specification in SIRT1-deleted hematopoietic stem and progenitor cells. Stem cell reports 2014 Jul; 3(1).
Price JG, Idoyaga J, Salmon H, Hogstad B, Bigarella CL, Ghaffari S, Leboeuf M, Merad M. CDKN1A regulates Langerhans cell survival and promotes Treg cell generation upon exposure to ionizing irradiation. Nature immunology 2015 Oct; 16(10).
Bigarella CL, Liang R, Ghaffari S. Stem cells and the impact of ROS signaling. Development (Cambridge, England) 2014 Nov; 141(22).
Zhang X, Campreciós G, Rimmelé P, Liang R, Yalcin S, Mungamuri SK, Barminko J, D'Escamard V, Baron MH, Brugnara C, Papatsenko D, Rivella S, Ghaffari S. FOXO3-mTOR metabolic cooperation in the regulation of erythroid cell maturation and homeostasis. American journal of hematology 2014 Oct; 89(10).
McIver SC, Kang YA, DeVilbiss AW, O'Driscoll CA, Ouellette JN, Pope NJ, Camprecios G, Chang CJ, Yang D, Bouhassira EE, Ghaffari S, Bresnick EH. The exosome complex establishes a barricade to erythroid maturation. Blood 2014 Oct; 124(14).
Rimmelé P, Lofek-Czubek S, Ghaffari S. Resveratrol increases the bone marrow hematopoietic stem and progenitor cell capacity. American journal of hematology 2014 Dec; 89(12).
Zhang X, Yalcin S, Lee DF, Lee S, Yeh T, Jie S, Kennedy M, Sellers R, Landthaler M, Tuschl T, Chi NW, Lemischka I, Keller G, Ghaffari S. FOXO1 is an essential regulator of pluripotency in human embryonic stem cells. Nature Cell Biology 2011 July;: doi:10.1038/ncb2293.
Yu D , dos Santos CO, Zhao G, Jiang J, Amigo JD, Khandros E , Dore LC, Yao Y, D'Souza J, Ghaffari S, Choi J, Friend S, Tong W, Orange JS, Paw BH, Weiss MJ. miR-451 Protects Against Erythroid Oxidant Stress by Repressing 14-3-3z.. Genes & Development 2010; 24(15): 1620-1633.
Yalcin S, Marinkovic D, Mungamuri S, Tong W, Ghaffari S. Oxidative stress-mediated amplification of AKT/mTOR signaling pathway leads to myeloproliferative syndrome in Foxo3-/- mice . EMBO Journal 2010 Nov 26; 29(24): 4118-31.
Ghaffari S. Oxidative stress in the regulation of normal and neoplastic hematopoiesis. Forum Issue Antioxidants & Redox Signaling 2008; 10: 1923-1940.
Zhang X, Rielland M, Yalcin S, Ghaffari S. Regulation and function of FoxO transcription factors in normal and cancer cells. What have we learned?. Current Drug Targets [Epub ahead of print] 2011 Mar 28;.
Shazib P, Ghaffari S, Taneja R. Oxidative Stress Regulation of Stem and Progenitor Cells. Forum Issue Antioxidants & Redox Signaling 2009; 11(11): 2777-2789.
Yalcin S, Zhang X, Marinkovic D, Luciano J, Sarkar A, Ghaffari C, Vercherat C, Taneja R, Ghaffari S. Foxo3 is essential for the regulation of ATM and oxidative stress-mediated homeostasis of hematopoietic stem cells. Journal of Biological Chemistry 2008; 283: 25692-25705.
Marinkovic D, Zhang X, Yalcin S, Brugnara C, Huber T, Ghaffari S, . Foxo3 is required for the regulation of oxidative stress in erythropoiesis. Journal of Clinical Investigation (This paper was highlighted in Conmentary: JCI (8): 2075-2077, 2077). 2007; 117(8): 2133-2144.
Zhao W, Kitidis C, Fleming MD, Lodish HF, Ghaffari S , . Erythropoietin stimulates phosphorylation and activation of GATA-1 via the PI3-kinase-AKT signaling pathway. Blood (this paper was highlighted in Inside Blood; 107 (3): 851-85) 2006; 107(3): 907-915.
Ghaffari S, Kitidis C, Zhao W, Marinkovic D, Fleming MD, Luo B, Marszalek J, Lodish HF. AKT induces erythroid-cell maturation of JAK2-deficient fetal liver progenitor cells and is required for Epo regulation of erythroid-cell differentiation. Blood Mar 1; 107(5): 1888-91.
Ghaffari S, Jagani Z, Kitidis C, Lodish HF, Khosravi-Far R. Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOXO3a transcription factor. Proc Natl Acad Sci U S A 2003; 100(11): 6523-6528.
Zhao X, Ghaffari S, Lodish HF, Malashkevich VN, Kim PS. Stucture of the BCR-ABL oncoprotein oligomerization domain. Nature Structural Biology 2002 ; 9(2): 1-4 .
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