Yupo Ma, MD, PhD
Yupo Ma, MD, PhD
Medical Director of Flow Cytometry
Scientific Director of Stem Cell Core
Basic Science Tower, Level 9
Stony Brook Medicine
Stony Brook, NY 11794-8691
Phone: (631) 444-2214
Fax: (631) 444-3424
Dr. Ma earned his Medical Degree from Jinan University (P.R. China), College of Medicine and a Ph.D. from the University of South Alabama College of Medicine. He completed a residency in Pathology at Brown University, clinical fellowship in Hematopathology at M.D. Anderson Cancer Center and has conducted Post Doctoral Training in Pathology at Harvard Medical School. Dr. Ma joins the Department as a hematopathologist and serves as Professor of Pathology and Medical Director of the Flow Cytometry Laboratory. Formerly, he was Chief of Hematopathology, Head of the Stem Cell Program, and Director of the Flow Cytometry Laboratory at Nevada Cancer Institute.
1. Leukemic stem cells.
We focus on the role of SALL4 in pluripotent progenitor cells and leukemic progenitor cells. The SALL gene family is the mammalian homologue of Drosophila gene Spalt (sal). In Drosophila, sal mutation can lead to the incomplete separation of the head and trunk of the fly. In the human, heterogeneous mutation of SALL1 causes Townes-Brock Syndrome with renal, cardiac, genital malformation. Heterogeneous mutation of SALL4 in humans is associated with Okihiro Syndrome with limitation of eye abduction, deafness, and digit malformation.
Recent works has suggested that SALL4 plays important roles during development. SALL4 plays an important role in the maintenance of pluripotent properties and self renewal during mammalian development. Consistently, SALL4 is able to bind to both OCT4 and NANOG. Loss of SALL4 expression results in cellular differentiation.
We have demonstrated that SALL4 is constitutively expressed in acute myeloid leukemias (AML) and fails to turn off in nearly all human AMLs. A fundamental unanswered question: is constitutive expression of SALL4 sufficient to induce AML? In addition, what mechanisms of SALL4 induce AML? How does SALL4 promoter leukemic progenitor cell self renewal? We have chosen a mammalian model system to approach these questions. This should allow us to test directly leukemogenic potential of constitutive expression of SALL4 in . A mammalian model overexpressing SALL4 develops hematopoietic disorders including myelodysplastic-like symptoms and subsequently acute myeloid leukemia. The constitutive expression of SALL4 is causal to the leukemic phenotype and SALL4 may interact with the Wnt/β-catenin pathway in the leukemogenesis. Our mammalian models should provide a useful platform to analyze the effect of SALL4 on hematopoiesis and its potential cooperation with Wnt/β-catenin pathway in the pathogenesis of leukemia progenitor cells. Leukemic progenitor cells are aberrant cells that maintain and propagate blood cancers.
A parallel project involves an investigation of the SALL4 function in development and hematopoiesis. We are creating a loss of function model for SALL4 using conventional and conditional knockout approaches. In characterizing the phenotype of SALL4 deficient models, we are focusing on the role of SALL4 in regulating hematopoiesis and hematopoietic progenitor cell function.
2. Stem cell therapy and tissue repair.
Our recent studies are also focused on a stem cell therapy by using adult somatic cells and turning back the development of these cells so they act like embryonic cells. This process, called retrodifferentiation, produces pluripotent stem cells. These induced pluripotent stem cells (iPS cells) in combination with growth factors can then be redifferentiated into cells which may be used to treatment specific diseases. In this case, the iPS derived cells function in the animal to synthesize a protein (clotting factor that has shown it can reverse excessive bleeding, which may eventually be useful for treating hemophilia patients. Our lab is the first to document the ability to “cure” mice with Hemophilia A by a single injection of endothelial cell precursors derived from iPS cells. Using similar strategies, our lab has generated a variety of differentiated cell types including hematopoietic cells, liver hepatocytes, pancreatic islet cells, heart cells, lung cells, and various neuronal cell types. These will be tested in various therapeutic model systems in the near future.
Wong BY, Ma Y, Fitzwilson R , Dang HD. De novo maintenance therapy with denileukin diftitox (Ontak®) in a patient with peripheral T-cell lymphoma is associated with prolonged remission. 2008, AM J Hematol Jul;83(7):596-8.
Yang Y, Chai L, Fowles T, Alipio Z, Fink LM, Ward DC and Ma Y SALL4 is a key regulator of survival and apoptosis in human leukemic cells. Blood, 2008 Aug 1;112(3):805-13. Epub 2008 May 16.
Yang Y, Chai L, Fowles T, Alipio Z, Fink LM, Ward DC and Ma Y. Genome-wide analysis reveals Sall4 to be a key master regulator of pluripotency in murine embryonic stem cells. 2008, Proc. Natl. Acad. Sci. USA. Dec 16;105(50):19756-61. Epub 2008 Dec 5
Goodman O.B., Fink L.M, Symanowski J, Wong B, Grobaski B, Pomerantz D, Ma Y, Ward D, Vogelzang N. Circulating Tumor Cells in Patients with Castration-resistant Prostate Cancer- baseline Values and Correlation with Prognostic Factors. Cancer Epidemiology, Biomarkers & Prevention, 2009 Jun;18(6):1904-13
Teresa MO, Melin T, Tarango M, Fink LM, Martin M, Ma Y, Waner M. Differential expression of Ski oncogene protein in hemangiomas. Otolaryngology-Head and Neck Surgery. 2009, 141, 213-218
Gai H, Leung EL, Costantino PD, Aguila JR, Nguyen DM, Fink LM, Ward DC, Ma Y. Generation and characterization of functional cardiomyocytes using induced pluripotent stem cells derived from human Fibroblasts. 2009, Cell Biol. International, Nov;33(11):1184-93. Epub 2009 Sep 1.
Bard D, Gelebart P, Amin HM, Young LC, Ma Y, Lai R. STAT3 is a transcriptional factor regulating the gene expression of SALL4. 2009 FASEB J. ;23(5):1405-14. Jan 16.
Lu J, Jeong H, Kong N, Yang Y, Carroll J, Luo HR, Silberstein LE, Ma Y, and L Chai. Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex. PLoS ONE 2009;4(5):e5577. Epub 2009 May 18
Xu D, Alipio Z, Fink LM, Adcock DM, Yang Y, Ward DC, Ma Y. Phenotypic correction of murine hemophilia A using an iPS cell-based therapy, 2009, Proc. Natl. Acad. Sci. USA. Jan 20;106(3):808-13.
Wang P, Wu F, Ma Y, Li L, Lai R, Young L. Functional Characterization of the kinase activation loop in nucleophosmin (NPM) -anaplastic lymphoma kinase (ALK) using tandem affinity purification and liquid chromatography-mass spectrometry, J Biol Chem 2009 Nov 2. [Epub ahead of print].
Alipio Z, Adcock DM, Waner M, TMing-Jung O T , Fink LM,, Ward DC, Ma Y. Sustained FVIII production in hemophiliac mice 1 year after engraftment with iPS cell-derived FVIII producing endothelial cells. 2010, Blood, Coagulation and Fibrinolysis. In Press
Gai H, Nguyen DV, Moon YJ, Aguila JR, Fink LM, Ward DC, Ma Y. Generation of Murine Hepatic Lineage Cells from Induced Pluripotent Stem Cells. 2010. Differentiation in Press.