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Researcher | Research Overview

The goal of the Orkin laboratory is to understand how commitment to specific blood lineages is programmed and how cell-specific patterns of gene expression are established. Since gene expression is controlled by nuclear regulatory factors (transcription factors), efforts have centered on identifying those crucial for development of stem cells or individual lineages. Research encompasses conventional molecular biology and contemporary mouse genetics in three focus areas:

  • Lineage specification and hematopoietic differentiation
    Red blood cells and megakaryocytes (which produce platelets) share a common precursor cell. They discovered a transcription factor, GATA-1, that participates in the regulation of virtually all red cell (erythroid) and megakaryocyte-specific expressed genes. Expression of GATA-1 in progenitors drives cells toward erythroid and megakaryocytic fates. Disruption of the GATA-1 gene in mice leads to a failure of maturation of both lineages. In addition to controlling end-stage markers of these lineages, GATA-1 influences proliferation and cell death decisions of precursor cells. Using this mouse model to dissect mechanisms of cell differentiation, Orkin and colleagues have sought to understand how GATA-1 functions in transcription. This line of investigation led us to hypothesize and then discover a cofactor required for GATA-1's function in these lineages. This novel cofactor, FOG (for friend of GATA-1), is also essential for normal red blood cell and megakaryocyte development. Current research focuses on how FOG modulates the function of GATA-1, how others factors (eg Gfi-1b) cooperate in differentiation, and the discovery of protein partners of these key regulators of development.
  • Hematopoiesis-leukemia interface
    Remarkably, many genes essential for normal hematopoietic development are involved in chromosomal translocations in human leukemias. This finding reflects perturbation of normal homeostasis by expression of an altered protein or excessive production of an otherwise normal factor. The Orkin lab is studying several transcription factors (e.g. SCL/tal-1, TEL, and GATA-1) affected by genetic events in leukemias. Of particular interest are infant leukemia of the megakaryoblastic variety occurring in the setting of Down syndrome and somatic mutation of GATA-1 and childhood TEL-AML B-cell ALL.
  • Modeling the first steps in human cancer in the mouse
    In an effort to improve models of human cancers the laboratory is generating gene targeted mice with conditional mutations that replicate the first steps in selected human cancers. For example, mice have been created that conditionally express the TEL-Ntrk fusion gene characteristic of one form of breast cancer. These mice develop invasive breast cancer with full penetrance and a consistent time-course. These mice are being used to explore the step-wise pathogenesis of breast cancer and the potential role of cancer stem cells.
  • Stem cell biology
    Stem cells provide for production of specific cell lineages during development and throughout adult life. Dr. Orkin and colleagues are focusing efforts on characterization of the genes required for hematopoietic stem self-renewal and survival, as well as genes within embryonic stem cells that maintain pluripotency. Characterization of the molecular underpinnings of stem cell functions will have broad implications for cellular development and cancer.

Researcher | Research Background

Dr. Orkin received his MD in 1972 from Harvard Medical School, followed by postdoctoral research at the National Institutes of Health and clinical training in pediatrics and hematology-oncology at Children's Hospital Boston and DFCI, where he joined the faculty in 1978. Dr. Orkin is a Howard Hughes Medical Institute Investigator and was elected to the 2019-2020 Council of the National Academy of Medicine. Over the past decade, his laboratory has defined critical nuclear regulators of hematopoiesis.


  • Harrington Prize for Innovation in Medicine, American Society for Clinical Investigation and Harrington Discovery Institute, 2020
  • King Faisal International Prize for Medicine, King Faisal Foundation, 2020
  • Mechthild Esser Nemmers Prize in Medical Science, Northwestern University, 2018
  • George M. Kober Medal, American Association of Physicians, 2018
  • Clotten Foundation Prize, 2017
  • Member, American Philosophical Society, 2017
  • Lifetime Impact award, Boston Children’s Hospital’s Global Pediatric Innovation Summit, 2015
  • William A. Allan Award, American Society for Human Genetics, 2014
  • Jessie Stevenson Kovalenko Medal, National Academy of Sciences, 2013
  • Donald Metcalf Award, International Society of Experimental Hematology, 2012
  • Basic Science Mentor Award, American Society of Hematology, 2009
  • Legends in Hematology, American Society of Hematology, 2008
  • AAMC Award for Distinguished Research in Medical Sciences, 2005
  • Frank Oski Award, American Society of Pediatric Hematology and Oncology, 2003
  • E. Donnell Thomas Prize, American Society of Hematology, 1998
  • Helmut Horten Research Award, 1995
  • Warren Alpert Foundation Prize, 1993
  • Member, American Academy of Arts and Sciences, 1993
  • Member, Institute of Medicine, 1992
  • Member, National Academy of Sciences, 1991
  • E. Mead Johnson Award, Society for Pediatric Research, 1987
  • William Dameshek Prize, American Society of Hematology, 1986
  • Research Career Development Award, National Institutes of Health, 1979
  • Young Investigator Award, National Institutes of Health, 1976

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Researcher | Publications