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.
About Stuart Orkin
Dr. Orkin received his MD from Harvard Medical School. He completed postdoctoral research at the National Institutes of Health and clinical training in pediatrics and hematology-oncology at Boston Children's Hospital and Dana Farber Cancer Institute.
He is a Howard Hughes Medical Institute Investigator as well as a member of the Institute of Medicine, the American Academy of Arts and Sciences, and the National Academy of Sciences. He has received the Warren Alpert Foundation Prize, the Dameshek Award from the American Society of Hematology, and the 2005 Distinguished Research Award of AAMC.
- Hock H, Hamblen MJ, Rooke HM, Schindler JW, Saleque S, Fujiwara Y, Orkin SH. Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells. Nature 2004; 431; 1002-1007.
- Gekas C, Dieterlen-Lievre F, Orkin SH, Mikkola HK. The placenta is a niche for hematopoietic stem cells. Dev. Cell 2005; 8; 365-375.
- Li Z, Godinho FJ, Klusmann JH, Garriga-Canut M, Yu C, Orkin SH. Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nat. Genet. 2005; 37; 613-619.