Stuart H. Orkin

Department of Pediatric Oncology, DFCI
Children's Hospital and Dana Farber Cancer Institute
Howard Hughes Medical Institute

Harvard Stem Cell Institute
300 Longwood Avenue
Boston, MA 02115
Tel: (617) 919-2042
Fax: (617) 730-0222
Email: orkin@bloodgroup.tch.harvard.edu
13 postdoctoral fellows, 1 graduate student, 1 undergraduate or visiting student
Assistant: Marie Palardy (palardy@bloodgroup.tch.harvard.edu), 617-919-2042

Molecular analysis of blood cell development has served as an important paradigm for stem cell biology. We have obtained a solid foundation in understanding how commitment to specific lineages is programmed and cell-specific patterns of gene expression are established. We are interested in how hematopoietic, and other, stem cells transcriptionally control developmental potency and how aberration may precipitate oncogenesis.

Our studies have focused primarily on the in vivo roles of transcriptional regulators in cell specification and differentiation. Studies involve diverse approaches, including conventional and conditional gene targeting and proteomics. We have characterized the roles of several major transcription factors in blood cell development, and how abnormalities in these may lead to hematopoietic malignancy. Ongoing projects include the following: 1. Defining and manipulating the protein network of mES cells that controls pluripotency; 2. Epigenetic regulation of hematopoietic stem cells and mES cell pluripotency and differentiation; 3. Dissecting the genetics of one form of early childhood leukemia with hES cells; and 4. Modeling osteosarcoma in the mouse with the goal of developing new approaches to controlling or preventing metastases based on high-throughput screens or epigenetics and 5. Defining the control of fetal hemoglobin (HbF) in humans and reactivation of HbF in adults.

References:

• Kim, J., Chu, J., Shen, X., Wang, J., and Orkin, S.H. An extended transcriptional network for pluripotency of embryonic stem cells. Cell, 132: 1049-1061,  2008.
• Shen, X., Liu, Y., Hsu, Y.J., Fujiwara, Y., Kim, J., Mao, X., Yuan, G.G., and Orkin, S. H. EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identify and executing pluripotency. Mol. Cell 32: 491-502,  2008.
• Sankaran, V.G., Menne, T.F., Xu, J., Akie, T.E., Lettre, G., Van Handel, B., Mikkola, H.K., Hirschhorn, J.N., Cantor, A.B., and Orkin, S.H.  Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science 322: 1839-1842, 2008.