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Abstract
While a number of DNA binding transcription factors have been identified that control hematopoietic cell fate decisions, only a limited number of transcriptional corepressors (e.g., the retinoblastoma protein [pRB] and the nuclear hormone corepressor [N-CoR]) have been linked to these functions. Here, we show that the transcriptional corepressor Mtg16 (myeloid translocation gene on chromosome 16), which is targeted by t(16;21) in acute myeloid leukemia, is required for hematopoietic progenitor cell fate decisions and for early progenitor cell proliferation. Inactivation of Mtg16 skewed early myeloid progenitor cells toward the granulocytic/macrophage lineage while reducing the numbers of megakaryocyte-erythroid progenitor cells. In addition, inactivation of Mtg16 impaired the rapid expansion of short-term stem cells, multipotent progenitor cells, and megakaryocyte-erythroid progenitor cells that is required under hematopoietic stress/emergency. This impairment appears to be a failure to proliferate rather than an induction of cell death, as expression of c-Myc, but not Bcl2, complemented the Mtg16−/− defect.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at http://mcb.asm.org/ .
ACKNOWLEDGMENTS
We thank the members of the Hiebert lab for helpful discussions and encouragement and the Vanderbilt-Ingram Cancer Center (CA68485) and the Vanderbilt Digestive Diseases Research Center (5P30DK58404) for support and the use of shared resources including flow cytometry, DNA sequencing, transgenic/embryonic stem cells, immunohistochemistry, and histological analysis.
This work was supported by the T. J. Martell Foundation; the Robert J. Kleberg, Jr., and Helen C. Kleberg Foundation; National Institutes of Health (NIH) grants RO1-CA64140, RO1-CA112005, and RO1-HL088494 (S.W.H.); the Leukemia and Lymphoma Society postdoctoral fellowship 5074-03 (B.J.C.); and T32CA009385-24 (M.A.S.).