Deletion of Mtg16, a target of t(16;21), alters hematopoietic progenitor cell proliferation and lineage allocation.
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.
Chyla
Brenda J
BJ
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Moreno-Miralles
Isabel
I
Steapleton
Melissa A
MA
Thompson
Mary Ann
MA
Bhaskara
Srividya
S
Engel
Michael
M
Hiebert
Scott W
SW
D000740:Anemia / Q000235:genetics; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D033481:Chromosomes, Mammalian / Q000235:genetics*; D003114:Colony-Forming Units Assay; D005260:Female; D017353:Gene Deletion; D053263:Gene Regulatory Networks / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D008297:Male; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D039902:Multipotent Stem Cells / Q000166:cytology / Q000187:drug effects; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000187:drug effects; D009687:Nuclear Proteins / Q000172:deficiency* / Q000378:metabolism; D010659:Phenylhydrazines / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D012097:Repressor Proteins; D013997:Time Factors; D014157:Transcription Factors / Q000172:deficiency* / Q000378:metabolism; D014178:Translocation, Genetic / Q000187:drug effects
D018952:Antigens, CD34; C117411:Cbfa2t3 protein, mouse; D009687:Nuclear Proteins; D010659:Phenylhydrazines; D016271:Proto-Oncogene Proteins c-myc; D017452:Receptors, IgG; D012097:Repressor Proteins; D014157:Transcription Factors; C030299:phenylhydrazine; D019009:Proto-Oncogene Proteins c-kit