c-Myb and p300 regulate hematopoietic stem cell proliferation and differentiation.
Precise control of hematopoietic stem cell (HSC) proliferation and differentiation is needed to maintain a lifetime supply of blood cells. Using genome-wide ENU mutagenesis and phenotypic screening, we have identified a mouse line that harbors a point mutation in the transactivation (TA) domain of the transcription factor c-Myb (M303V), which reduces c-Myb-dependent TA by disrupting its interaction with the transcriptional coactivator p300. The biological consequences of the c-Myb(M303V/M303V) mutation include thrombocytosis, megakaryocytosis, anemia, lymphopenia, and the absence of eosinophils. Detailed analysis of hematopoiesis in c-Myb(M303V/M303V) mice reveals distinct blocks in T cell, B cell, and red blood cell development, as well as a remarkable 10-fold increase in the number of HSCs. Cell cycle analyses show that twice as many HSCs from c-Myb(M303V/M303V) animals are actively cycling. Thus c-Myb, through interaction with p300, controls the proliferation and differentiation of hematopoietic stem and progenitor cells.
Sandberg
Mark L
ML
Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
Sutton
Susan E
SE
Pletcher
Mathew T
MT
Wiltshire
Tim
T
Tarantino
Lisa M
LM
Hogenesch
John B
JB
Cooke
Michael P
MP
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D001483:Base Sequence; D002454:Cell Differentiation; D049109:Cell Proliferation; D004247:DNA / Q000235:genetics; D050881:E1A-Associated p300 Protein; D005260:Female; D020570:Genes, myb; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D066298:In Vitro Techniques; D008297:Male; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D020598:Proto-Oncogene Proteins c-myb / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology; D013922:Thrombocytosis / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation
D009687:Nuclear Proteins; D020598:Proto-Oncogene Proteins c-myb; D015534:Trans-Activators; D004247:DNA; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse