Transcriptional regulation in myelopoiesis: Hematopoietic fate choice, myeloid differentiation, and leukemogenesis.
Myeloid cells (granulocytes and monocytes) are derived from multipotent hematopoietic stem cells. Gene transcription plays a critical role in hematopoietic differentiation. However, there is no single transcription factor that is expressed exclusively by myeloid cells and that, alone, acts as a "master" regulator of myeloid fate choice. Rather, myeloid gene expression is controlled by the combinatorial effects of several key transcription factors. Hematopoiesis has traditionally been viewed as linear and hierarchical, but there is increasing evidence of plasticity during blood cell development. Transcription factors strongly influence cellular lineage during hematopoiesis and expression of some transcription factors can alter the fate of developing hematopoietic progenitor cells. PU.1 and CCAAT/enhancer-binding protein alpha (C/EBPalpha) regulate expression of numerous myeloid genes, and gene disruption studies have shown that they play essential, nonredundant roles in myeloid cell development. They function in cooperation with other transcription factors, co-activators, and co-repressors to regulate genes in the context of chromatin. Because of their essential roles in regulating myeloid genes and in myeloid cell development, it has been hypothesized that abnormal expression of PU.1 and C/EBPalpha would contribute to aberrant myeloid differentiation, i.e. acute leukemia. Such a direct link has been elusive until recently. However, there is now persuasive evidence that mutations in both PU.1 and C/EBPalpha contribute directly to development of acute myelogenous leukemia. Thus, normal myeloid development and acute leukemia are now understood to represent opposite sides of the same hematopoietic coin.
Rosmarin
Alan G
AG
Department of Medicine, Brown Medical School, Providence, RI, USA. Rosmarin@Brown.edu
Yang
Zhongfa
Z
Resendes
Karen K
KK
D000818:Animals; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D022423:Myeloid Cells / Q000166:cytology / Q000473:pathology; D038042:Myelopoiesis / Q000502:physiology*; D014158:Transcription, Genetic