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Cancer Cell. 2009 Apr 7;15(4):341-52. doi: 10.1016/j.ccr.2009.02.016.

JunB protects against myeloid malignancies by limiting hematopoietic stem cell proliferation and differentiation without affecting self-renewal.

Author information

  • 1The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA 94143, USA.

Abstract

Loss of the JunB/AP-1 transcription factor induces a myeloproliferative disease (MPD) arising from the hematopoietic stem cell (HSC) compartment. Here, we show that junB inactivation deregulates the cell-cycle machinery and increases the proliferation of long-term repopulating HSCs (LT-HSCs) without impairing their self-renewal or regenerative potential in vivo. We found that JunB loss destabilizes a complex network of genes and pathways that normally limit myeloid differentiation, leading to impaired responsiveness to both Notch and TGF-beta signaling due in part to transcriptional deregulation of the Hes1 gene. These results demonstrate that LT-HSC proliferation and differentiation are uncoupled from self-renewal and establish some of the mechanisms by which JunB normally limits the production of myeloid progenitors, hence preventing initiation of myeloid malignancies.

Comment in

PMID:
19345332
[PubMed - indexed for MEDLINE]
PMCID:
PMC2669108
Free PMC Article

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