Regulation of murine hematopoietic stem cell quiescence by Dmtf1

Michihiro Kobayashi, Edward Srour

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

The cell-cycle status of hematopoietic stem cells (HSCs) is tightly regulated, most likely to balance maintenance of stem-cell status through quiescence and expansion/differentiation of the hematopoietic system. Tumor-suppressor genes (TSGs), with their cell cycle-regulatory functions, play important roles in HSC regulation. The cyclin-D binding myb-like transcription factor 1 (Dmtf1) was recently recognized as a TSG involved in human cancers by repressing oncogenic Ras/Raf signaling. However, the role of Dmtf1 in the hematopoietic system is entirely unknown. In the present study, we demonstrate that Dmtf1 regulates HSC function under both steady-state and stress conditions. Dmtf1 -/- mice showed increased blood cell counts in multiple parameters, and their progenitor cells had increased proliferation and accelerated cell-cycle progression. In addition, longterm HSCs from Dmtf1 -/- mice had a higher self-renewal capacity that was clearly demonstrated in secondary recipients in serial transplantation studies. Dmtf1 -/- BM cells showed hyper proliferation after 5-fluorouracil-induced myeloablation. Steady-state expression and Induction of CDKN1a (p21) and Arf were impaired in HSCs from Dmtf1 -/- mice. The function of Dmtf1 was mediated by both Arf-dependent and Arf-independent pathways. Our results implicate Dmtf1 in the regulation of HSC function through novel cell cycle-regulatory mechanisms.

Original languageEnglish
Pages (from-to)6562-6571
Number of pages10
JournalBlood
Volume118
Issue number25
DOIs
StatePublished - Dec 15 2011

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Hematopoietic Stem Cells
Stem cells
Transcription Factors
Cell Cycle
Cells
Hematopoietic System
Tumor Suppressor Genes
Stem Cells
Tumors
Cyclin D
Genes
Blood Cell Count
Fluorouracil
Transplantation
Maintenance
Blood
Mouse Hnf1a protein
Neoplasms

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Regulation of murine hematopoietic stem cell quiescence by Dmtf1. / Kobayashi, Michihiro; Srour, Edward.

In: Blood, Vol. 118, No. 25, 15.12.2011, p. 6562-6571.

Research output: Contribution to journalArticle

Kobayashi, Michihiro ; Srour, Edward. / Regulation of murine hematopoietic stem cell quiescence by Dmtf1. In: Blood. 2011 ; Vol. 118, No. 25. pp. 6562-6571.
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