Cyclin dependent kinase inhibitors differentially modulate synergistic cytokine responsiveness of hematopoietic progenitor cells

Hal E. Broxmeyer, David S. Franklin, Scott Cooper, Giao Hangoc, Charlie Mantel

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Cyclin dependent kinase inhibitors (CDKIs) influence proliferation of hematopoietic progenitor cells (HPCs), but little is known of how they influence proliferative responsiveness of HPCs to colony stimulating factors (CSFs), alone and in combination with other hematopoietically active factors, such as the potent co-stimulating cytokine stem cell factor (SCF), or inhibition by myelosuppressive chemokines. Using mice with deletions in p18INK4c, p21CIP1/WAF1, or p27KIP1 genes, and in mice with double gene deletions for either p18/p21 or p18/p27, we determined effects of absence of these CDKIs and their interactions on functional HPC numbers in vivo, and HPC proliferative responsiveness in vitro. There is a decrease in bone marrow HPC proliferation in p18-/- mice commensurate with decreased numbers of HPC, suggesting a positive role for p18 on HPC in vivo, similar to that for p21. These positive effects of p18 dominate negative effects of p27 gene deletion. Moreover, the CDKIs differentially regulate responsiveness of granulocyte macrophage (GM) progenitors to synergistic cell proliferation in response to GM-CSF plus SCF, which is considered important for normal hematopoiesis. Responsiveness of HPCs to inhibition by myelosuppressive chemokines is directly related to the capacity of HPCs to respond to synergistic stimulation, and their cell cycle status. P18INK4c gene deletion rescued the loss of chemokine suppression of synergistic proliferation due to deletion of p21 CIP1/WAF1. These findings underscore the complex interplay of cell cycle regulators in HPC, and demonstrate that loss of one can sometimes be compensated by loss of another CDKI in both, a pro- or anti-proliferative context.

Original languageEnglish (US)
Pages (from-to)1597-1603
Number of pages7
JournalStem cells and development
Volume21
Issue number10
DOIs
StatePublished - Jul 1 2012

ASJC Scopus subject areas

  • Hematology
  • Developmental Biology
  • Cell Biology

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