Deficiency of β Common Receptor Moderately Attenuates the Progression of Myeloproliferative Neoplasm in NrasG12D/+ Mice

J Biol Chem. 2015 Jul 31;290(31):19093-103. doi: 10.1074/jbc.M115.653154. Epub 2015 Jun 16.

Abstract

Activating Ras signaling is a major driver in juvenile and the myeloproliferative variant of chronic myelomonocytic leukemia (JMML/MP-CMML). Numerous studies suggest that GM-CSF signaling plays a central role in establishing and maintaining JMML/MP-CMML phenotypes in human and mouse. However, it remains elusive how GM-CSF signaling impacts on JMML/MP-CMML initiation and progression. Here, we investigate this issue in a well characterized MP-CMML model induced by endogenous Nras(G12D/+) mutation. In this model, Nras(G12D/+) hematopoietic stem cells (HSCs) are required to initiate and maintain CMML phenotypes and serve as CMML-initiating cells. We show that the common β chain of the GM-CSF receptor (βc) is dispensable for Nras(G12D/+) HSC function; loss of βc does not affect the expansion, increased self-renewal, or myeloid differentiation bias in Nras(G12D/+) HSCs. Therefore, βc(-/-) does not abrogate CMML in Nras(G12D/+) mice. However, βc deficiency indeed significantly reduces Nras(G12D/+)-induced splenomegaly and spontaneous colony formation and prolongs the survival of CMML-bearing mice, suggesting that GM-CSF signaling plays an important role in promoting CMML progression. Together, our results suggest that inhibiting GM-CSF signaling in JMML/MP-CMML patients might alleviate disease symptoms but would not eradicate the disease.

Keywords: animal model; beta common receptor; cancer stem cells; cell signaling; chronic myelomonocytic leukemia; oncogene; oncogenic Nras; transgenic mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytokine Receptor Common beta Subunit / genetics*
  • Cytokine Receptor Common beta Subunit / metabolism
  • Disease Progression
  • Granulocyte-Macrophage Colony-Stimulating Factor / physiology
  • Histiocytic Sarcoma / genetics
  • Histiocytic Sarcoma / metabolism
  • Leukemia, Myelomonocytic, Chronic / genetics*
  • Leukemia, Myelomonocytic, Chronic / pathology
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Monomeric GTP-Binding Proteins / genetics*
  • Signal Transduction
  • Spleen / pathology

Substances

  • Cytokine Receptor Common beta Subunit
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Monomeric GTP-Binding Proteins
  • Nras protein, mouse