Deficiency of beta common receptor moderately attenuates the progression of myeloproliferative neoplasm in Nras G12D/+ mice [Signal Transduction]

June 16th, 2015 by Zhang, J., Ranheim, E. A., Du, J., Liu, Y., Wang, J., Kong, G.,

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 beta chain of the GM-CSF receptor (beta c) is dispensable for Nras G12D/+ HSC function; loss of beta c does not affect the expansion, increased self-renewal, or myeloid differentiation bias in Nras G12D/+ HSCs. Therefore, beta c-/- does not abrogate CMML in Nras G12D/+ mice. However, beta c 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.
  • Posted in Journal of Biological Chemistry, Publications
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