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

Authors: Zhang, J  Ranheim, EA  Du, J  Liu, Y  Wang, J  Kong, G  Zhang, J 
Citation: Zhang J, etal., J Biol Chem. 2015 Jul 31;290(31):19093-103. doi: 10.1074/jbc.M115.653154. Epub 2015 Jun 16.
Pubmed: (View Article at PubMed) PMID:26082490
DOI: Full-text: DOI:10.1074/jbc.M115.653154

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 (betac) is dispensable for Nras(G12D/+) HSC function; loss of betac does not affect the expansion, increased self-renewal, or myeloid differentiation bias in Nras(G12D/+) HSCs. Therefore, betac(-/-) does not abrogate CMML in Nras(G12D/+) mice. However, betac 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.


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CRRD Object Information
CRRD ID: 11535058
Created: 2016-09-20
Species: All species
Last Modified: 2016-09-20
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.