title: Deficiency of β Common Receptor Moderately Attenuates the Progression of Myeloproliferative Neoplasm in NrasG12D/+ Mice.
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.
authors.affiliation: From the McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin 53705 and.
authors.forename: Jingfang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: the Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin Carbone Cancer Center, Madison, Wisconsin 53705.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Ranheim
authors.affiliation: From the McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin 53705 and.
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.affiliation: From the McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin 53705 and.
authors.forename: Yangang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin 53705 and.
authors.forename: Jinyong
authors.initials: J
authors.lastname: Wang
authors.affiliation: From the McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin 53705 and.
authors.forename: Guangyao
authors.initials: G
authors.lastname: Kong
authors.affiliation: From the McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin 53705 and zhang@oncology.wisc.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D053648:Cytokine Receptor Common beta Subunit / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D054747:Histiocytic Sarcoma / Q000235:genetics / Q000378:metabolism; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics* / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D015398:Signal Transduction; D013154:Spleen / Q000473:pathology
chemical_list: D053648:Cytokine Receptor Common beta Subunit; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020559:Monomeric GTP-Binding Proteins; C586503:Nras protein, mouse
keywords: animal model; beta common receptor; cancer stem cells; cell signaling; chronic myelomonocytic leukemia; oncogene; oncogenic Nras; transgenic mice