title: Kras is Required for Adult Hematopoiesis.
abstract: Previous studies indicate that Kras is dispensable for fetal liver hematopoiesis, but its role in adult hematopoiesis remains unclear. Here, we generated a Kras conditional knockout allele to address this question. Deletion of Kras in adult bone marrow (BM) is mediated by Vav-Cre or inducible Mx1-Cre. We find that loss of Kras leads to greatly reduced thrombopoietin (TPO) signaling in hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs), while stem cell factor-evoked ERK1/2 activation is not affected. The compromised TPO signaling is associated with reduced long term- and intermediate-term HSC compartments and a bias toward myeloid differentiation in MPPs. Although granulocyte macrophage colony-stimulating factor (GM-CSF)-evoked ERK1/2 activation is only moderately decreased in Kras(-/-) myeloid progenitors, it is blunted in neutrophils and neutrophil survival is significantly reduced in vitro. At 9-12 months old, Kras conditional knockout mice develop profound hematopoietic defects, including splenomegaly, an expanded neutrophil compartment, and reduced B cell number. In a serial transplantation assay, the reconstitution potential of Kras(-/-) BM cells is greatly compromised, which is attributable to defects in the self-renewal of Kras(-/-) HSCs and defects in differentiated hematopoietic cells. Our results demonstrate that Kras is a major regulator of TPO and GM-CSF signaling in specific populations of hematopoietic cells and its function is required for adult hematopoiesis. Stem Cells 2016;34:1859-1871.
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Alisa
authors.initials: A
authors.lastname: Damnernsawad
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Guangyao
authors.initials: G
authors.lastname: Kong
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wen
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Yangang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Cellular and Molecular Biology Program, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Adhithi
authors.initials: A
authors.lastname: Rajagopalan
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Xiaona
authors.initials: X
authors.lastname: You
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Jinyong
authors.initials: J
authors.lastname: Wang
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Ranheim
authors.affiliation: Department of Pathology, Harvard Medical School and Boston Children's Hospital, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Hongbo R
authors.initials: HR
authors.lastname: Luo
authors.affiliation: Department of Medical Genetics and Department of Neurology, Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chang
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D002451:Cell Compartmentation / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D000066673:Cell Self Renewal / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017353:Gene Deletion; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D023461:Myeloid Progenitor Cells / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000172:deficiency / Q000378:metabolism*
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D048049:Extracellular Signal-Regulated MAP Kinases; C045073:Cre recombinase; D019426:Integrases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Adult hematopoiesis; Cytokine signaling; Hematopoietic progenitor cells; Hematopoietic stem cells; Kras; Nras; Stem cell self-renewal