Open AccessKras is Required for Adult Hematopoiesis
Author(s) -
Damnernsawad Alisa,
Kong Guangyao,
Wen Zhi,
Liu Yangang,
Rajagopalan Adhithi,
You Xiaona,
Wang Jinyong,
Zhou Yun,
Ranheim Erik A.,
Luo Hongbo R.,
Chang Qiang,
Zhang Jing
Publication year - 2016
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.2355
Subject(s) - biology , kras , haematopoiesis , myeloid , stem cell , progenitor cell , cancer research , stem cell factor , immunology , bone marrow , hematopoietic stem cell , conditional gene knockout , microbiology and biotechnology , cancer , genetics , phenotype , colorectal cancer , gene
A bstract 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. S tem C ells 2016;34:1859–1871