期刊
EXPERIMENTAL HEMATOLOGY
卷 37, 期 2, 页码 276-284出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.exphem.2008.10.005
关键词
-
资金
- Case Western Reserve University
- National Institutes of Health [HL073738]
Objective. The aim of this study was to identify and characterize the causative mutation in the thrombocytopenic mouse strain HI,13219 that was generated at the Jackson Laboratory as part of a large-scale N-ethyl-N-nitrosourea mutagenesis screen. Materials and Methods. The HLB219 mutation was identified by interval mapping of F2 mice generated from intercross breeding of HLB219 to both BALB/cByJ (BALB) and 129/SvImJ (129/Sv). Mpl was identified as a candidate gene and sequenced. The mutation was characterized in vivo in mouse hematopoietic stem/progenitor cell assays and in cell culture by expression in Ba/F3 cells. Results. A novel mutation in the thrombopoietin (TPO) receptor Mpl in HLB219 mice caused a Cys -> Arg substitution at codon 40 in the extracellular region of the receptor. Mice homozygous for the Mpl(hlb219) mutation had in 80% decrease in the number of platelets in comparison to the wild-type C57BL/6J strain, low numbers of bone marrow megakaryocytes, high TPO levels, and decreased competitive repopulating ability, consistent with a loss-of-function mutation in the receptor. Mice heterozygous for Mpl(hlb219) however, showed an overdominance effect with a significant increase in platelet number. Functional analysis in vitro demonstrated that Ba/F3 cells expressing the mutant MPLhlb219 protein failed to activate extracellular signal-regulated kinase and signal transducers and activators of transcription 5, but proliferated in the absence of TPO and required constitutive phosphorylation of RAC-alpha serine/threonine protein kinase (AKT) for cytokine-independent growth. Conclusion. Thrombocytopenia in HLB219 mice is caused by a recessive mutation in Mpl that abrogates mitogen-activated protein kinase-extracellular signal regulated kinase and Janus kinase-signal transducers and activators of transcription signaling. (C) 2009 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.
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