Open AccessLeukemogenic Ptpn11 Allele Causes Defective Erythropoiesis in Mice
Author(s) -
Tatiana Usenko,
Gabriel Chan,
Emina Torlakovic,
Ursula Klingmüller,
Benjamin G. Neel
Publication year - 2014
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0109682
Subject(s) - erythropoiesis , biology , ptpn11 , haematopoiesis , cancer research , ineffective erythropoiesis , mapk/erk pathway , progenitor cell , microbiology and biotechnology , signal transduction , genetics , stem cell , mutation , gene , medicine , kras , anemia
Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2), encoded by PTPN11 , regulates signaling networks and cell fate in many tissues. Expression of oncogenic PTPN11 in the hematopoietic compartment causes myeloproliferative neoplasm (MPN) in humans and mice. However, the stage-specific effect(s) of mutant Ptpn11 on erythroid development have remained unknown. We found that expression of an activated, leukemogenic Ptpn11 allele, Ptpn11 D61Y , specifically in the erythroid lineage causes dyserythropoiesis in mice. Ptpn11 D61Y progenitors produce excess cKIT + CD71 + Ter119 − cells and aberrant numbers of cKIT l °CD71 + erythroblasts. Mutant erythroblasts show elevated activation of ERK, AKT and STAT3 in response to EPO stimulation, and MEK inhibitor treatment blocks Ptpn11 D61Y -evoked erythroid hyperproliferation in vitro. Thus, the expression of oncogenic Ptpn11 causes dyserythropoiesis in a cell-autonomous manner in vivo.