Leukemogenic Ptpn11 Allele Causes Defective Erythropoiesis in Mice

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.