Leukemogenic Ptpn11 allele causes defective erythropoiesis in mice

PLoS One. 2014 Oct 7;9(10):e109682. doi: 10.1371/journal.pone.0109682. eCollection 2014.

Abstract

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, Ptpn11D61Y, specifically in the erythroid lineage causes dyserythropoiesis in mice. Ptpn11D61Y progenitors produce excess cKIT+ CD71+ Ter119- cells and aberrant numbers of cKITl° CD71+ erythroblasts. Mutant erythroblasts show elevated activation of ERK, AKT and STAT3 in response to EPO stimulation, and MEK inhibitor treatment blocks Ptpn11D61Y-evoked erythroid hyperproliferation in vitro. Thus, the expression of oncogenic Ptpn11 causes dyserythropoiesis in a cell-autonomous manner in vivo.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Bone Marrow / drug effects
  • Bone Marrow / metabolism*
  • Bone Marrow / pathology
  • Butadienes / pharmacology
  • Cell Proliferation / drug effects
  • Erythroblasts / drug effects
  • Erythroblasts / metabolism*
  • Erythroblasts / pathology
  • Erythropoiesis / drug effects
  • Erythropoiesis / genetics*
  • Erythropoietin / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation, Leukemic*
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / pathology
  • Leukemia / drug therapy
  • Leukemia / genetics*
  • Leukemia / metabolism
  • Leukemia / pathology
  • Mice
  • Nitriles / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-kit / genetics
  • Proto-Oncogene Proteins c-kit / metabolism
  • Receptors, Transferrin / genetics
  • Receptors, Transferrin / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction

Substances

  • Antigens, CD
  • Butadienes
  • CD71 antigen
  • Nitriles
  • Protein Kinase Inhibitors
  • Receptors, Transferrin
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • U 0126
  • Erythropoietin
  • Proto-Oncogene Proteins c-kit
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Ptpn11 protein, mouse