title: Leukemogenic Ptpn11 allele causes defective erythropoiesis in mice.
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.
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Usenko
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
authors.forename: Gordon
authors.initials: G
authors.lastname: Chan
authors.affiliation: Department of Laboratory Hematology, Toronto General Hospital, University Health Network, Toronto, Canada.
authors.forename: Emina
authors.initials: E
authors.lastname: Torlakovic
authors.affiliation: Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), DKFZ-ZMBH-Alliance, Heidelberg, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Klingmüller
authors.affiliation: Princess Margaret Cancer Center, University Health Network, Toronto, Canada; Departments of Medical Biophysics and Biochemistry, University of Toronto, Toronto, Canada.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Neel
mesh_terms: D000483:Alleles; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002070:Butadienes / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004900:Erythroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004920:Erythropoiesis / Q000187:drug effects / Q000235:genetics*; D004921:Erythropoietin / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009570:Nitriles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; D002070:Butadienes; C068126:CD71 antigen; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011990:Receptors, Transferrin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C113580:U 0126; D004921:Erythropoietin; D019009:Proto-Oncogene Proteins c-kit; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse