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Blood, 30 April 2009, Vol. 113, No. 18, pp. 4414-4424.
Prepublished online as a Blood First Edition Paper on January 29, 2009; DOI 10.1182/blood-2008-10-182626.
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Submitted October 6, 2008
Accepted January 24, 2009
Leukemogenic Ptpn11 causes fatal myeloproliferative disorder via cell-autonomous effects on multiple stages of hematopoiesis
Gordon Chan*, Demetrios Kalaitzidis, Tatiana Usenko, Jeffery L. Kutok, Wentian Yang, M. Golam Mohi, and Benjamin G. Neel
Department of Stem Cell and Developmental Biology, Ontario Cancer Institute, Toronto, ON, Canada
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
Department of Pathology, Brigham and Women's Hospital, Boston, MA, United States
Department of Orthopedics, Brown University Alpert Medical School, Providence, RI, United States
Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY, United States
* Corresponding author; email: gordon.chan{at}uhnresearch.ca.
PTPN11, which encodes the tyrosine phosphatase SHP2, is mutated in ~35% of patients with juvenile myelomonocytic leukemia (JMML) and at lower incidence in other neoplasms. To model JMML pathogenesis, we generated knock-in mice that
conditionally express the leukemia-associated mutant Ptpn11D61Y. Expression of Ptpn11D61Y in all hematopoietic cells evokes a fatal myeloproliferative disorder (MPD), featuring leukocytosis, anemia, hepatosplenomegaly, and factor-independent colony formation by bone marrow (BM) and spleen cells. The Lin-Sca1+cKit+ (LSK) compartment is expanded and "right-shifted", accompanied by increased stem cell factor (SCF)-evoked colony formation and Erk and Akt activation. However, repopulating activity is decreased in diseased mice, and mice that do engraft with Ptpn11D61Y stem cells fail to develop MPD. Ptpn11D61Y common myeloid (CMP) and granulocyte-monocyte (GMP) progenitors produce cytokine-independent colonies in a cell-autonomous manner and demonstrate elevated Erk and Stat5 activation in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation. Ptpn11D61Y megakaryocyte-erythrocyte
progenitors (MEP) yield increased numbers of erythrocyte burst-forming units (BFU-E), but MEP and erythrocyte-committed progenitors (EP) produce fewer erythrocyte colony-forming units (CFU-E), indicating defective erythroid
differentiation. Our studies provide a mouse model for Ptpn11-evoked MPD and show that this disease results from cell-autonomous and distinct lineage-specific effects of mutant Ptpn11 on multiple stages of hematopoiesis.
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