Expression of Leukemogenic Ptpn11 Causes a Fatal Myeloproliferative Disorder by Affecting Multiple Stages of Hematopoiesis

The Src homology-2 (SH2) domain-containing phosphatase 2 (Shp2), encoded by Ptpn11, is an ubiquitously expressed non-receptor protein tyrosine phosphatase (PTP) that positively regulates Ras/Erk activation in many receptor protein tyrosine kinases (RTK) and cytokine receptors. Mutations in PTPN11 are found 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 Ptpn11^D61Y. Ptpn11^D61Y expression in all hematopoietic cells evokes a fatal myeloproliferative disorder (MPD), featuring leukocytosis, anemia, hepatosplenomegaly with extramedullary hematopoiesis, 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, stem cell activity is decreased in diseased mice, and mice engrafted with Ptpn11^D16Y stem cells fail to develop MPD. Ptpn11^D16Y 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-SCF) stimulation. Ptpn11^D61Y megakaryocyte-erythrocyte progenitors (MEP) yield increased numbers of erythrocyte burst-forming units (BFU-E), but MEP and erythrocyte-committed progenitors (EP) produce fewer erythrocyte colonyforming units (CFU-E), indicating defective erythroid differentiation. Our studies provide a mouse model for Ptpn11-evoked MPD and show that this disease results from cellautonomous, and distinct lineage-specific effects of mutant Ptpn11 on multiple stages of hematopoiesis.