Presentation Abstract

Abstract Number: 4296A
Presentation Title: Myeloproliferative disease induced by leukemogenic Ptpn11 (Shp-2) phosphatase arises from hematopoietic stem cells
Presentation Time: Tuesday, Apr 20, 2010, 2:00 PM - 5:00 PM
Location: Exhibit Hall A-C, Poster Section 16
Poster Section: 16
Poster Board Number: 30
Author Block: Dan Xu1, Siying Wang1, Wen-Mei Yu1, Gordon Chan2, Toshiyuki Araki2, Kevin D. Bunting1, Benjamin G. Neel2, Cheng-Kui Qu1. 1Department of Medicine, Division of Hematology/Oncology, Center for Stem Cell and Regenerative Medicine, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH; 2Department of Stem Cell and Developmental Biology, Ontario Cancer Institute, Toronto, ON, Canada
Abstract Body: Germline and somatic gain-of-function (GOF) mutations in the tyrosine phosphatase PTPN11 (SHP-2) are associated with juvenile myelomonocytic leukemia (JMML), a clonal myeloproliferative disease (MPD) of early childhood. However, the mechanism by which PTPN11 mutations induce this disease is not fully understood. Here we report that the germline mutation Ptpn11D61G increases mouse hematopoietic stem cell (HSC) activity, as evidenced by accelerated cycling, increased stem cell pool, enhanced self-renewal, and elevated short-term and long-term repopulating capabilities. More importantly, the MPD is reproduced in primary and secondary recipient mice transplanted with Ptpn11D61G mutant marrow cells or sorted Lineage- Sca-1+c-Kit+ cells, indicative of the long-term stem cell origin of the disease. The leukemogenic effect of Ptpn11D61G mutation appears to be attributed to enhancing cytokine signaling. Furthermore, HSC homeostasis disrupted by Ptpn11D61G mutation is partially restored by deletion of Gab2, an important interacting protein/target of SHP-2. MPD phenotypes are markedly ameliorated in Ptpn11D61G/+/Gab2-/- double mutant mice. Together, these studies suggest that SHP-2 associated JMML arises from HSCs and that targeting SHP-2/Gab2 mediated signaling in stem cells may be useful for the treatment of this disease.