Open AccessThe protein tyrosine phosphatase, Shp2, positively contributes to FLT3-ITD-induced hematopoietic progenitor hyperproliferation and malignant disease in vivo
Author(s) -
Nabinger Sc,
Li Xj,
Baskar Ramdas,
Yang He,
Xifeng Zhang,
Lingqiu Zeng,
Briana M. Richine,
Bowling Jd,
Seiji Fukuda,
Shreevrat Goenka,
Liu Z,
Gong Kan Feng,
Miao Yu,
Sandusky Ge,
Boswell Hs,
Zhang Zy,
Reuben Kapur,
Chan Rj
Publication year - 2012
Publication title -
leukemia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.539
H-Index - 192
eISSN - 1476-5551
pISSN - 0887-6924
DOI - 10.1038/leu.2012.308
Subject(s) - protein tyrosine phosphatase , fms like tyrosine kinase 3 , cancer research , haematopoiesis , progenitor cell , stat5 , myeloid leukemia , biology , bone marrow , myeloid , leukemia , receptor tyrosine kinase , gene knockdown , tyrosine kinase , signal transduction , stem cell , immunology , microbiology and biotechnology , mutation , gene , genetics
Internal tandem duplications (ITDs) in the fms-like tyrosine kinase receptor (FLT3-ITDs) confer a poor prognosis in acute myeloid leukemia (AML). We hypothesized that increased recruitment of the protein tyrosine phosphatase, Shp2, to FLT3-ITDs contributes to FLT3 ligand (FL)-independent hyperproliferation and STAT5 activation. Co-immunoprecipitation demonstrated constitutive association of Shp2 with the FLT3-ITD, N51-FLT3, as well as with STAT5. Knockdown of Shp2 in Baf3/N51-FLT3 cells significantly reduced proliferation while having little effect on WT-FLT3-expressing cells. Consistently, mutation of N51-FLT3 tyrosine 599 to phenylalanine or genetic disruption of Shp2 in N51-FLT3-expressing bone marrow low-density mononuclear cells reduced proliferation and STAT5 activation. In transplants, genetic disruption of Shp2 in vivo yielded increased latency to and reduced severity of FLT3-ITD-induced malignancy. Mechanistically, Shp2 co-localizes with nuclear phospho-STAT5, is present at functional interferon-γ activation sites (GAS) within the BCL2L1 promoter, and positively activates the human BCL2L1 promoter, suggesting that Shp2 works with STAT5 to promote pro-leukemogenic gene expression. Further, using a small molecule Shp2 inhibitor, the proliferation of N51-FLT3-expressing bone marrow progenitors and primary AML samples was reduced in a dose-dependent manner. These findings demonstrate that Shp2 positively contributes to FLT3-ITD-induced leukemia and suggest that Shp2 inhibition may provide a novel therapeutic approach to AML.