The protein tyrosine phosphatase, Shp2, positively contributes to FLT3-ITD-induced hematopoietic progenitor hyperproliferation and malignant disease in vivo
| Autor: | Boswell Hs, Reuben Kapur, Menggang Yu, Xinna Zhang, Gen-Sheng Feng, Sarah C. Nabinger, Baskar Ramdas, Shifalika Goenka, Rebecca J. Chan, George E. Sandusky, Yantao He, Bowling Jd, Xing Jun Li, Briana M. Richine, Ziyue Liu, Zhong Yin Zhang, Li-Fan Zeng, Seiji Fukuda |
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| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
Myeloid Indoles Fluorescent Antibody Technique Protein Tyrosine Phosphatase Non-Receptor Type 11 Protein tyrosine phosphatase Receptor tyrosine kinase Mice 0302 clinical medicine fluids and secretions hemic and lymphatic diseases STAT5 Transcription Factor Tyrosine Phosphorylation Promoter Regions Genetic STAT5 Bone Marrow Transplantation Mice Knockout 0303 health sciences Reverse Transcriptase Polymerase Chain Reaction Myeloid leukemia hemic and immune systems Hematology 3. Good health Survival Rate Leukemia Leukemia Myeloid Acute medicine.anatomical_structure Oncology Tandem Repeat Sequences 030220 oncology & carcinogenesis embryonic structures Acute Myeloid Leukemia Chromatin Immunoprecipitation FLT3-ITD Blotting Western Molecular Sequence Data bcl-X Protein Biology Real-Time Polymerase Chain Reaction Article 03 medical and health sciences medicine Animals Humans Immunoprecipitation RNA Messenger 030304 developmental biology Cell Proliferation Base Sequence Precursor Cells B-Lymphoid Triazoles medicine.disease Hematopoietic Stem Cells Molecular biology Mice Inbred C57BL fms-Like Tyrosine Kinase 3 Fms-Like Tyrosine Kinase 3 Mutation biology.protein Cancer research Shp2 Bone marrow |
| Zdroj: | Leukemia |
| ISSN: | 1476-5551 |
| Popis: | Internal tandem duplications in the fms-like tyrosine kinase receptor (FLT3-ITDs) confer a poor prognosis in acute myeloid leukemia. 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. Knock-down 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 acute myeloid leukemia. |
| Databáze: | OpenAIRE |
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