Journal Article

The protein tyrosine phosphatase, Shp2, positively contributes to FLT3-ITD-induced hematopoietic progenitor hyperproliferation and malignant disease in vivo

Goenka, S, Yu, M, Nabinger, S C, Ramdas, B, Liu, Z, Fukuda, S, Chan, R J, He, Y, Zhang, X, Boswell, H S, Li, X J, Zeng, L, Sandusky, G E, Richine, B, Feng, G-S, Bowling, J D, Zhang, Z-Y, Kapur, R

2013

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/136/2091 / 631/208/737/2007 / 631/80/304 / 692/699/67/1990/283/1897 / Acute myeloid leukemia / Animals / Base Sequence / bcl-X Protein - genetics / bcl-X Protein - metabolism / Blotting, Western / Bone density / Bone marrow / Bone Marrow Transplantation / Cancer Research / Cell growth / Cell Proliferation / Chromatin Immunoprecipitation / Critical Care Medicine / Disruption / FLT3L protein / Fluorescent Antibody Technique / fms-Like Tyrosine Kinase 3 - genetics / fms-Like Tyrosine Kinase 3 - metabolism / Gene expression / Genetic aspects / Hematology / Hematopoietic Stem Cells - cytology / Hematopoietic Stem Cells - metabolism / Hemopoiesis / Humans / Immunoprecipitation / Indoles - pharmacology / Intensive / Interferon / Internal Medicine / Kinases / Latency / Leukemia / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - mortality / Leukemia, Myeloid, Acute - pathology / Leukocytes (mononuclear) / Ligands / Malignancy / Medicine / Medicine & Public Health / Mice / Mice, Inbred C57BL / Mice, Knockout / Molecular Sequence Data / Mutation / Mutation - genetics / Oncology / original-article / Osteoprogenitor cells / Pediatrics / Phenylalanine / Phosphatase / Phosphatases / Phosphorylation / Phosphorylation - drug effects / Physiological aspects / Precursor Cells, B-Lymphoid - cytology / Precursor Cells, B-Lymphoid - drug effects / Precursor Cells, B-Lymphoid - metabolism / Progenitor cells / Promoter Regions, Genetic - genetics / Protein Tyrosine Phosphatase, Non-Receptor Type 11 - antagonists & inhibitors / Protein Tyrosine Phosphatase, Non-Receptor Type 11 - physiology / Protein-tyrosine kinase receptors / Protein-tyrosine-phosphatase / Proteins / Real-Time Polymerase Chain Reaction / Reverse Transcriptase Polymerase Chain Reaction / RNA, Messenger - genetics / Stat5 protein / STAT5 Transcription Factor - genetics / STAT5 Transcription Factor - metabolism / Stem cells / Survival Rate / Tandem Repeat Sequences - genetics / Transplants / Triazoles - pharmacology / Tyrosine / γ-Interferon