title: The protein tyrosine phosphatase, Shp2, positively contributes to FLT3-ITD-induced hematopoietic progenitor hyperproliferation and malignant disease in vivo.
abstract: 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.
authors.affiliation: Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Nabinger
authors.forename: X J
authors.initials: XJ
authors.lastname: Li
authors.forename: B
authors.initials: B
authors.lastname: Ramdas
authors.forename: Y
authors.initials: Y
authors.lastname: He
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: L
authors.initials: L
authors.lastname: Zeng
authors.forename: B
authors.initials: B
authors.lastname: Richine
authors.forename: J D
authors.initials: JD
authors.lastname: Bowling
authors.forename: S
authors.initials: S
authors.lastname: Fukuda
authors.forename: S
authors.initials: S
authors.lastname: Goenka
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.forename: G-S
authors.initials: GS
authors.lastname: Feng
authors.forename: M
authors.initials: M
authors.lastname: Yu
authors.forename: G E
authors.initials: GE
authors.lastname: Sandusky
authors.forename: H S
authors.initials: HS
authors.lastname: Boswell
authors.forename: Z-Y
authors.initials: ZY
authors.lastname: Zhang
authors.forename: R
authors.initials: R
authors.lastname: Kapur
authors.forename: R J
authors.initials: RJ
authors.lastname: Chan
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D005455:Fluorescent Antibody Technique; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007211:Indoles / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D020080:Tandem Repeat Sequences / Q000235:genetics*; D014230:Triazoles / Q000494:pharmacology; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: C549053:3-(1-(3-(biphenyl-4-ylamino)-3-oxopropyl)-1H-1,2,3-triazol-4-yl)-6-hydroxy-1-methyl-2-phenyl-1H-indole-5-carboxylic acid; C494811:BCL2L1 protein, human; D007211:Indoles; D012333:RNA, Messenger; D050799:STAT5 Transcription Factor; D014230:Triazoles; D051020:bcl-X Protein; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11