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Oncogenes, Fusion Genes and Tumor Suppressor Genes

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

Leukemia volume 27, pages 398–408 (2013)Cite this article

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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.

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Acknowledgements

This work was supported by the Riley Children's Foundation, the Clarian Values Fund for Research (VFR-245, RJC), and the US National Institutes of Health (F31AG031648, SCN; RO1HL082981 and RO1CA134777, RJC; RO1HL075816, RO1HL077177, and RO1CA134777, RK; RO1CA069202 and RO1CA152194, ZYZ). We acknowledge the contribution of Baindu Bayon for generation of the pBCL2L1-L plasmid. We appreciate the helpful discussions and technical assistance from Dr Karen Pollok and Tony Sinn in the Indiana University in vivo Therapeutics Core, from Susan Rice in the Flow Cytometry Core, and from the Indiana Center for Biological Microscopy. We thank Drs Yan Liu, Nadia Carlesso and Merv Yoder for critical reading of the manuscript and gratefully acknowledge the administrative assistance of Linda S Henson.

Author contributions

Sarah C Nabinger and Xingjun Li: designed and performed the research and wrote the manuscript; Baskar Ramdas, Yantao He, Xian Zhang, Lifan Zeng, Briana Richine and Joshua D Bowling: designed and performed the research; Seiji Fukuda, Gen-Sheng Feng and Zhong-Yin Zhang: provided reagent; Shreevrat Goenka and Reuben Kapur: designed the research; Ziyue Liu and Menggang Yu: performed statistical analyses; George E Sandusky: performed pathological analyses; H Scott Boswell: provided primary AML samples; Rebecca J Chan: designed the research and wrote the manuscript.

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Authors and Affiliations

  1. Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA

    S C Nabinger, X J Li, B Ramdas, B Richine, J D Bowling, S Goenka, R Kapur & R J Chan

  2. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    S C Nabinger, B Richine, R Kapur & R J Chan

  3. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA

    X J Li, B Ramdas, J D Bowling, S Goenka, R Kapur & R J Chan

  4. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA

    Y He, X Zhang, L Zeng, Z-Y Zhang & R Kapur

  5. Department of Pediatrics, Shimane University School of Medicine, Izumo, Shimane, Japan

    S Fukuda

  6. Department of Medicine, Division of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, USA

    Z Liu

  7. Department of Pathology, UC San Diego, La Jolla, CA, USA

    G-S Feng

  8. Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA

    M Yu

  9. Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, USA

    G E Sandusky

  10. Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA

    H S Boswell

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  1. S C Nabinger
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Nabinger, S., Li, X., Ramdas, B. et al. The protein tyrosine phosphatase, Shp2, positively contributes to FLT3-ITD-induced hematopoietic progenitor hyperproliferation and malignant disease in vivo. Leukemia 27, 398–408 (2013). https://doi.org/10.1038/leu.2012.308

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