Syk kinase and Shp2 phosphatase inhibition cooperate to reduce FLT3-ITD-induced STAT5 activation and proliferation of acute myeloid leukemia

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References

  1. 1

    Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366: 1079–1089.

  2. 2

    Nabinger SC, Li XJ, Ramdas B, He Y, Zhang X, Zeng L et al. The protein tyrosine phosphatase, Shp2, positively contributes to FLT3-ITD-induced hematopoietic progenitor hyperproliferation and malignant disease in vivo. Leukemia 2013; 27: 398–408.

  3. 3

    Heiss E, Masson K, Sundberg C, Pedersen M, Sun J, Bengtsson S et al. Identification of Y589 and Y599 in the juxtamembrane domain of Flt3 as ligand-induced autophosphorylation sites involved in binding of Src family kinases and the protein tyrosine phosphatase SHP2. Blood 2006; 108: 1542–1550.

  4. 4

    Puissant A, Fenouille N, Alexe G, Pikman Y, Bassil CF, Mehta S et al. SYK is a critical regulator of FLT3 in acute myeloid leukemia. Cancer Cell 2014; 25: 226–242.

  5. 5

    Masson K, Liu T, Khan R, Sun J, Ronnstrand L . A role of Gab2 association in Flt3 ITD mediated Stat5 phosphorylation and cell survival. Br J Haematol 2009; 146: 193–202.

  6. 6

    Zhang S, Broxmeyer HE . p85 subunit of PI3 kinase does not bind to human Flt3 receptor, but associates with SHP2, SHIP, and a tyrosine-phosphorylated 100-kDa protein in Flt3 ligand-stimulated hematopoietic cells. Biochem Biophys Res Commun 1999; 254: 440–445.

  7. 7

    Zhang S, Broxmeyer HE . Flt3 ligand induces tyrosine phosphorylation of gab1 and gab2 and their association with shp-2, grb2, and PI3 kinase. Biochem Biophys Res Commun 2000; 277: 195–199.

  8. 8

    Kelly LM, Liu Q, Kutok JL, Williams IR, Boulton CL, Gilliland DG . FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood 2002; 99: 310–318.

  9. 9

    Kornblau SM, Womble M, Qiu YH, Jackson CE, Chen W, Konopleva M et al. Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia. Blood 2006; 108: 2358–2365.

  10. 10

    Mizuki M, Fenski R, Halfter H, Matsumura I, Schmidt R, Muller C et al. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood 2000; 96: 3907–3914.

  11. 11

    Janke H, Pastore F, Schumacher D, Herold T, Hopfner KP, Schneider S et al. Activating FLT3 mutants show distinct gain-of-function phenotypes in vitro and a characteristic signaling pathway profile associated with prognosis in acute myeloid leukemia. PLoS ONE 2014; 9: e89560.

  12. 12

    Zhang X, He Y, Liu S, Yu Z, Jiang ZX, Yang Z et al. Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2). J Med Chem 2010; 53: 2482–2493.

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Acknowledgements

This work was supported by the Riley Children’s Foundation and U.S. National Institutes of Health (F31 CA183342 to BMR; RO1 CA134777 to RJC, RK; RO1 HL077177, HL081111 and CA173852 to RK; RO1 CA96202 to Z-YZ; and the Indiana Clinical and Translational Sciences Institute, funded in part by UL1 TR000006 to JDB). We appreciate the technical assistance from Dr Karen Pollok and Tony Sinn in the Indiana University In Vivo Therapeutics Core and from Susan Rice in the Flow Cytometry Resource Facility (supported by P30 CA082709). We gratefully acknowledge the administrative assistance of Marilyn L Wales and Tracy Winkle.

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Correspondence to R J Chan.

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