Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Transcriptional control and signal transduction, cell cycle

Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations

Leukemia volume 31, pages 1415–1422 (2017)Cite this article

Subjects

Abstract

Activating mutations, such as E76K and D61Y, in PTPN11 (SHP2), a protein tyrosine phosphatase implicated in multiple cell signaling processes, are associated with 35% of patients with juvenile myelomonocytic leukemia (JMML), an aggressive childhood myeloproliferative neoplasm (MPN). Here we show that the interaction between leukemia-associated mutant Shp2 and Gab2, a scaffolding protein important for cytokine-induced PI3K/Akt signaling, was enhanced, and that the mTOR pathway was elevated in Ptpn11E76K/+ leukemic cells. Importantly, MPN induced by the Ptpn11E76K/+ mutation was markedly attenuated in Ptpn11E76K/+/Gab2−/− double mutant mice—overproduction of myeloid cells was alleviated, splenomegaly was diminished and myeloid cell infiltration in nonhematopoietic organs was decreased in these double mutants. Excessive myeloid differentiation of stem cells was also normalized by depletion of Gab2. Acute leukemia progression of MPN was reduced in the double mutant mice and, as such, their survival was much prolonged. Furthermore, treatment of Ptpn11E76K/+ mice with Rapamycin, a specific and potent mTOR inhibitor, mitigated MPN phenotypes. Collectively, this study reveals an important role of the Gab2/PI3K/mTOR pathway in mediating the pathogenic signaling of the PTPN11 gain-of-function mutations and a therapeutic potential of Rapamycin for PTPN11 mutation-associated JMML.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Birnbaum RA, O'Marcaigh A, Wardak Z, Zhang YY, Dranoff G, Jacks T et al. Nf1 and Gmcsf interact in myeloid leukemogenesis. Mol Cell 2000; 5: 189–195.

    Article  CAS  PubMed  Google Scholar 

  2. Emanuel PD, Bates LJ, Castleberry RP, Gualtieri RJ, Zuckerman KS . Selective hypersensitivity to granulocyte-macrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors. Blood 1991; 77: 925–929.

    CAS  PubMed  Google Scholar 

  3. Chang TY, Dvorak CC, Loh ML . Bedside to bench in juvenile myelomonocytic leukemia: insights into leukemogenesis from a rare pediatric leukemia. Blood 2014; 124: 2487–2497.

    Article  CAS  PubMed  Google Scholar 

  4. Liu X, Sabnis H, Bunting KD, Qu CK . Molecular targets for the treatment of juvenile myelomonocytic leukemia. Adv Hematol 2012; 2012: 308252.

    Article  PubMed  Google Scholar 

  5. Emanuel PD . Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. Leukemia 2008; 22: 1335–1342.

    Article  CAS  PubMed  Google Scholar 

  6. Loh ML, Vattikuti S, Schubbert S, Reynolds MG, Carlson E, Lieuw KH et al. Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood 2004; 103: 2325–2331.

    Article  CAS  PubMed  Google Scholar 

  7. Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 2003; 34: 148–150.

    Article  CAS  PubMed  Google Scholar 

  8. Loh ML, Sakai DS, Flotho C, Kang M, Fliegauf M, Archambeault S et al. Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood 2009; 114: 1859–1863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Muramatsu H, Makishima H, Jankowska AM, Cazzolli H, O'Keefe C, Yoshida N et al. Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia. Blood 2010; 115: 1969–1975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhang Y, Taylor BR, Shannon K, Clapp DW . Quantitative effects of Nf1 inactivation on in vivo hematopoiesis. J Clin Invest 2001; 108: 709–715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chan IT, Kutok JL, Williams IR, Cohen S, Kelly L, Shigematsu H et al. Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease. J Clin Invest 2004; 113: 528–538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Braun BS, Tuveson DA, Kong N, Le DT, Kogan SC, Rozmus J et al. Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc Natl Acad Sci USA 2004; 101: 597–602.

    Article  CAS  PubMed  Google Scholar 

  13. Araki T, Mohi MG, Ismat FA, Bronson RT, Williams IR, Kutok JL et al. Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. Nat Med 2004; 10: 849–857.

    Article  CAS  PubMed  Google Scholar 

  14. Chan RJ, Leedy MB, Munugalavadla V, Voorhorst CS, Li Y, Yu M et al. Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor. Blood 2005; 105: 3737–3742.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chan G, Kalaitzidis D, Usenko T, Kutok JL, Yang W, Mohi MG et al. Leukemogenic Ptpn11 causes fatal myeloproliferative disorder via cell-autonomous effects on multiple stages of hematopoiesis. Blood 2009; 113: 4414–4424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Xu D, Liu X, Yu WM, Meyerson HJ, Guo C, Gerson SL et al. Non-lineage/stage-restricted effects of a gain-of-function mutation in tyrosine phosphatase Ptpn11 (Shp2) on malignant transformation of hematopoietic cells. J Exp Med 2011; 208: 1977–1988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mohi MG, Williams IR, Dearolf CR, Chan G, Kutok JL, Cohen S et al. Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations. Cancer Cell 2005; 7: 179–191.

    Article  CAS  PubMed  Google Scholar 

  18. Sanada M, Suzuki T, Shih LY, Otsu M, Kato M, Yamazaki S et al. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature 2009; 460: 904–908.

    Article  CAS  PubMed  Google Scholar 

  19. Chan G, Kalaitzidis D, Neel BG . The tyrosine phosphatase Shp2 (PTPN11) in cancer. Cancer Metastasis Rev 2008; 27: 179–192.

    Article  CAS  PubMed  Google Scholar 

  20. Nabinger SC, Chan RJ . Shp2 function in hematopoietic stem cell biology and leukemogenesis. Curr Opin Hematol 2012; 19: 273–279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Xu D, Qu CK . Protein tyrosine phosphatases in the JAK/STAT pathway. Front Biosci 2008; 13: 4925–4932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Eck MJ, Pluskey S, Trub T, Harrison SC, Shoelson SE . Spatial constraints on the recognition of phosphoproteins by the tandem SH2 domains of the phosphatase SH-PTP2. Nature 1996; 379: 277–280.

    Article  CAS  PubMed  Google Scholar 

  23. Hof P, Pluskey S, Dhe-Paganon S, Eck MJ, Shoelson SE . Crystal structure of the tyrosine phosphatase SHP-2. Cell 1998; 92: 441–450.

    Article  CAS  PubMed  Google Scholar 

  24. Keilhack H, David FS, McGregor M, Cantley LC, Neel BG . Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J Biol Chem 2005; 280: 30984–30993.

    Article  CAS  PubMed  Google Scholar 

  25. Goodwin CB, Li XJ, Mali RS, Chan G, Kang M, Liu Z et al. PI3K p110delta uniquely promotes gain-of-function Shp2-induced GM-CSF hypersensitivity in a model of JMML. Blood 2014; 123: 2838–2842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gritsman K, Yuzugullu H, Von T, Yan H, Clayton L, Fritsch C et al. Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110alpha. J Clin Invest 2014; 124: 1794–1809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 1994; 370: 527–532.

    Article  CAS  PubMed  Google Scholar 

  28. Gu H, Neel BG . The 'Gab' in signal transduction. Trends Cell Biol 2003; 13: 122–130.

    Article  CAS  PubMed  Google Scholar 

  29. Nishida K, Wang L, Morii E, Park SJ, Narimatsu M, Itoh S et al. Requirement of Gab2 for mast cell development and KitL/c-Kit signaling. Blood 2002; 99: 1866–1869.

    Article  PubMed  Google Scholar 

  30. Zhang Y, Diaz-Flores E, Li G, Wang Z, Kang Z, Haviernikova E et al. Abnormal hematopoiesis in Gab2 mutant mice. Blood 2007; 110: 116–124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yu WM, Daino H, Chen J, Bunting KD, Qu CK . Effects of a Leukemia-associated Gain-of-Function Mutation of SHP-2 Phosphatase on Interleukin-3 Signaling. J Biol Chem 2006; 281: 5426–5434.

    Article  CAS  PubMed  Google Scholar 

  32. Yu WM, Hawley TS, Hawley RG, Qu CK . Catalytic-dependent and -independent roles of SHP-2 tyrosine Phosphatase in interleukin-3 signaling. Oncogene 2003; 22: 5995–6004.

    Article  CAS  PubMed  Google Scholar 

  33. Liu YL, Castleberry RP, Emanuel PD . PTEN deficiency is a common defect in juvenile myelomonocytic leukemia. Leuk Res 2009; 33: 671–677.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to Dr Toshio Hirano for Gab2+/− mice. This work was supported by National Institutes of Health grants HL130995 and DK092722, and a Hyundai Hope on Wheels scholar grant (to CKQ).

Author contributions

WL, WMY, and JZ conducted the research and summarized the data. RJC, MLL, ZZ, and KDB provided critical reagents, discussed the work and edited the manuscript. CKQ designed the experiments and provided technical training to the first three authors. WL and CKQ wrote the manuscript.

Author information

Author notes

  1. W Liu, W-M Yu and J Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Division of Hematology/Oncology, Case Western Reserve University, Cleveland, OH, USA

    W Liu, W-M Yu & C-K Qu

  2. Department of Pediatrics, Division of Hematology and Oncology, Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University, Atlanta, GA, USA

    W-M Yu, J Zhang, K D Bunting & C-K Qu

  3. The First Affiliated Hospital, Lanzhou University, Lanzhou, China

    J Zhang & Z Zhang

  4. Herman B. Wells Center for Pediatric Research, Indiana University, Indianapolis, IN, USA

    R J Chan

  5. Department of Pediatrics, Division of Pediatric Hematology-Oncology, University of California, San Francisco, CA, USA

    M L Loh

Authors
  1. W Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W-M Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R J Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M L Loh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Z Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K D Bunting
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C-K Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C-K Qu.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, W., Yu, WM., Zhang, J. et al. Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations. Leukemia 31, 1415–1422 (2017). https://doi.org/10.1038/leu.2016.326

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2016.326

This article is cited by

Search

Advanced search

Quick links