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Acute Leukemias

Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition

Leukemia volume 29, pages 1290–1300 (2015)Cite this article

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Abstract

PTPN11 encodes the Shp2 non-receptor protein-tyrosine phosphatase implicated in several signaling pathways. Activating mutations in Shp2 are commonly associated with juvenile myelomonocytic leukemia but are not as well defined in other neoplasms. Here we report that Shp2 mutations occur in human acute myeloid leukemia (AML) at a rate of 6.6% (6/91) in the ECOG E1900 data set. We examined the role of mutated Shp2 in leukemias harboring MLL translocations, which co-occur in human AML. The hyperactive Shp2E76K mutant, commonly observed in leukemia patients, significantly accelerated MLL-AF9-mediated leukemogenesis in vivo. Shp2E76K increased leukemic stem cell frequency and affords MLL-AF9 leukemic cells IL3 cytokine hypersensitivity. As Shp2 is reported to regulate anti-apoptotic genes, we investigated Bcl2, Bcl-xL and Mcl1 expression in MLL-AF9 leukemic cells with and without Shp2E76K. Although the Bcl2 family of genes was upregulated in Shp2E76K cells, Mcl1 showed the highest upregulation in MLL-AF9 cells in response to Shp2E76K. Indeed, expression of Mcl1 in MLL-AF9 cells phenocopies expression of Shp2E76K, suggesting Shp2 mutations cooperate through activation of anti-apoptotic genes. Finally, we show Shp2E76K mutations reduce sensitivity of AML cells to small-molecule-mediated Mcl1 inhibition, suggesting reduced efficacy of drugs targeting MCL1 in patients with hyperactive Shp2.

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Acknowledgements

We thank Dr Jay Hess for helpful discussion. This work was supported by NIH grants R01-CA149442 (ZN-C), R00 CA158136 (AGM) and an American Society of Hematology Scholar Award (AGM)

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Authors and Affiliations

  1. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA

    L Chen, W Chen, M Mysliwski, J Serio, J Ropa, F A Abulwerdi, Z Nikolovska-Coleska & A G Muntean

  2. Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA

    L Chen, W Chen, M Mysliwski, J Serio, J Ropa, Z Nikolovska-Coleska & A G Muntean

  3. Interdepartmental Program in Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA

    F A Abulwerdi

  4. Department of Medical and Molecular Genetics, Herman B Wells Center for Pediatric Research, University School of Medicine, Indianapolis, IN, USA

    R J Chan

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

    R J Chan

  6. Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan–Kettering Cancer Center, New York, NY, USA

    J P Patel, M S Tallman, R L Levine & O Abdel-Wahab

  7. Montefiore Medical Center-North Division, Immunology Laboratory, Cancer Center, Bronx, NY, USA

    E Paietta

  8. Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    A Melnick

  9. Department of Pharmacology, Weill Cornell Medical College, New York, NY, USA

    A Melnick

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  1. L Chen
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Chen, L., Chen, W., Mysliwski, M. et al. Mutated Ptpn11 alters leukemic stem cell frequency and reduces the sensitivity of acute myeloid leukemia cells to Mcl1 inhibition. Leukemia 29, 1290–1300 (2015). https://doi.org/10.1038/leu.2015.18

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