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Molecular Targets for Therapy

Effective targeting of STAT5-mediated survival in myeloproliferative neoplasms using ABT-737 combined with rapamycin

Leukemia volume 24, pages 1397–1405 (2010)Cite this article

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Abstract

Signal transducer and activator of transcription-5 (STAT5) is a critical transcription factor for normal hematopoiesis and its sustained activation is associated with hematologic malignancy. A persistently active mutant of STAT5 (STAT5aS711F) associates with Grb2-associated binding protein 2 (Gab2) in myeloid leukemias and promotes growth in vitro through AKT activation. Here we have retrovirally transduced wild-type or Gab2−/− mouse bone marrow cells expressing STAT5aS711F and transplanted into irradiated recipient mice to test an in vivo myeloproliferative disease model. To target Gab2-independent AKT/mTOR activation, we treated wild-type mice separately with rapamycin. In either case, mice lacking Gab2 or treated with rapamycin showed attenuated myeloid hyperplasia and modestly improved survival, but the effects were not cytotoxic and were reversible. To improve on this approach, we combined in vitro targeting of STAT5-mediated AKT/mTOR using rapamycin with inhibition of the STAT5 direct target genes bcl-2 and bcl-XL using ABT-737. Striking synergy with both drugs was observed in mouse BaF3 cells expressing STAT5aS711F, TEL-JAK2 or BCR-ABL and in the relatively single agent-resistant human BCR-ABL-positive K562 cell line. Therefore, targeting distinct STAT5-mediated survival signals, for example, bcl-2/bcl-XL and AKT/mTOR may be an effective therapeutic approach for human myeloproliferative neoplasms.

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Acknowledgements

We thank Henry Koon for critical review of the article and Fang Xu for biostatistical support. We also thank Jalpa Patel and Emma Arriola at Abbott Laboratories for supplying ABT-737. This work was supported by NIH R01DK059380 (KDB), The Center for Stem Cell and Regenerative Medicine, SFB-F28 (RM) and the Flow Cytometry, Radiation Resources, and Histology Core Facilities of the Case Comprehensive Cancer Center (P30CA43703).

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Author notes

  1. Z Wang & K D Bunting

    Present address: 5Current address: Department of Pediatrics, Aflac Cancer Center and Blood Disorders Service, Emory University, Atlanta, GA, USA.,

  2. W Tse

    Present address: 6Current address: Department of Medicine, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV, USA.,

  3. W Tse & K D Bunting

    Present address: 7Current address: Case Comprehensive Cancer Center, Cleveland, OH, USA.,

Authors and Affiliations

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

    G Li, K L Miskimen, Z Wang, W Tse & K D Bunting

  2. Department of Pathology, Summa Health Barberton Hospital, Barberton, OH, USA

    X Y Xie

  3. Department of Medicine, INSERM, Universite de Picardie J. Verne, Amiens, France

    F Gouilleux

  4. Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria

    R Moriggl

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The material is original research, has not been previously published and has not been submitted for publication elsewhere while under consideration. The authors also have no conflicts of interest to declare regarding the studies performed.

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Li, G., Miskimen, K., Wang, Z. et al. Effective targeting of STAT5-mediated survival in myeloproliferative neoplasms using ABT-737 combined with rapamycin. Leukemia 24, 1397–1405 (2010). https://doi.org/10.1038/leu.2010.131

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