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Mutations in the catalytic subunit of class IA PI3K confer leukemogenic potential to hematopoietic cells

Oncogene volume 27, pages 4096–4106 (2008)Cite this article

Abstract

Constitutive activation of the phosphoinositide 3-kinase (PI3K)–AKT pathway is observed in up to 70% of acute myelogenous leukemia. To investigate the relevance of an intrinsic PI3K–AKT pathway activation in hematopoietic malignancies, we analysed the effect of point mutations in the catalytic (p110α) and regulatory (p85α) subunit of class IA PI3K. We demonstrated that mutations in the helical (E542K, E545A) and kinase domain (H1047R) of p110α constitutively activate the PI3K–AKT pathway and lead to factor-independent growth of early hematopoietic cells. Proliferation and survival of the cells were inhibited in a time- and dose-dependent manner using either PI3K or AKT inhibitors. The mammalian target of rapamycin (mTOR) was demonstrated to be important for mitogenic, but not antiapoptotic signaling of mutant p110α. In a syngenic mouse model, hematopoietic cells expressing mutated p110α induced a leukemia-like disease characterized by anemia, neoplastic infiltration of hematopoietic organs and 90% mortality within 5 weeks, whereas activated mutants of the receptor tyrosine kinase c-KIT led to 100% mortality within 10 days. Our data show that point mutations in the p110α subunit of class IA PI3K confer factor independence to hematopoietic cells in vitro and leukemogenic potential in vivo, but have lower transforming activity than a deregulated class III receptor tyrosine kinase.

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Acknowledgements

We thank Marion Ziegler, Susanne Roscher and Arne Düsedau for excellent technical assistance, and Alberto Martelli for critical discussion. This work was supported by the Deutsche Krebshilfe. The Heinrich-Pette-Institut is supported by the Freie und Hansestadt Hamburg and the German Ministry of Health.

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Authors and Affiliations

  1. Department of Hematology and Oncology, University of Göttingen, Göttingen, Germany

    S Horn, L Trümper & J Bäsecke

  2. Molecular Pathology Group, Program Area Cellular Dysregulation, Heinrich-Pette-Institute, Hamburg, Germany

    U Bergholz & C Stocking

  3. Department of Biochemistry and Molecular Biology I: Cellular Signal Transduction, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    M Jücker

  4. Department of Microbiology and Immunology, Brody School of Medicine, University of Greenville, Greenville, NC, USA

    J A McCubrey

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  1. S Horn
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Correspondence to J Bäsecke.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Horn, S., Bergholz, U., Jücker, M. et al. Mutations in the catalytic subunit of class IA PI3K confer leukemogenic potential to hematopoietic cells. Oncogene 27, 4096–4106 (2008). https://doi.org/10.1038/onc.2008.40

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