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Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy

Leukemia volume 22, pages 708–722 (2008)Cite this article

Abstract

The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are frequently activated in leukemia and other hematopoietic disorders by upstream mutations in cytokine receptors, aberrant chromosomal translocations as well as other genetic mechanisms. The Jak2 kinase is frequently mutated in many myeloproliferative disorders. Effective targeting of these pathways may result in suppression of cell growth and death of leukemic cells. Furthermore it may be possible to combine various chemotherapeutic and antibody-based therapies with low molecular weight, cell membrane-permeable inhibitors which target the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to ultimately suppress the survival pathways, induce apoptosis and inhibit leukemic growth. In this review, we summarize how suppression of these pathways may inhibit key survival networks important in leukemogenesis and leukemia therapy as well as the treatment of other hematopoietic disorders. Targeting of these and additional cascades may also improve the therapy of chronic myelogenous leukemia, which are resistant to BCR-ABL inhibitors. Furthermore, we discuss how targeting of the leukemia microenvironment and the leukemia stem cell are emerging fields and challenges in targeted therapies.

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Acknowledgements

JAM and LSS have been supported in part by a grant from the NIH (R01098195). JB was supported in part by the Deutsche Krebshilfe. AB, PL, MM and AT were supported in part by grants from Associazione Italiana Ricerca sul Cancro (AIRC). AMM was supported in part by grants from the CARISBO Foundation and the Progetti Strategici Università di Bologna EF2006.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA

    J A McCubrey, L S Steelman, S L Abrams & F E Bertrand

  2. ImClone Systems, New York, NY, USA

    D E Ludwig

  3. Division of Hematology and Oncology, Department of Medicine, Georg-August University, Göttingen, Germany

    J Bäsecke

  4. Department of Biomedical Sciences, University of Catania, Catania, Italy

    M Libra & F Stivala

  5. Regina Elena Cancer Center, Rome, Italy

    M Milella

  6. Department of Cellular Biotechnologies and Hematology, University ‘La Sapienza’ of Rome, Rome, Italy

    A Tafuri

  7. Department of Clinical Sciences, University of Parma, Parma, Italy

    P Lunghi & A Bonati

  8. Unit of Hematology and Bone-Marrow Transplantation, University Hospital of Parma, Parma, Italy

    A Bonati

  9. Department of Human Anatomical Sciences, University of Bologna, Bologna, Italy

    A M Martelli

  10. IGM/C.N.R., c/o I.O.R., Bologna, Italy

    A M Martelli

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  1. J A McCubrey
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McCubrey, J., Steelman, L., Abrams, S. et al. Targeting survival cascades induced by activation of Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways for effective leukemia therapy. Leukemia 22, 708–722 (2008). https://doi.org/10.1038/leu.2008.27

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