1. ¹Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA
2. ²ImClone Systems, New York, NY, USA
3. ³Division of Hematology and Oncology, Department of Medicine, Georg-August University, Göttingen, Germany
4. ⁴Department of Biomedical Sciences, University of Catania, Catania, Italy
5. ⁵Regina Elena Cancer Center, Rome, Italy
6. ⁶Department of Cellular Biotechnologies and Hematology, University 'La Sapienza' of Rome, Rome, Italy
7. ⁷Department of Clinical Sciences, University of Parma, Parma, Italy
8. ⁸Unit of Hematology and Bone-Marrow Transplantation, University Hospital of Parma, Parma, Italy
9. ⁹Department of Human Anatomical Sciences, University of Bologna, Bologna, Italy
10. ¹⁰IGM/C.N.R., c/o I.O.R., Bologna, Italy

Correspondence: Dr JA McCubrey, Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, 600 Moye Boulevard, Greenville, NC 27858, USA. E-mail: mccubreyj@ecu.edu

Received 28 November 2007; Revised 22 January 2008; Accepted 23 January 2008; Published online 13 March 2008.

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.