1. ¹Department of Microbiology and Immunology, Brody School of Medicine, 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 Biotechnology 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-CNR, c/o IOR, Bologna, Italy

Correspondence: Dr JA McCubrey, Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, 600 Moye Boulevard, 5th Floor Brody Building 5N98C, 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

Mutations and chromosomal translocations occur in leukemic cells that result in elevated expression or constitutive activation of various growth factor receptors and downstream kinases. The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are often activated by mutations in upstream genes. The Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways are regulated by upstream Ras that is frequently mutated in human cancer. Recently, it has been observed that the FLT-3 and Jak kinases and the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) phosphatase are also frequently mutated or their expression is altered in certain hematopoietic neoplasms. Many of the events elicited by the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways have direct effects on survival pathways. Aberrant regulation of the survival pathways can contribute to uncontrolled cell growth and lead to leukemia. In this review, we describe the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT signaling cascades and summarize recent data regarding the regulation and mutation status of these pathways and their involvement in leukemia.