Abstract

Numerous studies have revealed that the BCR–ABL oncoprotein abnormally engages a multitude of signaling pathways, some of which may be important for its leukemogenic properties. Central to this has been the determination that the tyrosine kinase function of BCR–ABL is mainly responsible for its transforming potential, and can be targeted with small molecule inhibitors, such as imatinib mesylate (Gleevec, STI-571). Despite this apparent success, the development of clinical resistance to imatinib therapy, and the inability of imatinib to eradicate BCR–ABL-positive malignant hematopoietic progenitors demand detailed investigations of additional effector pathways that can be targeted for CML treatment. The promotion of cellular survival via the suppression of apoptotic pathways is a fundamental characteristic of tumor cells that enables resistance to anti-cancer therapies. As substrates of survival kinases such as Akt, the FoxO family of transcription factors, particularly FoxO3a, has emerged as playing an important role in the cell cycle arrest and apoptosis of hematopoietic cells. This review will discuss our current understanding of BCR–ABL signaling with a focus on apoptotic suppressive mechanisms and alternative approaches to CML therapy, as well as the potential for FoxO transcription factors as novel therapeutic targets.

Keywords: Apoptosis; BCR–ABL; CML; FoxO; Imatinib resistance; Proteasomal degradation

Article Outline

1. Introduction

2. BCR–ABL and chronic myeloid leukemia (CML)

3. The tyrosine kinase activity of BCR–ABL and avenues for therapy

4. Imatinib: The success story

5. Clinical resistance to imatinib and the need for alternative therapies

6. Signaling pathways activated by BCR–ABL and the suppression of apoptosis

7. BCR–ABL activation of STAT

8. BCR–ABL activation of NF-κB

9. BCR–ABL activation of the Ras pathway

10. BCR–ABL inhibition of the PP2A phosphatase

11. BCR–ABL activation of the PI3-K/Akt pathway

12. Signaling downstream of the serine/threonine kinase Akt

13. The FoxO sub-class of forkhead transcription factors

14. FoxO regulation in mammalian systems

15. Multiple functions of the FoxO transcription factors: A focus on apoptosis

16. FoxO transcription factors and tumorigenesis

17. FoxO transcription factors in leukemia

18. Current and future approaches for CML treatment

19. Proteasome inhibitors: A new class of anti-cancer agents

20. FoxO transcription factors as potential targets in cancer therapy

21. Targeting the “right” population of tumor cells in anti-cancer therapy

22. Perspectives and conclusion

Acknowledgements

References