FoxO tumor suppressors and BCR-ABL-induced leukemia: a matter of evasion of apoptosis.
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.
Jagani
Zainab
Z
Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Singh
Amrik
A
Khosravi-Far
Roya
R
D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000502:physiology*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology; D008954:Models, Biological; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction
D001549:Benzamides; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl