Mutant transcription factors and tyrosine kinases as therapeutic targets for leukemias: from acute promyelocytic leukemia to chronic myeloid leukemia and beyond.

Abstract

Mutations in transcription factors (TFs) and protein tyrosine kinases (PTKs), which result in inhibition of differentiation/apoptosis or enhanced proliferative/survival advantage of hematopoietic stem/progenitor cells, are two classes of the most frequently detected genetic abnormalities in leukemias. The critical roles for mutant TFs and/or PTKs to play in leukemogenesis, and the absence of mutant TFs/PTKs in normal hematopoietic cells, suggest that the two types of aberrant molecules may serve as ideal therapeutic targets. The great success of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) in treating acute promyelocytic leukemia through modulation of the causative PML-RARalpha oncoprotein represents the first two paradigms of mutant TFs-targeting therapeutic strategies for leukemia. More recently, tyrosine kinase inhibitor STI-571/Imatinib mesylate/Gleevec in the treatment of Breakpoint Cluster Region-Abelson (BCR-ABL) positive leukemia elicits paradigm of mutant PTKs as ideal antileukemia targets. Thus to further improve clinical outcome of leukemia patients, elucidation of pathogenesis of leukemia, screening for oncoprotein-targeting small molecules, as well as rationally designed combination of drugs with potential synergy are of importance.

• Authors: Jiong Hu, Guang-Biao Zhou, Zhen-Yi Wang, Sai-Juan Chen, Zhu Chen
• Journal: Advances in cancer research (Adv Cancer Res) Vol. 98 Pg. 191-220 ( 2007) ISSN: 0065-230X [Print] United States
• PMID: 17433911 (Publication Type: Journal Article, Review)

Chemical References

• Antineoplastic Agents
• Transcription Factors
• Protein-Tyrosine Kinases

Topics

• Antineoplastic Agents (therapeutic use)
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, genetics, metabolism)
• Leukemia, Promyelocytic, Acute (drug therapy, genetics, metabolism)
• Mutation (genetics)
• Protein-Tyrosine Kinases (antagonists & inhibitors, genetics)
• Transcription Factors (antagonists & inhibitors, genetics)