Mutant Transcription Factors and Tyrosine Kinases as Therapeutic Targets for Leukemias: From Acute Promyelocytic Leukemia to Chronic Myeloid Leukemia and Beyond

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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 - RARα 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.

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