Mutant transcription factors and tyrosine kinases as therapeutic targets for leukemias: from acute promyelocytic leukemia to chronic myeloid leukemia and beyond.
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.
Hu
Jiong
J
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University (SJTU) and Shanghai Center for Systems Biomedicine, SJTU, Shanghai 200025, China.
Zhou
Guang-Biao
GB
Wang
Zhen-Yi
ZY
Chen
Sai-Juan
SJ
Chen
Zhu
Z
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics
D000970:Antineoplastic Agents; D014157:Transcription Factors; D011505:Protein-Tyrosine Kinases