Histone deacetylases and transcriptional therapy with their inhibitors.
Acute promyelocytic leukemia (APL) is characterized by the expansion of malignant myeloid cells blocked at the promyelocytic stage of hemopoietic development and is invariably associated with reciprocal chromosomal translocations involving the retinoic acid receptor alpha (RARalpha) gene on chromosome 17. RARalpha variably fuses to PML, PLZF, NPM, NuMA, and Stat5B genes (X genes/proteins). These translocations are balanced and reciprocal, thus leading to the generation of X-RARalpha and RARalpha-X fusion genes of which the products coexist in the APL blast. The invariable involvement in these translocations of RARalpha, a prototypical transcription factor, makes APL a compelling example of aberrant transcriptional mechanisms in the etiopathogenesis of cancer. This paper focuses on the recent progress in defining the molecular mechanisms underlying APL pathogenesis and addresses how this new understanding has allowed the proposal and development of novel therapeutic strategies with compounds such as histone deacetylase inhibitors and inorganic arsenicals such as As2O3 which are currently being tested in murine leukemia models as well as in human APL patients. In particular, the crucial role played by the aberrant transcriptional activities of X-RARalpha and RARalpha-X fusion proteins in APL pathogenesis is discussed by reviewing the relevant therapeutic implications resulting from this analysis.
Pandolfi
P P
PP
Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, Graduate School of Medical Sciences, Cornell University, New York, NY 10021, USA. p-pandolfi@ski.mskcc.org
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology; D010087:Oxides / Q000494:pharmacology*; D018168:Receptors, Retinoic Acid / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001152:Arsenicals; D056572:Histone Deacetylase Inhibitors; C120276:NPM-RARalpha protein, human; D009363:Neoplasm Proteins; C412764:NuMa-RARalpha protein, human; D015514:Oncogene Proteins, Fusion; D010087:Oxides; C118318:PLZF-RARalpha fusion protein, human; C492209:PLZF-RARalpha fusion protein, mouse; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D000077237:Arsenic Trioxide