title: Understanding the molecular pathogenesis of acute promyelocytic leukemia.
abstract: Acute promyelocytic leukemia (APL) is a distinct subset of acute myeloid leukemia (AML) associated with peculiar biologic and clinical features and requiring specific management. At the genetic level, APL is featured by a unique chromosome translocation t(15;17) which results in the PML-RARα gene fusion and chimeric protein. APL is the first example of differentiation therapy targeted to a defined genetic target i.e. PML-RARα. PML-RARα behaves as an altered retinoic acid receptor with an ability of transmitting oncogenic signaling leading to accumulation of undifferentiated promyelocytes. All-trans-retinoic acid (ATRA) induces disease remission in APL patients by triggering terminal differentiation of leukemic promyelocytes. More recently, arsenic trioxide (ATO) has been shown to contribute degradation of the PML-RARα oncoprotein through bonding the PML moiety and has shown excellent synergism with ATRA in clinical trials. Elucidating the oncogenic signaling of PML-RARα through various transcription factors and the study of APL mouse models have greatly helped to understand the molecular pathogenesis of APL. However, the precise molecular mechanism by which t(15;17) is formed and initiates leukemia remains unknown. While transforming oncogenic potential of PML-RARα has been described extensively, the mechanistic events important for the formation of t(15;17) have been taken from the model of Therapy-related APL (t-APL).
authors.affiliation: Department of Biomedicine and Prevention, University of Rome 'Tor Vergata' and Fondazione Santa Lucia, Rome, Italy. Electronic address: francesco.lo.coco@uniroma2.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Lo-Coco
authors.affiliation: Department of Biomedicine and Prevention, University of Rome 'Tor Vergata' and Fondazione Santa Lucia, Rome, Italy; Department of Medical Oncology, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai, India.
authors.forename: Syed Khizer
authors.initials: SK
authors.lastname: Hasan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics / Q000648:ultrastructure; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics / Q000648:ultrastructure; D002986:Clinical Trials as Topic; D059766:DNA End-Joining Repair; D004195:Disease Models, Animal; D004357:Drug Synergism; D042381:Granulocyte Precursor Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics; D051379:Mice; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D016609:Neoplasms, Second Primary / Q000139:chemically induced / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000187:drug effects; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D010087:Oxides / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D059005:Topoisomerase II Inhibitors / Q000009:adverse effects; D014178:Translocation, Genetic; D014212:Tretinoin / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D010087:Oxides; D059005:Topoisomerase II Inhibitors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D000077237:Arsenic Trioxide
keywords: DNA damage; PML–RARα; mouse models; non-homologous end joining; t-APL