title: Acute promyelocytic leukemia: a novel PML/RARalpha fusion that generates a frameshift in the RARalpha transcript and ATRA resistance.
abstract: Acute promyelocytic leukemia (APL) is characterized by increased promyelocytes in the marrow that harbor a t(15;17) and promyelocyte leukemia (PML)/RARalpha fusion gene. The oncogenic gene product is believed to act through disruption of the transcription-modulating function of RARalpha. Differentiation of promyelocytes and remission is achieved with all transretinoic acid (ATRA) therapy usually in combination with chemotherapy. This report describes a patient with the t(15;17) who did not respond typically to ATRA and IDAC induction chemotherapy, although achieved and remains in complete remission five years following induction and one consolidation with high dose cytarabine (HIDAC). RT-PCR and sequencing revealed a novel fusion of RARalpha exon 3 to PML exon 5 that creates a frameshift and premature stop codon in the RARalpha portion of the transcript. Since none of the RARalpha functional domains are maintained, this case highlights the possibility that PML/RARalpha may directly affect promyelocyte differentiation through disruption of PML function.
authors: Department of Pathology and Laboratory Medicine, Dalhousie University, Halifax, NS, Canada.
authors: Adham
authors: A
authors: Zayed
authors: Stephen
authors: S
authors: Couban
authors: Ormille
authors: O
authors: Hayne
authors: Nebojsa
authors: N
authors: Sparavalo
authors: Allam
authors: A
authors: Shawwa
authors: Irene
authors: I
authors: Sadek
authors: Wenda
authors: W
authors: Greer
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D003561:Cytarabine / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D000072482:Retinoic Acid Receptor alpha; D014178:Translocation, Genetic; D014212:Tretinoin / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D015514:Oncogene Proteins, Fusion; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D003561:Cytarabine; D014212:Tretinoin