Acute promyelocytic leukemia: a novel PML/RARalpha fusion that generates a frameshift in the RARalpha transcript and ATRA resistance

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.