A novel RARA-SNX15 fusion in PML-RARA-positive acute promyelocytic leukemia with t(11;17;15)(q13;q21.2;q24.1).

Abstract

Acute promyelocytic leukemia (APL) is characterized by a series of retinoic acid receptor (RAR) fusion genes that lead to the dysregulation of RAR signaling and onset of APL. PML-RARA is the most common fusion generated from t(15;17)(q24;q21). In addition, the reciprocal fusion RARA-PML is present in over 80% of t(15;17) APL cases. The bcr3 types of RARA-PML and RARA-PLZF in particular are reciprocal fusions that contribute to leukemogenesis. Here, we report a variant APL case with t(11;17;15)(q13;q21.2;q24.1). Massive parallel sequencing of patient RNA detected the novel fusion transcripts RARA-SNX15 and SNX15-LINC02255 along with the bcr3 type of PML-RARA. Genetic analysis revealed that RARA-SNX15L is an in-frame fusion due to intron retention caused by RNA mis-splicing. RARA-SNX15L consisted mainly of SNX15 domains, including the Phox-homology domain, which has a critical role in protein-protein interactions among sorting nexins and with other partners. Co-immunoprecipitation analysis revealed that RARA-SNX15L is directly associated with SNX15 and with itself. Further studies are needed to evaluate the biological significance of RARA-SNX15L in APL. In conclusion, this is the first report of APL with a complex chromosomal rearrangement involving SNX15.