Hirade Kentaro, Kusumoto Shigeru, Abe Akihiro, Noritake Hatsune, Ito Asahi, Ri Masaki, Komatsu Hirokazu, Iida Shinsuke, Yamamoto Yukiya
Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
Department of Hematology, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan.
Int J Hematol. 2022 Dec;116(6):956-960. doi: 10.1007/s12185-022-03421-w. Epub 2022 Jul 19.
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.
急性早幼粒细胞白血病（APL）的特征是一系列维甲酸受体（RAR）融合基因，这些基因导致RAR信号失调和APL发病。PML-RARA是由t(15;17)(q24;q21)产生的最常见融合基因。此外，在超过80%的t(15;17) APL病例中存在相互融合的RARA-PML。特别是RARA-PML和RARA-PLZF的bcr3类型是有助于白血病发生的相互融合基因。在此，我们报告一例伴有t(11;17;15)(q13;q21.2;q24.1)的变异型APL病例。对患者RNA进行大规模平行测序检测到新的融合转录本RARA-SNX15和SNX15-LINC02255以及bcr3类型的PML-RARA。基因分析显示，RARA-SNX15L是由于RNA错配剪接导致内含子保留而形成的读码框内融合基因。RARA-SNX15L主要由SNX15结构域组成，包括Phox同源结构域，该结构域在分选连接蛋白之间以及与其他伙伴的蛋白质-蛋白质相互作用中起关键作用。免疫共沉淀分析显示，RARA-SNX15L与SNX15直接相关且能自身相互作用。需要进一步研究来评估RARA-SNX15L在APL中的生物学意义。总之，这是首例报道的伴有涉及SNX15的复杂染色体重排的APL病例。
