The novel ETV6::RARA fusion gene, identified in acute promyelocytic leukemia, is sensitive to invitro all-tans retinoic acid and arsenic trioxide administrations

Acute promyelocytic leukemia (APL) is characterized by the presence of PML::RARA fusion gene, and a favorable response to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) administration. Here, we studied the leukemogenic properties of a novel fusion gene, ETV6::RARA t(12;17)(p13;q21), identified in an APL patient lacking the PML::RARA rearrangement. The ETV6-RARA fusion protein was over-expressed via lentiviral transfection in leukemia cells and its effects on cell growth were evaluated with cell counting kit 8 (CCK8) assay and on apoptosis and cellular differentiation with flow cytometry. The expression features induced by ETV6-RARA were studied by whole transcriptomic RNA sequencing analysis. ETV6-RARA over-expression enhanced the differentiation of U937 and HL60 cells to ATRA administration. ATRA, but not ATO, decreased the in-vitro levels of ETV6-RARA protein. ETV6-RARA significantly reduced the proliferation rates of U937 cells as compared to the control. Apoptosis in U937 ETV6-RARA+ cells was induced with combined ATRA and ATO administration. Differential gene expression analysis showed significant up-regulation of RARA in U937 ETV6-RARA+ cells, and gene set enrichment analysis revealed similarity between cells with ETV6::RARA and patients with PML::RARA based on their total RNA expression profiles. Furthermore, the expression profiles of U937 ETV6-RARA+ cells presented the activated enrichment of HALLMARK_EPITHELIAL_MESENCHYMAL_TRANSITION, and inhibited enrichment of HALLMARK_E2F_TARGETS pathways compared to the control cells. ETV6::RARA is an ATRA/ATO sensitive fusion gene.