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 HALLMARKEPITHELIALMESENCHYMALTRANSITION, and inhibited enrichment of HALLMARKE2FTARGETS pathways compared to the control cells. ETV6: : RARA is an ATRA/ATO sensitive fusion gene.
Hassani et al. (Sat,) studied this question.