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Background   GTF2I - RARA  is a newly identified  RARA  fusion gene in variant acute promyelocytic leukemia (APL) patients with t(7;17)(q11;q21). Clinical manifestation in the patient showed that it is a sort of ATRA-insensitive oncogene and is different from the classic  PML - RARA  in terms of therapeutic reaction.    Methods  To reveal the functional characteristics and regulating mechanism of the  GTF2I - RARA  fusion gene, we established a  GTF2I - RARA -transfected HL60 cell model and examined its sensitivity to ATRA by western blot, MTT assay, flow cytometry, and Wright-Giemsa staining. Coimmunoprecipitation and confocal microscopy were used to examine the binding of GTF2I-RARA and transcriptional corepressors. We also performed ChIP-seq to search for potential target genes. Immunoprecipitation, ubiquitination assay, western blot, luciferase assay, and real-time PCR were used to analyze the effects of RNF8 on RARA. Flow cytometry and Wright-Giemsa staining were used to study the effect of MG132 and ATRA on the  GTF2I - RARA -transfected HL60 cell model.    Result  We confirmed resistance of GTF2I-RARA to ATRA. Compared with  PML - RARA, GTF2I - RARA  has a higher affinity to HDAC3 under ATRA treatment. Using the ChIP-sequencing approach, we identified 221  GTF2I - RARA  binding sites in model cells and found that the RING finger protein 8 (RNF8) is a target gene of  GTF2I - RARA . RNF8 participates in disease progression and therapy resistance in APL with the  GTF2I - RARA  transcript. Elevated RNF8 expression promotes the interaction between RARA and RNF8 and induces  RARA  Lys-48 linkage ubiquitylation and degradation, resulting in attenuated transcriptional activation of  RARA .    Conclusion  Our results suggest that RNF8 is a key  GTF2I - RARA  downstream event. Using the combination of MG132 and ATRA to treat  GTF2I - RARA -HL60 cells, a synergistic effect leading to  GTF2I - RARA -HL60 cell differentiation was confirmed. Taken together, the targeting of  RNF8  may be an alternative choice for treatment in variant APL with  GTF2I - RARA  fusion.    Electronic supplementary material  The online version of this article (10.1186/s12935-019-0803-4) contains supplementary material, which is available to authorized users.

cancer cell international

RNF8 is responsible for ATRA resistance in variant acute promyelocytic leukemia with GTF2I/RARA fusion, and inhibition of the ubiquitin–proteasome pathway contributes to the reversion of ATRA resistance