Targeting interferon pathway in TBLR1-RARa-driven promyelocytic leukemia in the context of ATRA and ATO unresponsiveness

Abstract

Abstract Background TBLR1-RARα (TR) is a novel oncogene to induce acute promyelocytic leukemia (APL) identified in our previous studies, which elicited differed response and worse prognosis in contrast to the canonical PML-RARα (PR) fusion gene. Despite the textbook rationale of all-trans retinoid acid (ATRA) and arsenic trioxide (ATO) has turned most PR-driven APL from highly fatal to highly curable, TR-driven APL did not yield long-term remission, highlighting the necessity to decipher drug unresponsiveness and explore novel therapies. Methods In this study, doxycycline-inducible cell models were established to initiate the expression of TR and PR in U937 cells, respectively. Then RNA-seq was performed to identify differential genes and pathways directly induced by TR and PR oncogene. Based on transcriptomic analyses, different drugs were administered to compare therapy responses and biological phenotypes between TR and PR-induced leukemia through in vitro studies. The efficacy of IFNs and its upstream regulator STING agonist were further validated in TR murine models with survival analysis. Results Transcriptome sequencing analyses showed interferon (IFN) pathway were significantly suppressed in TR- rather than PR-induced APL. IFNs as well as the traditional regimen of ATRA and ATO elicit differed responses in biological phenotypes between TR- and PR-induced APL. Specifically, in TR-induced APL, firstly, ATO failed to elicit oncoprotein degradation, apoptosis and loss of self-renewal. Secondly, increasing doses of ATRA further promoted oncoprotein degradation with impaired colony formation capacity, and ultimately conferred survival benefits. Thirdly, type I IFNs is promising, which induced apoptosis, cooperated with ATRA to boost differentiation, and exhibited potential to reduce self-renewal. Finally, type I IFNs combining with ATRA and STING agonist significantly endowed TR mice with extended survival. Conclusions For TR-driven APL, the canonical regimen of ATO and lower doses of ATRA are unresponsive and inadequate to elicit oncoprotein degradation, apoptosis and loss of self-renewal, while type I IFNs and STING agonist are promising to endow TR mice with extended survival. Our study aims to gain further understanding of TR-driven APL and integrate insights into leukemogenesis mediated by rare RARα fusion genes, which may benefit a therapy-resistant population and enable APL to be bona fide curable leukemia.