Targeting Interferon Pathway in TBLR1-RARa-Driven Promyelocytic Leukemia in the Context of ATRA and ATO Unresponsiveness

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid (AML) mostly driven by the t(15;17) translocation that yields PML-RARα (PR) fusion protein. Apart from PML, other partner genes have been uncovered to fuse with RARα forming rare X-RARα genes. Among them, TBLR1-RARα (TR) novel oncogene induce APL identified in our previous studies, which elicited differed response and worse prognosis contrast canonical PR gene. Despite textbook rationale all-trans retinoid acid (ATRA) arsenic trioxide (ATO) turning most patients gene highly fatal curable, TR-driven did not yield long-term remission both murine models patients, highlighting necessity dissect mechanism drug unresponsiveness explore targeted therapies. In this study, we first established two doxycycline-inducible cell lines directly initiate expression TR protein U937 cells, respectively. Transcriptome sequencing analysis showed interferon (IFN) pathways were significantly suppressed rather than PR-induced cells. Then administered IFNs as well standard regimen ATRA ATO TR- APL, comparing therapy responses biological phenotypes vitro vivo studies. Main results are summarized follows concerning comparison PR-driven APL. Firstly, was unresponsive TR-induced failed elicit oncoprotein degradation, apoptosis loss self-renewal. Secondly, lower doses inadequate. Although dose sufficient trigger differentiation, increasing further promoted degradation reduced colony formation capacity leukemic ultimately conferred survival benefits mice. Thirdly, type I promising, induced apoptosis, cooperated boost exhibited potential reduce self-renewal, reflecting anti-leukemia efficacy. Finally, combining displayed advantage mice, STING agonist DMXAA, acted upstream produce IFNs, endowed mice extended time. Based on results, propose mechanistic hypotheses TR-APL classic PR-APL. despite ATO, may utilize STING-IFN pathway upregulate PML expression, obliterate self-renewal independent triggered initial nuclear body disruption observed providing therapeutic implications for Our study aims gain understanding integrate insights into principles underlying leukemogenesis mediated genes, benefit such therapy-resistant population enable be bona fide curable leukemia.