Abstract A025: Targeted degradation of leukemogenic fusion proteins in non-APL leukemia

Abstract Acute myeloid leukemia (AML) is driven by fusion and/or mutant proteins that disrupt cellular differentiation and apoptosis. The targeted degradation of such oncoproteins as a therapy has been successfully achieved in acute promyelocytic leukemia (APL), where the PML-RARα fusion protein is eliminated by arsenic trioxide (ATO). In APL, PML-RARα is stabilized within the PML nuclear bodies; ATO directly binds to both PML and PML-RARα, disrupts this nuclear structure, and thereby induces protein degradation and apoptosis—a process influenced by intracellular glutathione levels. In contrast, many other leukemogenic fusion proteins depend on the HSP90/HDAC6 chaperone complex for stabilization. To investigate whether the therapeutic effect of ATO could be extended to non-APL AML, we evaluated its impact on other fusion proteins existing in AML cells. At a therapeutically relevant concentration of 1 μM, ATO selectively induced the degradation of FLT3-ITD and CBFβ-SMMHC, but not of AML1-ETO or BCR-ABL. Correspondingly, cells harboring FLT3-ITD or CBFβ-SMMHC showed inherent sensitivity to ATO-induced apoptosis, which was associated with lower basal glutathione levels. Mechanistically, we found that ATO promotes HDAC6 degradation, resulting in HSP90 acetylation, and in turn facilitates the degradation of both fusion proteins. These results uncover a novel targeted degradation pathway of ATO in non-APL AML and underscore its potential as a therapeutic strategy for specific AML subtypes based on fusion oncoprotein degradation. Citation Format: Jingyi Zhang, Jiqiang Qu, Yafei Kuang, Ziyi Zhang, Samuel Waxman, Yongkui Jing. Targeted degradation of leukemogenic fusion proteins in non-APL leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr A025.