THRAP3 promotes ferroptosis resistance in acute myelocytic leukemia through SLU7-mediated alternative splicing of GIT2.

Induction of ferroptosis is a potential strategy to eliminate chemotherapy-resistant acute myeloid leukemia (AML) cells. Here, we investigate the role and mechanism of thyroid hormone receptor-associated protein 3 (THRAP3) in ferroptosis of AML cells. We show that high expression of THRAP3 is correlated with a poor prognosis in AML patients. THRAP3 knockdown suppresses AML cell proliferation, and delays orthotopic and subcutaneous tumor growth in male mice; however, THRAP3 overexpression exerts the opposite roles. THRAP3 overexpression promotes resistance of AML cells to RSL3/erastin-induced ferroptosis via inhibiting iron accumulation and promoting GSH synthesis. Mechanistically, THRAP3 recruits SLU7 homolog, splicing factor (SLU7) to facilitate GIT ArfGAP 2 (GIT2) Exon14 skipping. Inhibition of GIT2 Exon14 skipping reverses THRAP3-induced ferroptosis resistance in vitro and in vivo. Altogether, THRAP3 contributes to ferroptosis resistance of AML cells via interaction with SLU7 to trigger GIT2 Exon14 skipping, which suggests THRAP3 to be a therapeutic target for AML.