Therapy-persistent leukemia is selectively vulnerable to SLC23A1 restoration via targeting KHSRP (AML patient samples)

Acute myeloid leukemia (AML) remains highly prone to relapse driven by therapy-persistent residual cells. To discover specific vulnerabilities in this population, we performed genome-wide CRISPR interference screens in AML cells treated with multiple agents. KHSRP was the top hit, whose depletion sensitized AML cells to therapy and substantially prolonged survival in treated AML-bearing mice. Profiling in vivo residual disease after therapy identified downregulation of the vitamin C and uric acid transporter SLC23A1 as a resistance mechanism. KHSRP depletion restored SLC23A1 through a previously unrecognized function by preventing ZC3H4-mediated nuclear mRNA degradation. KHSRP depletion therefore enhanced the synergistic cytotoxicity of vitamin C and uric acid, particularly in therapy-persistent leukemia cells. Re-expression of TET2 overrode the chemosensitizing effect of KHSRP depletion in TET2-mutant leukemia, suggesting that KHSRP phenotypes were linked to vitamin C and uric acid-mediated TET activation. These findings nominate targeting KHSRP to enhance treatment efficacy and selectively eradicate residual AML.