Therapy-Persistent Leukemia Is Selectively Vulnerable to SLC23A1 Restoration via Targeting KHSRP
9 affiliations
- 1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
- 2Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- 3Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts.
- 4Department of Epidemiology and Preventive Medicine, The School of Public Health and Preventive Medicine, Monash University, Victoria, Australia.
- 5Suzhou Industrial Park Monash Research Institute of Science and Technology, Monash University, Suzhou, China.
- 6Southeast University-Monash University Joint Graduate School, Suzhou, China.
- 7State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
- 8Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
- 9Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
Abstract
Acute myeloid leukemia (AML) is prone to relapse driven by therapy-persistent residual cells. To discover specific vulnerabilities in this population, we performed genome-wide CRISPR interference screens in leukemia cells treated with multiple agents. KHSRP was the top hit, the depletion of which sensitized AML cells to therapy and substantially prolonged survival in treated AML-bearing mice. Analysis of in vivo residual disease after venetoclax/azacitidine treatment identified downregulation of the vitamin C and uric acid transporter SLC23A1, which mediated resistance to multiple therapies. KHSRP depletion restored SLC23A1 expression by preventing its 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-linked phenotypes were related to vitamin C– and uric acid–mediated TET activation. These findings suggest targeting KHSRP to enhance treatment efficacy and selectively eradicate residual AML.
Significance:: Residual AML cells that persist following therapy have distinct biological properties compared with initial disease or overt relapse. Here, we nominate KHSRP as a target to improve therapy efficacy and exploit selective vulnerabilities of AML residual disease.
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BibTeX
@article{luo2026therapypersistent,
title = {{Therapy-Persistent Leukemia Is Selectively Vulnerable to SLC23A1 Restoration via Targeting KHSRP}},
author = {Qingyu Luo and Karley S. Whalen and Xiaowei Wu and Amanda L. Fortune and Jacqueline S. Garcia and Kate Marinchev and Lin Zhang and Weiye Qian and Evangeline G. Raulston and Yabing Nan and Christopher A.G. Booth and Kezhi Yan and David E. Root and John G. Doench and Andrew A. Lane},
journal = {Blood Cancer Discovery},
year = {2026},
month = sep,
doi = {10.1158/2643-3230.bcd-26-0030},
url = {https://doi.org/10.1158/2643-3230.bcd-26-0030},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Therapy-Persistent Leukemia Is Selectively Vulnerable to SLC23A1 Restoration via Targeting KHSRP
AU - Qingyu Luo
AU - Karley S. Whalen
AU - Xiaowei Wu
AU - Amanda L. Fortune
AU - Jacqueline S. Garcia
AU - Kate Marinchev
AU - Lin Zhang
AU - Weiye Qian
AU - Evangeline G. Raulston
AU - Yabing Nan
AU - Christopher A.G. Booth
AU - Kezhi Yan
AU - David E. Root
AU - John G. Doench
AU - Andrew A. Lane
PY - 2026
DA - 2026/09/02
JO - Blood Cancer Discovery
DO - 10.1158/2643-3230.bcd-26-0030
UR - https://doi.org/10.1158/2643-3230.bcd-26-0030
AB - Acute myeloid leukemia (AML) is prone to relapse driven by therapy-persistent residual cells. To discover specific vulnerabilities in this population, we performed genome-wide CRISPR interference screens in leukemia cells treated with multiple agents. KHSRP was the top hit, the depletion of which sensitized AML cells to therapy and substantially prolonged survival in treated AML-bearing mice. Analysis of in vivo residual disease after venetoclax/azacitidine treatment identified downregulation of the vitamin C and uric acid transporter SLC23A1, which mediated resistance to multiple therapies. KHSRP depletion restored SLC23A1 expression by preventing its 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-linked phenotypes were related to vitamin C– and uric acid–mediated TET activation. These findings suggest targeting KHSRP to enhance treatment efficacy and selectively eradicate residual AML. Significance:: Residual AML cells that persist following therapy have distinct biological properties compared with initial disease or overt relapse. Here, we nominate KHSRP as a target to improve therapy efficacy and exploit selective vulnerabilities of AML residual disease.
SN - 2643-3230
SN - 2643-3249
ER -