{
  "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.\n\nSignificance:: 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.",
    "Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.",
    "Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts.",
    "Department of Epidemiology and Preventive Medicine, The School of Public Health and Preventive Medicine, Monash University, Victoria, Australia.",
    "Suzhou Industrial Park Monash Research Institute of Science and Technology, Monash University, Suzhou, China.",
    "Southeast University-Monash University Joint Graduate School, Suzhou, China.",
    "State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.",
    "Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.",
    "Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts."
  ],
  "article_type": "brief report",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Qingyu Luo",
      "orcid": "0000-0003-4164-637X"
    },
    {
      "affs": [
        0
      ],
      "name": "Karley S. Whalen",
      "orcid": "0009-0009-4699-3662"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Xiaowei Wu",
      "orcid": "0000-0003-4176-7198"
    },
    {
      "affs": [
        0
      ],
      "name": "Amanda L. Fortune",
      "orcid": "0009-0005-6774-8042"
    },
    {
      "affs": [
        0
      ],
      "name": "Jacqueline S. Garcia",
      "orcid": "0000-0003-2118-6302"
    },
    {
      "affs": [
        0
      ],
      "name": "Kate Marinchev",
      "orcid": "0009-0004-0647-0342"
    },
    {
      "affs": [
        3,
        4,
        5
      ],
      "name": "Lin Zhang",
      "orcid": "0000-0002-2064-8440"
    },
    {
      "affs": [
        3,
        6
      ],
      "name": "Weiye Qian",
      "orcid": "0009-0005-3274-3575"
    },
    {
      "affs": [
        0
      ],
      "name": "Evangeline G. Raulston",
      "orcid": "0009-0005-6828-2950"
    },
    {
      "affs": [
        1,
        7
      ],
      "name": "Yabing Nan",
      "orcid": "0000-0001-8744-9617"
    },
    {
      "affs": [
        0
      ],
      "name": "Christopher A.G. Booth",
      "orcid": "0000-0003-3841-6637"
    },
    {
      "affs": [
        0
      ],
      "name": "Kezhi Yan",
      "orcid": "0000-0002-2964-0963"
    },
    {
      "affs": [
        8
      ],
      "name": "David E. Root",
      "orcid": "0000-0001-5122-861X"
    },
    {
      "affs": [
        8
      ],
      "name": "John G. Doench",
      "orcid": "0000-0002-3707-9889"
    },
    {
      "affs": [
        0
      ],
      "name": "Andrew A. Lane",
      "orcid": "0000-0001-7380-0226"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3hg97tt6t9eyp.bib",
  "cited_by": 1,
  "doi": "10.1158/2643-3230.bcd-26-0030",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13728788/",
  "id": "3hg97tt6t9eyp",
  "issns": [
    "2643-3230",
    "2643-3249"
  ],
  "landing_url": "https://doi.org/10.1158/2643-3230.bcd-26-0030",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Drug Resistance"
    ],
    [
      "heading",
      "Hematological Cancers"
    ],
    [
      "heading",
      "Leukemias"
    ],
    [
      "heading",
      "Novel Mechanisms"
    ],
    [
      "heading",
      "Research Brief"
    ],
    [
      "heading",
      "Small Molecule Agents"
    ],
    [
      "openalex",
      "2720|Acute Myeloid Leukemia Research"
    ]
  ],
  "openalex": "W7206200243",
  "pdf_url": null,
  "pmcid": "PMC13728788",
  "pmid": "42685286",
  "published": "2026-09-02",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/3hg97tt6t9eyp.ris",
  "sources": [
    {
      "first_seen": "2026-11-07T12:21:42Z",
      "native_id": "PMC13728788",
      "source": "pmc",
      "url": "https://doi.org/10.1158/2643-3230.bcd-26-0030"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2720|Acute Myeloid Leukemia Research",
      "subfield": "general"
    }
  ],
  "title": "Therapy-Persistent Leukemia Is Selectively Vulnerable to SLC23A1 Restoration via Targeting KHSRP",
  "title_text": "Therapy-Persistent Leukemia Is Selectively Vulnerable to SLC23A1 Restoration via Targeting KHSRP",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T12:21:42Z",
  "url": "https://research.draconitic.com/paper/3hg97tt6t9eyp",
  "venue": "Blood Cancer Discovery",
  "versions": []
}