{
  "abstract": "Venetoclax combined with azacitidine has improved treatment outcomes in acute myeloid leukemia (AML), yet relapse and treatment persistence remain major clinical challenges. To investigate proteomic mechanisms associated with venetoclax-azacitidine response and adaptation, we applied a multi-layer combinatorial proteome integral solubility/stability alteration analysis (CoPISA) strategy in SKM-1 AML cells. Cells were treated with venetoclax, azacitidine, their combination, or vehicle control and profiled across four orthogonal layers: short-term lysate CoPISA, short-term intact-cell CoPISA, long-term intact-cell CoPISA after 5 days of treatment, and long-term expression proteomics of surviving cells. The venetoclax-azacitidine combination induced treatment-specific protein solubility and abundance changes that were not fully reproduced by either single agent. Long-term surviving cells displayed extensive proteomic remodeling, consistent with the emergence of an adaptive drug-tolerant state, although contributions from pre-existing resilient cell populations cannot be excluded. Integration of short- and long-term solubility changes with abundance remodeling revealed distinct adaptive regimes, including retained biochemical targets, dosage-compensated targets, sensitive-state-specific targets, and remodeled adaptive targets. This framework prioritized candidate resistance-associated proteins, including NRP2, RPL18, PLP2, RPS28, and NOTCH1. NRP2 emerged as a top candidate across all proteomics layers, consistently showing increased abundance. Overall, this study shows that combining CoPISA with expression proteomics can resolve temporally distinct proteomic states of venetoclax-azacitidine response and identify candidate adaptive vulnerabilities in AML.",
  "abstract_shown": true,
  "affiliations": [
    "University of Helsinki"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "name": "E. Gholizadeh"
    },
    {
      "name": "U. Vadadokhau"
    },
    {
      "name": "M. Varli"
    },
    {
      "name": "D. Ritz"
    },
    {
      "name": "K. K. Javarappa"
    },
    {
      "name": "B. George"
    },
    {
      "name": "R. Itzykson"
    },
    {
      "name": "M. Varjosalo"
    },
    {
      "name": "M. Kontro"
    },
    {
      "name": "R. Renkonen"
    },
    {
      "name": "E. Kankuri"
    },
    {
      "name": "P. Haynes"
    },
    {
      "name": "A. A. Saei"
    },
    {
      "affs": [
        0
      ],
      "name": "M. Jafari"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/44q6jez1xdt5q.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.22.752285",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.22.752285v1.full",
  "id": "44q6jez1xdt5q",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.22.752285v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "openalex",
      "2720|Acute Myeloid Leukemia Research"
    ]
  ],
  "openalex": "W7214108513",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.22.752285v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-22",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/44q6jez1xdt5q.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:24:06Z",
      "native_id": "10.64898/2026.09.22.752285",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.22.752285v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Chemical Proteomics of Residual Acute Myeloid Leukemia Cells Reveals Therapeutic Vulnerabilities",
  "title_text": "Chemical Proteomics of Residual Acute Myeloid Leukemia Cells Reveals Therapeutic Vulnerabilities",
  "type": "preprint",
  "updated_at": "2026-10-30T12:24:06Z",
  "url": "https://research.draconitic.com/paper/44q6jez1xdt5q",
  "venue": "bioRxiv",
  "versions": []
}