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<p>Chronic Myeloid Leukemia (CML) is primarily driven by the BCR-ABL fusion oncogene, yet the mechanisms underlying progression to advanced phases remain unclear. Through Sanger sequencing of 22 CML patients, we identified a novel missense mutation in MUC3A (3025&#xa0;C &gt; T; P258S) exclusively in advanced-phase cases. PCR amplification and Sanger sequencing confirmed its presence, while control and chronic-phase patients lacked the variant. Structural and physicochemical analyses revealed that the P258S substitution alters protein stability, secondary structure, and conformational flexibility. Molecular docking of 22 DrugBank ligands demonstrated enhanced binding affinity of the mutant protein, particularly with Capmatinib, which was further validated by molecular dynamics simulations showing increased flexibility and compactness. Principal component analysis and hydrogen bond profiling supported significant dynamic changes in the mutant structure. Collectively, these findings suggest that MUC3A P258S acts as a potential candidate biomarker of CML progression and influences therapeutic response, highlighting Capmatinib and related inhibitors as candidates for drug repurposing in hematological malignancies. To our knowledge, this is the first report implicating MUC3A in leukemia biology, extending its role beyond epithelial cancers. </p>

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Association of MUC3A P258S mutation with advanced phase CML structural and in silico insights

  • 期刊论文

  • 发表日期：

    2026年5月1日

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  • Sameen Shahid,
  • Zafar Iqbal,
  • Muhammad Abbas Khokhar,
  • Muhammad Farooq Sabar

摘要

Chronic Myeloid Leukemia (CML) is primarily driven by the BCR-ABL fusion oncogene, yet the mechanisms underlying progression to advanced phases remain unclear. Through Sanger sequencing of 22 CML patients, we identified a novel missense mutation in MUC3A (3025 C > T; P258S) exclusively in advanced-phase cases. PCR amplification and Sanger sequencing confirmed its presence, while control and chronic-phase patients lacked the variant. Structural and physicochemical analyses revealed that the P258S substitution alters protein stability, secondary structure, and conformational flexibility. Molecular docking of 22 DrugBank ligands demonstrated enhanced binding affinity of the mutant protein, particularly with Capmatinib, which was further validated by molecular dynamics simulations showing increased flexibility and compactness. Principal component analysis and hydrogen bond profiling supported significant dynamic changes in the mutant structure. Collectively, these findings suggest that MUC3A P258S acts as a potential candidate biomarker of CML progression and influences therapeutic response, highlighting Capmatinib and related inhibitors as candidates for drug repurposing in hematological malignancies. To our knowledge, this is the first report implicating MUC3A in leukemia biology, extending its role beyond epithelial cancers.