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Background <p>Proteasome inhibitors (PIs) are indispensable for the treatment of multiple myeloma (MM), the second most common hematologic malignancy. Although primary resistance to PIs is rare, most patients eventually relapse and develop acquired resistance, with underlying mechanisms that remain incompletely understood and appear to be drug-specific. In the case of bortezomib, resistance is often associated with <i>PSMB5</i> mutations. In contrast, resistance to carfilzomib (CFZ) is mediated by overexpression of the drug efflux transporter ABCB1. However, the regulatory mechanisms driving ABCB1 upregulation in CFZ-resistant MM remain unclear.</p> Methods <p>An integrative multi-omics analysis was conducted using paired samples from a CFZ-sensitive and -resistant MM patient, alongside resistant cell line models. Whole-genome sequencing (WGS), whole-genome bisulfite sequencing (WGBS), and RNA sequencing (RNA-seq) were used to assess the genotype (structural variants, single nucleotide variants, and copy number variations), methylation status, and the expression of the <i>ABCB1</i> locus. <i>ABCB1</i> promoter methylation levels and expression levels in an independent MM subcohort were analyzed to determine clinical relevance. Functional validation was performed using dual-luciferase reporter assays, <i>DNMT1</i> knockdown, and treatment with DNA methyltransferase inhibitors (DNMTis) to evaluate methylation-dependent regulation of <i>ABCB1</i> expression.</p> Results <p>Significant hypomethylation of the <i>ABCB1</i> downstream promoter region was identified (GH07J087598) in a CFZ-resistant patient sample, which correlated with elevated <i>ABCB1</i> expression. Consistent with the paired CFZ-resistant case, the independent MM subcohort showed a significant inverse association between <i>ABCB1</i> promoter methylation and <i>ABCB1</i> expression. These findings align with results obtained from CFZ-resistant MM cell line models, which demonstrated reduced promoter methylation and elevated <i>ABCB1</i> expression compared to their wild-type counterparts. Furthermore, treatment with DNA methyltransferase inhibitors as well as <i>DNMT1</i> knockdown enhanced <i>ABCB1</i> expression while demethylating the promoter, thereby validating the functional significance of promoter hypomethylation in <i>ABCB1</i> overexpression.</p> Conclusions <p>Our findings highlight <i>ABCB1</i> promoter hypomethylation as a potential epigenetic driver of CFZ resistance in MM. These results underscore the clinical relevance of epigenetic regulation in drug resistance and the potential of targeting DNA methylation as a therapeutic strategy to overcome resistance in MM.</p>

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Promoter hypomethylation drives ABCB1-mediated carfilzomib resistance in multiple myeloma

  • 期刊论文

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  • 发表日期：

    2026年4月1日

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  • Seungbin Han,
  • Larissa Haertle,
  • Umair Munawar,
  • Marietta Truger,
  • Ann-Sophie Hainold,
  • Chien-Yun Lee,
  • Shilpa Kurian,
  • Christina Verbruggen,
  • Silvia Nerreter,
  • Cornelia Vogt,
  • Emma Besant,
  • Nina Rein,
  • Johanna Lehmann,
  • Max Köppel,
  • Yoko Tamamushi,
  • Xiang Zhou,
  • Torsten Steinbrunn,
  • Thomas Haaf,
  • Bernhard Küster,
  • Ondrej Slaby,
  • Claudia Haferlach,
  • Hermann Einsele,
  • Leo Rasche,
  • Johannes Waldschmidt,
  • Andrej Besse,
  • Christoph Driessen,
  • Lenka Besse,
  • K. Martin Kortüm

摘要

Background

Proteasome inhibitors (PIs) are indispensable for the treatment of multiple myeloma (MM), the second most common hematologic malignancy. Although primary resistance to PIs is rare, most patients eventually relapse and develop acquired resistance, with underlying mechanisms that remain incompletely understood and appear to be drug-specific. In the case of bortezomib, resistance is often associated with PSMB5 mutations. In contrast, resistance to carfilzomib (CFZ) is mediated by overexpression of the drug efflux transporter ABCB1. However, the regulatory mechanisms driving ABCB1 upregulation in CFZ-resistant MM remain unclear.

Methods

An integrative multi-omics analysis was conducted using paired samples from a CFZ-sensitive and -resistant MM patient, alongside resistant cell line models. Whole-genome sequencing (WGS), whole-genome bisulfite sequencing (WGBS), and RNA sequencing (RNA-seq) were used to assess the genotype (structural variants, single nucleotide variants, and copy number variations), methylation status, and the expression of the ABCB1 locus. ABCB1 promoter methylation levels and expression levels in an independent MM subcohort were analyzed to determine clinical relevance. Functional validation was performed using dual-luciferase reporter assays, DNMT1 knockdown, and treatment with DNA methyltransferase inhibitors (DNMTis) to evaluate methylation-dependent regulation of ABCB1 expression.

Results

Significant hypomethylation of the ABCB1 downstream promoter region was identified (GH07J087598) in a CFZ-resistant patient sample, which correlated with elevated ABCB1 expression. Consistent with the paired CFZ-resistant case, the independent MM subcohort showed a significant inverse association between ABCB1 promoter methylation and ABCB1 expression. These findings align with results obtained from CFZ-resistant MM cell line models, which demonstrated reduced promoter methylation and elevated ABCB1 expression compared to their wild-type counterparts. Furthermore, treatment with DNA methyltransferase inhibitors as well as DNMT1 knockdown enhanced ABCB1 expression while demethylating the promoter, thereby validating the functional significance of promoter hypomethylation in ABCB1 overexpression.

Conclusions

Our findings highlight ABCB1 promoter hypomethylation as a potential epigenetic driver of CFZ resistance in MM. These results underscore the clinical relevance of epigenetic regulation in drug resistance and the potential of targeting DNA methylation as a therapeutic strategy to overcome resistance in MM.