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<p>Chronic lymphocytic leukemia is a malignant lymphoproliferative disorder for which primary or acquired drug resistance represents a major challenge. To investigate the underlying molecular mechanisms, we generate a mouse model of ibrutinib resistance, in which, after initial treatment response, relapse under therapy occurrs with an aggressive outgrowth of malignant cells, resembling observations in patients. A comparative analysis of exome, transcriptome and proteome of sorted leukemic murine cells during treatment and after relapse suggests alterations in the proteasome activity as a driver of ibrutinib resistance. Preclinical treatment with the irreversible proteasome inhibitor carfilzomib administered upon ibrutinib resistance prolongs survival of mice. Longitudinal proteomic analysis of ibrutinib-resistant patients identifies deregulation in protein post-translational modifications. Additionally, cells from ibrutinib-resistant patients effectively respond to several proteasome inhibitors in co-culture assays. Altogether, our results from orthogonal omics approaches identify proteasome inhibition as potentially attractive treatment for chronic lymphocytic leukemia patients resistant or refractory to ibrutinib.</p>

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Longitudinal omics data and preclinical treatment suggest the proteasome inhibitor carfilzomib as therapy for ibrutinib-resistant CLL

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月26日

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  • Lavinia Arseni,
  • Gianluca Sigismondo,
  • Haniyeh Yazdanparast,
  • Johanne U. Hermansen,
  • Norman Mack,
  • Sibylle Ohl,
  • Verena Kalter,
  • Murat Iskar,
  • Mathias Kalxdorf,
  • Dennis Friedel,
  • Mandy Rettel,
  • Yashna Paul,
  • Ingo Ringshausen,
  • Eric Eldering,
  • Julie Dubois,
  • Arnon P. Kater,
  • Marc Zapatka,
  • Philipp M. Roessner,
  • Eugen Tausch,
  • Stephan Stilgenbauer,
  • Sascha Dietrich,
  • Mikhail M. Savitski,
  • Sigrid S. Skånland,
  • Jeroen Krijgsveld,
  • Peter Lichter,
  • Martina Seiffert

摘要

Chronic lymphocytic leukemia is a malignant lymphoproliferative disorder for which primary or acquired drug resistance represents a major challenge. To investigate the underlying molecular mechanisms, we generate a mouse model of ibrutinib resistance, in which, after initial treatment response, relapse under therapy occurrs with an aggressive outgrowth of malignant cells, resembling observations in patients. A comparative analysis of exome, transcriptome and proteome of sorted leukemic murine cells during treatment and after relapse suggests alterations in the proteasome activity as a driver of ibrutinib resistance. Preclinical treatment with the irreversible proteasome inhibitor carfilzomib administered upon ibrutinib resistance prolongs survival of mice. Longitudinal proteomic analysis of ibrutinib-resistant patients identifies deregulation in protein post-translational modifications. Additionally, cells from ibrutinib-resistant patients effectively respond to several proteasome inhibitors in co-culture assays. Altogether, our results from orthogonal omics approaches identify proteasome inhibition as potentially attractive treatment for chronic lymphocytic leukemia patients resistant or refractory to ibrutinib.