Arseni Lavinia, Sigismondo Gianluca, Yazdanparast Haniyeh, Hermansen Johanne U, Mack Norman, Ohl Sibylle, Kalter Verena, Iskar Murat, Kalxdorf Mathias, Friedel Dennis, Rettel Mandy, Paul Yashna, Ringshausen Ingo, Eldering Eric, Dubois Julie, Kater Arnon P, Zapatka Marc, Roessner Philipp M, Tausch Eugen, Stilgenbauer Stephan, Dietrich Sascha, Savitski Mikhail M, Skånland Sigrid S, Krijgsveld Jeroen, Lichter Peter, Seiffert Martina
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Division of Proteomics of Stem Cells and Cancer, German Cancer Research Center, Heidelberg, Germany.
Nat Commun. 2025 Jan 26;16(1):1041. doi: 10.1038/s41467-025-56318-7.
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.
慢性淋巴细胞白血病是一种恶性淋巴细胞增殖性疾病，原发性或获得性耐药是其主要挑战。为了研究潜在的分子机制，我们构建了一种依鲁替尼耐药的小鼠模型，在该模型中，初始治疗有反应后，治疗期间会复发，恶性细胞呈侵袭性生长，类似于在患者身上观察到的情况。对治疗期间和复发后分选的白血病小鼠细胞的外显子组、转录组和蛋白质组进行比较分析，结果表明蛋白酶体活性改变是依鲁替尼耐药的驱动因素。在依鲁替尼耐药后给予不可逆蛋白酶体抑制剂卡非佐米进行临床前治疗可延长小鼠生存期。对依鲁替尼耐药患者进行纵向蛋白质组学分析，发现蛋白质翻译后修饰失调。此外，在共培养试验中，来自依鲁替尼耐药患者的细胞对几种蛋白酶体抑制剂有有效反应。总之，我们从正交组学方法获得的结果表明，蛋白酶体抑制对于对依鲁替尼耐药或难治的慢性淋巴细胞白血病患者可能是一种有吸引力的治疗方法。
