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<p>The gain of chromosome 2p (2p<sup>+</sup>) is a recurrent abnormality in chronic lymphocytic leukemia (CLL), frequently observed in advanced or relapsed disease, associated with poor prognosis and reduced response to Bruton’s tyrosine kinase inhibitors (BTKi). To investigate the mechanisms of 2p<sup>+</sup>-mediated resistance, we performed single-cell RNA sequencing, revealing NF-κB pathway enrichment and <i>REL</i> overexpression in 2p<sup>+</sup> B cells. In vitro analyses confirmed increased <i>REL</i> expression and DNA-binding activity in a large cohort of 2p<sup>+</sup> primary CLL samples. Functionally, 2p<sup>+</sup> CLL cells showed reduced sensitivity to both covalent and non-covalent BTKi. Moreover, upon ibrutinib treatment, REL DNA-binding activity decreased in 2p<sup>WT</sup> CLL cells but remained sustained in 2p<sup>+</sup> CLL cells following BCR stimulation, suggesting that persistent NF-κB activation contributes to resistance. Consistently, CRISPR/Cas9-mediated inactivation of REL in a 2p<sup>+</sup> B-lymphoid cell line led to downregulation of canonical NF-κB signaling and restored BTKi sensitivity. Clinically, patients with 2p<sup>+</sup> CLL treated with BTKi had a shorter time-to-next-treatment than 2p<sup>WT</sup> patients. Altogether, our study identifies <i>REL</i> overexpression as a novel 2p<sup>+</sup>-driven mechanism of BTKi resistance in CLL, complementing the well described BTK and PLCG2 mutations. These findings support the clinical relevance of detecting 2p gain to guide treatment strategies and improve outcomes in CLL.</p>

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REL overexpression and sustained NF-κB signaling associated with 2p gain induce resistance to BTK inhibitors in Chronic Lymphocytic Leukemia

  • 期刊论文

  • 发表日期：

    2025年12月9日

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  • Léa Dehgane,
  • Eliane Mallet,
  • Constance Brasseur,
  • Daphné Krzisch,
  • Wail Zeitouni,
  • Casilda Hitier,
  • Marianne Ayoub,
  • Kenza Dubois,
  • Claudia Pérez Carretero,
  • Damien Roos-Weil,
  • Sylvain Choquet,
  • Karim Maloum,
  • Clotilde Bravetti,
  • Marine Armand,
  • Delphine Garnier,
  • Jesús-María Hernández-Rivas,
  • Santos A. Susin,
  • Florence Nguyen-Khac,
  • Elise Chapiro

摘要

The gain of chromosome 2p (2p+) is a recurrent abnormality in chronic lymphocytic leukemia (CLL), frequently observed in advanced or relapsed disease, associated with poor prognosis and reduced response to Bruton’s tyrosine kinase inhibitors (BTKi). To investigate the mechanisms of 2p+-mediated resistance, we performed single-cell RNA sequencing, revealing NF-κB pathway enrichment and REL overexpression in 2p+ B cells. In vitro analyses confirmed increased REL expression and DNA-binding activity in a large cohort of 2p+ primary CLL samples. Functionally, 2p+ CLL cells showed reduced sensitivity to both covalent and non-covalent BTKi. Moreover, upon ibrutinib treatment, REL DNA-binding activity decreased in 2pWT CLL cells but remained sustained in 2p+ CLL cells following BCR stimulation, suggesting that persistent NF-κB activation contributes to resistance. Consistently, CRISPR/Cas9-mediated inactivation of REL in a 2p+ B-lymphoid cell line led to downregulation of canonical NF-κB signaling and restored BTKi sensitivity. Clinically, patients with 2p+ CLL treated with BTKi had a shorter time-to-next-treatment than 2pWT patients. Altogether, our study identifies REL overexpression as a novel 2p+-driven mechanism of BTKi resistance in CLL, complementing the well described BTK and PLCG2 mutations. These findings support the clinical relevance of detecting 2p gain to guide treatment strategies and improve outcomes in CLL.