Scholarlink

<p>Mutations in <i>NOTCH1</i>, which occur in ~10% of Chronic Lymphocytic Leukemia (CLL) patients at diagnosis, are typically associated with unmutated (UM) B-cell receptor (BCR) subsets and define patients with earlier treatment need. Using primary CLL cells classified as <i>NOTCH1</i> wild-type (CLL/N<sup>WT</sup>) or mutated (CLL/N<sup>M</sup>), both with UM-BCR, we show that BCR stimulation activates the NOTCH1 pathway, upregulating metabolic programs and mitochondrial biogenesis, selectively in CLL/N<sup>M</sup>. These cells display enhanced basal respiration and glycolysis, driven by higher mitochondrial mass, and further increase metabolic activity upon BCR triggering. To directly implicate <i>NOTCH1</i> mutations, we engineered an MEC-1 model to generate wild-type (MEC-1/N<sup>WT</sup>) or mutated (MEC-1/N<sup>M</sup>) clones in a UM-BCR background. Here, <i>NOTCH1</i> hyperactivation promoted mitochondrial metabolism through TFAM-dependent transcriptional control. Gene expression profiling, metabolic assays, and stable isotope tracing confirmed that MEC-1/N<sup>M</sup> cells rely on oxidative metabolism, with increased glutamine dependency and strengthened anabolic pathways, leading to augmented proliferation compared to MEC-1/N<sup>WT</sup>. Importantly, CLL/N<sup>M</sup> cells exhibit a marked vulnerability to glutamine deprivation. Combined inhibition of glutamine utilization and BCL2 triggered rapid apoptosis, providing a rationale for tailored therapeutic strategies in <i>NOTCH1</i>-mutated CLL.</p><p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Functional cooperation between the B-cell receptor and NOTCH1 in regulating metabolic reprogramming in chronic lymphocytic leukemia

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月23日

查看全文
  • Amelia Fascì,
  • Francesco Edoardo Vallone,
  • Nahal Nabelsi,
  • Elodie Viry,
  • Ilenia Sana,
  • Alessia Morabito,
  • Silvia Seghezzi,
  • Noemi Anna Pesce,
  • Matteo Rovere,
  • Nadia Bertola,
  • Chloé Duculty,
  • Silvia Ravera,
  • Samir Mouhssine,
  • Marta Muzio,
  • Paolo Ghia,
  • Candida Vitale,
  • Marta Coscia,
  • Etienne Moussay,
  • Gianluca Gaidano,
  • John Allan,
  • Richard R. Furman,
  • Jerome Paggetti,
  • Tiziana Vaisitti,
  • Silvia Deaglio

摘要

Mutations in NOTCH1, which occur in ~10% of Chronic Lymphocytic Leukemia (CLL) patients at diagnosis, are typically associated with unmutated (UM) B-cell receptor (BCR) subsets and define patients with earlier treatment need. Using primary CLL cells classified as NOTCH1 wild-type (CLL/NWT) or mutated (CLL/NM), both with UM-BCR, we show that BCR stimulation activates the NOTCH1 pathway, upregulating metabolic programs and mitochondrial biogenesis, selectively in CLL/NM. These cells display enhanced basal respiration and glycolysis, driven by higher mitochondrial mass, and further increase metabolic activity upon BCR triggering. To directly implicate NOTCH1 mutations, we engineered an MEC-1 model to generate wild-type (MEC-1/NWT) or mutated (MEC-1/NM) clones in a UM-BCR background. Here, NOTCH1 hyperactivation promoted mitochondrial metabolism through TFAM-dependent transcriptional control. Gene expression profiling, metabolic assays, and stable isotope tracing confirmed that MEC-1/NM cells rely on oxidative metabolism, with increased glutamine dependency and strengthened anabolic pathways, leading to augmented proliferation compared to MEC-1/NWT. Importantly, CLL/NM cells exhibit a marked vulnerability to glutamine deprivation. Combined inhibition of glutamine utilization and BCL2 triggered rapid apoptosis, providing a rationale for tailored therapeutic strategies in NOTCH1-mutated CLL.