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Using primary CLL cells classified as\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    wild-type (CLL\/N\n                    <jats:sup>WT<\/jats:sup>\n                    ) or mutated (CLL\/N\n                    <jats:sup>M<\/jats:sup>\n                    ), both with UM-BCR, we show that BCR stimulation activates the NOTCH1 pathway, upregulating metabolic programs and mitochondrial biogenesis, selectively in CLL\/N\n                    <jats:sup>M<\/jats:sup>\n                    . These cells display enhanced basal respiration and glycolysis, driven by higher mitochondrial mass, and further increase metabolic activity upon BCR triggering. To directly implicate\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    mutations, we engineered an MEC-1 model to generate wild-type (MEC-1\/N\n                    <jats:sup>WT<\/jats:sup>\n                    ) or mutated (MEC-1\/N\n                    <jats:sup>M<\/jats:sup>\n                    ) clones in a UM-BCR background. Here,\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    hyperactivation promoted mitochondrial metabolism through TFAM-dependent transcriptional control. Gene expression profiling, metabolic assays, and stable isotope tracing confirmed that MEC-1\/N\n                    <jats:sup>M<\/jats:sup>\n                    cells rely on oxidative metabolism, with increased glutamine dependency and strengthened anabolic pathways, leading to augmented proliferation compared to MEC-1\/N\n                    <jats:sup>WT<\/jats:sup>\n                    . Importantly, CLL\/N\n                    <jats:sup>M<\/jats:sup>\n                    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\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    -mutated CLL.\n                  <\/jats:p>","DOI":"10.1038\/s41375-026-02912-7","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:10:43Z","timestamp":1774271443000},"page":"982-995","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional cooperation between the B-cell receptor and NOTCH1 in regulating metabolic reprogramming in chronic lymphocytic leukemia"],"prefix":"10.1038","volume":"40","author":[{"given":"Amelia","family":"Fasc\u00ec","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco 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