Abstract 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/N WT ) or mutated (CLL/N M ), both with UM-BCR, we show that BCR stimulation activates the NOTCH1 pathway, upregulating metabolic programs and mitochondrial biogenesis, selectively in CLL/N M . 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/N WT ) or mutated (MEC-1/N M ) 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/N M cells rely on oxidative metabolism, with increased glutamine dependency and strengthened anabolic pathways, leading to augmented proliferation compared to MEC-1/N WT . Importantly, CLL/N M 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.
Fascì et al. (Mon,) studied this question.