Immunoglobulin heavy-chain status and stromal interactions shape ferroptosis sensitivity in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of clonal B cells. Although targeted therapies have improved outcomes, resistance remains a challenge, particularly in high-risk patients with TP53 mutations or unmutated immunoglobulin heavy-chain variable region (IGHV) genes (U-CLL). Ferroptosis, a regulated, iron-dependent form of cell death, may represent an exploitable vulnerability in CLL; however, its mechanisms and clinical relevance remain poorly understood. Here, we identified IGHV status and microenvironmental cues as determinants of ferroptosis sensitivity. Using CLL cell lines, patient samples, and in vivo models, we show that CLL cells exhibit elevated basal levels of lipid peroxides and labile iron, predisposing them to ferroptosis. However, stromal interactions enhance cystine import and glutathione synthesis, thereby mitigating susceptibility to ferroptosis. Mechanistically, BTK inhibition sensitizes CLL cells to ferroptosis by increasing the transferrin receptor (TFRC, CD71) and increasing the intracellular Fe²⁺ level. High TFRC expression was associated with improved survival in two independent CLL patient cohorts, supporting its therapeutic and prognostic relevance. Combining ibrutinib with the GPX4 inhibitor RSL3 enhances ferroptosis and improves antileukemic efficacy in vivo. CLL cells with mutated IGHV genes (M-CLL) display greater TFRC expression and ferroptosis sensitivity than U-CLL cells do. This resistance can be overcome by ibrutinib-mediated TFRC induction or via metabolic targeting of fatty acid metabolism. Notably, ACSL1 is selectively upregulated in U-CLL cells and represents a targetable metabolic enhancer of ferroptosis sensitivity, as shown in vivo. Our findings reveal that TFRC and ACSL1 are functionally distinct yet targetable nodes that govern ferroptosis vulnerability in CLL patients and may guide novel therapeutic strategies for high-risk patients.