Highlighted research articles

Aberrant turnover of cellular proteins can drive lymphomagenesis. Kelch-like family member 6 (KLHL6) encodes a substrate-determining module for a powerful protein degradation machinery with undetermined targets, and it is recurrently mutated in diffuse large B-cell lymphoma (DLBCL). By applying high-throughput proteomic screens and functional studies, Meriranta and colleagues revealed that KLHL6 targets and downregulates B-cell receptor (BCR). In B cells, selected KLHL6 mutants localized abnormally, resulting in elevated plasma membrane BCR levels that fueled BCR signaling. Loss of KLHL6 expression characterized activated B-cell–like DLBCLs with poor outcomes and associated with a targetable phenotype with high BCR levels.See article, p. 331.With axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) now approved for large B-cell lymphoma (LBCL), criteria for choosing the optimal CAR T-cell therapy become a pressing clinical question. Stella and colleagues tackle it in a real-life prospective study spanning 21 institutions, matching baseline characteristics of 485 patients by propensity-score weighting. Whereas non-relapse mortality and overall survival are similar between the two CART products, axi-cel’s progression-free survival (PFS) and overall response rate were superior to tisa-cel. Axi-cel’s advantage extends to patients who fail bridging therapy. Polatuzumab-based bridging was associated with better PFS outcomes. At the same time, toxicity rates are higher with axi-cel, reinforcing the need of balancing prognostic factors for efficacy and safety for individual cases. The CAR-HEMATOX score is validated as a predictor of survival and hematologic toxicity, aiding in future risk stratification and therapy development.See article, p. 318.Successful cancer therapies have to target the cell of origin. Sarchi and colleagues engineer human hematopoietic stem and progenitor cells (HSPCs) with the SF3B1 K700E point mutation, common in myeloid malignancies. A drug screen identifies CHK1 as a unique dependency of SF3B1-mutant HSPCs, which is validated in patient-derived cultures and xenografts using clinically relevant CHK1 inhibitor prexasertib. Mechanistically, vulnerability of SF3B1-mutant cells to CHK1 inhibition is linked to mis-splicing of key cell cycle regulators BUBR1 and CDC27, which translates into decreased protein levels. Shortage of BUBR1 and CDC27 function results in the delayed G2/M transition and activation of mitotic checkpoint, including CHK1. This study offers a new avenue to targeted therapy of spliceosome-mutant myeloid neoplasms.See article, p. 353.