RIF1 acts as a gatekeeper of B cell identity during late differentiation

RIF1 is a multifunctional protein that promotes immunoglobulin (Ig) isotype diversification. Whether RIF1 plays additional roles in adaptive immunity is unknown. In this study, we showed that Rif1 expression is upregulated following mature B cell activation, while its deficiency skewed the transcriptional profile of activated B cells towards plasmablasts (PBs) and plasma cells (PCs). Additionally, RIF1 ablation resulted in increased PB formation ex vivo and enhanced terminal differentiation into PCs upon immunization. Therefore, RIF1 serves as a cell identity gatekeeper during late B cell differentiation, providing an additional layer of control in the establishment of humoral immunity

PDGFA-associated protein 1 protects mature B lymphocytes from stress-induced cell death and promotes antibody gene diversification

The establishment of protective humoral immunity is dependent on the ability of mature B cells to undergo antibody gene diversification while adjusting to the physiological stressors induced by activation with the antigen. Mature B cells diversify their antibody genes by class switch recombination (CSR) and somatic hypermutation (SHM), which are both dependent on efficient induction of activation-induced cytidine deaminase (AID). Here, we identified PDGFA-associated protein 1 (Pdap1) as an essential regulator of cellular homeostasis in mature B cells. Pdap1 deficiency leads to sustained expression of the integrated stress response (ISR) effector activating transcription factor 4 (Atf4) and induction of the ISR transcriptional program, increased cell death, and defective AID expression. As a consequence, loss of Pdap1 reduces germinal center B cell formation and impairs CSR and SHM. Thus, Pdap1 protects mature B cells against chronic ISR activation and ensures efficient antibody diversification by promoting their survival and optimal function

Pdap1 protects mature B lymphocytes from stress-induced cell death and promotes antibody gene diversification

The establishment of protective humoral immunity is dependent on the ability of mature B cells to undergo antibody gene diversification while adjusting to the physiological stressors induced by activation with the antigen. Mature B cells diversify their antibody genes by class switch recombination (CSR) and somatic hypermutation (SHM), which are both dependent on efficient induction of activation-induced cytidine deaminase (AID). Here, we identified PDGFA-associated protein 1 (Pdap1) as an essential regulator of cellular homeostasis in mature B cells. Pdap1 deficiency leads to sustained expression of the integrated stress response (ISR) effector activating transcription factor 4 (Atf4) and induction of the ISR transcriptional program, increased cell death, and defective AID expression. As a consequence, loss of Pdap1 reduces germinal center B cell formation and impairs CSR and SHM. Thus, Pdap1 protects mature B cells against chronic ISR activation and ensures efficient antibody diversification by promoting their survival and optimal function

Clinical implications and dynamics of clonal hematopoiesis in anti-CD19 CAR T-cell treated patients

Recent evidence revealed important interactions between clonal hematopoiesis (CH) and cellular therapies established for the treatment of hematologic malignancies. The impact of CH on safety, efficacy, and outcome of chimeric antigen receptor (CAR) T-cell therapy is currently under investigation. We analyzed 110 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (n = 105) or acute lymphoblastic leukemia (ALL) (n = 5), treated with Axicabtagene-Ciloleucel (39%), Tisagenlecleucel (51%), or Brexucabtagene autoleucel (10%). Using error-corrected targeted sequencing, a high CH prevalence of 56.4% (variant allele frequency [VAF] ≥1%) at the time of CAR T-cell infusion was detected. The most frequently mutated gene was PPM1D followed by DNMT3A, TET2, ASXL1, and TP53. Variant allele frequencies were significantly lower in B and T cells compared with monocytes and granulocytes. CH did not increase the risk of CAR T-related toxicities. The incidences of cytokine release syndrome and immune effector-cell-associated neurotoxicity syndrome were similar between CH(pos) and CH(neg) patients, regardless of clone size, age, or CAR T product. Prolonged cytopenias were not associated with CH. Best overall response rates (ORRs) were numerically but not significantly higher in CH(pos) patients (ORR 76.7% versus 62.2%; P = 0.13). Furthermore, CH status did not predict progression-free survival or overall survival. Lastly, sequential analysis showed a modest VAF increase of 1.3% and acquisition of novel mutations within 100 days postinfusion. CH was frequent in large B-cell lymphoma/ALL patients receiving CAR T-cells but did not affect toxicity nor treatment response or outcome