Spoeck, S. | bioRxiv Science

bioRxiv2026

TET2 loss promotes premalignant survival and clonal selection in MYC-driven B cell lymphoma

The DNA demethylase ten-eleven translocation enzyme 2 (TET2) is frequently inactivated in hematologic malignancies, yet how its loss shapes oncogene-driven transformation remains unclear. Using a mouse model in which MYC is overexpressed in the B cell lineage, driving aggressive B cell lymphoma, we show that Tet2 loss increases lymphoma penetrance and biases disease toward an IgM immunophenotype. Established lymphomas are broadly similar across genotypes, suggesting that Tet2 loss exerts much of its effects before lymphoma onset. Accordingly, Tet2 loss expands a premalignant IgM B cell subset with reduced apoptotic sensitivity and an increased frequency of BCL2BIMhi cells. Consistently, Tet2 deficient IgM B cells persist better in in vitro cultures, show increased clonogenic survival, and exhibit clonal skewing. These findings support a model in which Tet2 loss heightens MYC-driven lymphoma penetrance by promoting the survival and selection of premalignant B cells under apoptotic stress.

cancer biology↗

bioRxiv2026

Plasmalogen metabolism shapes germinal center immunity

Plasmalogens are membrane lipids whose roles in immunity are emerging through identification of the PEDS1 gene and advances in lipid analytics. Because PEDS1 catalyses the final step of plasmalogen biosynthesis, Peds1 knockout models plasmalogen loss. Building on reports of a haematopoietic phenotype in Peds1-deficient mice, we performed extended profiling to characterise haematological and immune phenotypes. In line with these previous investigations, mice showed reduced red blood cell counts and haematocrit, with increased mean platelet volume. At steady state, plasmalogen deficiency was associated with reduced germinal centre (GC) B cell frequencies in mucosal lymphoid tissues and lower basal serum IgG1 levels. Following immunisation, GC B cell frequencies and ovalbumin-specific IgG1 were similar across genotypes, yet GC B cells exhibited elevated mitochondrial superoxide and plasma cells displayed increased lipid peroxidation. To test for B cell-intrinsic effects, we used an in vitro GC culture, where Peds1-deficient B cells showed reduced class switching to IgG1, intracellular IgG1 accumulation and diminished IgG1 secretion. Together, these findings support a role for plasmalogens and PEDS1 as a lipid-metabolic modulator of GC dynamics and IgG1 output, consistent with broader ether lipid perturbations. Plasmalogen metabolism may therefore offer a potential entry point to modulate humoral immunity or haematopoiesis.

immunology↗