Hoffmeyer, E. | bioRxiv Science

bioRxiv2026

Progressive deterioration of adaptive immune repertoires in Down syndrome linked to interferon hyperactivity and lymphoid tissue disorganization

Persons with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display strong dysregulation of adaptive immunity, which underlies high risk of complications from infections, widespread autoimmunity, and poor vaccine responses. However, the mechanisms by which T21 dysregulates adaptive immunity across the lifespan remain poorly understood. We report here a multimodal analysis of adaptive immunity across development and aging in DS, including deep B cell profiling by mass cytometry matched to transcriptome and proteome data, B and T cell receptor sequencing (BCR, TCR), and spatial transcriptomics of tonsil tissue. T21 causes progressive shifts in B cell subsets together with accelerated age-dependent B cell loss linked to hyperactive interferon and JAK/STAT signaling. The peripheral immunoglobulin repertoire shows dysregulated class switching, progressive loss of diversity, differential VDJ usage, and imbalanced rates of somatic hypermutation across immunoglobulin isotypes mirrored by contraction and skewing of the TCR repertoire. In children with DS, tonsil tissues are highly disorganized with smaller germinal centers, fibrotic intrusions, lower rates of cell proliferation, strong inflammatory signaling, and transcriptional programs indicative of dysregulated lymphocyte homing and residence. Together, these results point to hyperactive interferon signaling as a driver of dysregulated adaptive immunity in DS amenable to early therapeutic intervention.

immunology↗

bioRxiv2024

Metabolic vulnerabilities in Down syndrome B-cell acute lymphoblastic leukemia can be targeted using Venetoclax

Children with Down syndrome (DS) and B-cell acute lymphoblastic leukemia (B-ALL) are at increased risk for treatment-related mortality and relapse, highlighting the need for new therapies. Leukemia cell lines (CLs) have been fundamental to understanding therapeutic responses to pharmacological agents. We generated three DS B-ALL CLs characterized with diverse genomic alterations, including IGH::CRLF2 rearrangement (BCR::ABL1 like), mutations in FLT3 and TP53, and a novel ERG::CEBPD rearrangement. DS CLs had diminished proliferation, metabolism, and mitochondrial function when compared to non-DS (NDS) CLs and interestingly, these findings were similar to NDS Philadelphia chromosome-like (Ph-like) B-ALL CLs. Based on similar mitochondrial defects and prior preclinical data using Venetoclax for Ph-like B-ALL, we hypothesized that Venetoclax would be effective in DS. Intriguingly, Venetoclax was more effective in DS when compared to both NDS and Ph-like CLs. Efficacy was observed in DS patient derived xenografts (PDXs) and diagnostic/relapsed patient samples treated with Venetoclax, which synergized with Trametinib and Vincristine. Mass spectrometry-based multiomics analyses in DS and NDS B-ALL patient samples revealed an enriched metabolite profile in DS, particularly in the hubs of glucose metabolism and polyunsaturated phosphatidylcholines and phosphatidylinositols. Transcriptome analyses in DS B-ALL patients (n=249) supported enhanced glucose and fatty acid metabolism. Glucose regulated B-ALL viability through de novo serine biosynthesis. Targeting serine synergized with Venetoclax in DS B-ALL CLs. In summary, we have generated novel tools for studying DS B-ALL and identify altered metabolism in DS that responds to Venetoclax.

cancer biology↗