Biology subjects

Paietta, E.

Publications and source records attributed to Paietta, E..

4 recordsLinked to original sources

bioRxiv2023

Dynamic phosphatase-recruitment controls B-cell selection and oncogenic signaling

Initiation of B-cell receptor (BCR)1 signaling, and subsequent antigen-encounter in germinal centers2,3 represent milestones of B-lymphocyte development that are both marked by sharp increases of CD25 surface-expression. Oncogenic signaling in B-cell leukemia (B-ALL)4 and lymphoma5 also induced CD25-surface expression. While CD25 is known as an IL2-receptor chain on T- and NK-cells6-9, the significance of its expression on B-cells was unclear. Our experiments based on genetic mouse models and engineered patient-derived xenografts revealed that, rather than functioning as an IL2-receptor chain, CD25 expressed on B-cells assembled an inhibitory complex including PKC{delta} and SHIP1 and SHP1 phosphatases for feedback control of BCR-signaling or its oncogenic mimics. Recapitulating phenotypes of genetic ablation of PKC{delta}10-12, SHIP113,14 and SHP114, 15,16, conditional CD25-deletion decimated early B-cell subsets but expanded mature B-cell populations and induced autoimmunity. In B-cell malignancies arising from early (B-ALL) and late (lymphoma) stages of B-cell development, CD25-loss induced cell death in the former and accelerated proliferation in the latter. Clinical outcome annotations mirrored opposite effects of CD25-deletion: high CD25 expression levels predicted poor clinical outcomes for patients with B-ALL, in contrast to favorable outcomes for lymphoma-patients. Biochemical and interactome studies revealed a critical role of CD25 in BCR-feedback regulation: BCR-signaling induced PKC{delta}-mediated phosphorylation of CD25 on its cytoplasmic tail (S268). Genetic rescue experiments identified CD25-S268 tail-phosphorylation as central structural requirement to recruit SHIP1 and SHP1 phosphatases to curb BCR-signaling. A single point mutation CD25S268A abolished recruitment and activation of SHIP1 and SHP1 to limit duration and strength of BCR-signaling. Loss of phosphatase-function, autonomous BCR-signaling and Ca2+-oscillations induced anergy and negative selection during early B-cell development, as opposed to excessive proliferation and autoantibody production in mature B-cells. These findings highlight the previously unrecognized role of CD25 in assembling inhibitory phosphatases to control oncogenic signaling in B-cell malignancies and negative selection to prevent autoimmune disease.

immunology↗

bioRxiv2023

Epigenomic mapping in B-cell acute lymphoblastic leukemia identifies transcriptional regulators and noncoding variants promoting distinct chromatin architectures

B-cell lineage acute lymphoblastic leukemia (B-ALL) is comprised of diverse molecular subtypes and while transcriptional and DNA methylation profiling of B-ALL subtypes has been extensively examined, the accompanying chromatin landscape is not well characterized for many subtypes. We therefore mapped chromatin accessibility using ATAC-seq for 10 B-ALL molecular subtypes in primary ALL cells from 154 patients. Comparisons with B-cell progenitors identified candidate B-ALL cell-of-origin and AP-1-associated cis-regulatory rewiring in B-ALL. Cis-regulatory rewiring promoted B-ALL-specific gene regulatory networks impacting oncogenic signaling pathways that perturb normal B-cell development. We also identified that over 20% of B-ALL accessible chromatin sites exhibit strong subtype enrichment, with transcription factor (TF) footprint profiling identifying candidate TFs that maintain subtype-specific chromatin architectures. Over 9000 inherited genetic variants were further uncovered that contribute to variability in chromatin accessibility among individual patient samples. Overall, our data suggest that distinct chromatin architectures are driven by diverse TFs and inherited genetic variants which promote unique gene regulatory networks that contribute to transcriptional differences among B-ALL subtypes. HIGHLIGHTSO_LIPro-B progenitor cells as the most common cell-of-origin for B-ALL C_LIO_LIAP-1 TF-associated cis-regulatory rewiring in B-ALL C_LIO_LISubtype-specific accessible chromatin signatures representing 20% of all B-ALL sites C_LIO_LIRole for distinct TFs in promoting subtype-specific chromatin architectures C_LIO_LIThousands of inherited genetic variants identified impacting chromatin state C_LI

cancer biology↗

bioRxiv2021

Variational autoencoders learn universal latent representations of metabolomics data

Dimensionality reduction approaches are commonly used for the deconvolution of high-dimensional metabolomics datasets into underlying core metabolic processes. However, current state-of-the-art methods are widely incapable of detecting nonlinearities in metabolomics data. Variational Autoencoders (VAEs) are a deep learning method designed to learn nonlinear latent representations which generalize to unseen data. Here, we trained a VAE on a large-scale metabolomics population cohort of human blood samples consisting of over 4,500 individuals. We analyzed the pathway composition of the latent space using a global feature importance score, which showed that latent dimensions represent distinct cellular processes. To demonstrate model generalizability, we generated latent representations of unseen metabolomics datasets on type 2 diabetes, schizophrenia, and acute myeloid leukemia and found significant correlations with clinical patient groups. Taken together, we demonstrate for the first time that the VAE is a powerful method that learns biologically meaningful, nonlinear, and universal latent representations of metabolomics data.

bioinformatics↗

bioRxiv2019

Dynamic 3D chromosomal landscapes in acute leukemia

Three-dimensional (3D) chromatin architectural changes can alter the integrity of topologically associated domains (TADs) and rewire specific enhancer-promoter interactions impacting gene expression. Recently, such alterations have been implicated in human disease, highlighting the need for a deeper understanding of their role. Here, we investigate the reorganization of chromatin architecture in T cell acute lymphoblastic leukemia (T-ALL) using primary human leukemia specimens and its dynamic responses to pharmacological agents. Systematic integration of matched in situ Hi-C, RNA-Seq and CTCF ChIP-Seq datasets revealed widespread changes in intra-TAD chromatin interactions and TAD boundary insulation in T-ALL. Our studies identify and focus on a TAD \"fusion\" event being associated with loss of CTCF-mediated insulation, enabling direct interactions between the MYC promoter and a distal super-enhancer. Moreover, our data show that small molecule inhibitors targeting either oncogenic signal transduction or epigenetic regulation reduce specific 3D interactions associated with transformation. Overall, our study highlights the impact, complexity and dynamic nature of 3D chromatin architecture in human acute leukemia.\n\nOne Sentence Summary3D chromatin alterations in T cell leukemia are accompanied by changes in insulation and oncogene expression and can be partially restored by targeted drug treatments.

cancer biology↗