Clark, Z. S. | Search bioRxiv

bioRxiv2025

Integrated multi-omic analysis reveals novel subtype-specific regulatory interactions in pediatric B-cell acute lymphoblastic leukemia

Molecular subtyping of pediatric B-cell acute lymphoblastic leukemia (B-ALL) has improved patient outcomes through stratification and selection of targeted therapies. Despite extensive genomic and transcriptomic profiling of this cancer, few studies to date have characterized the proteomic landscape, although proteins are the direct targets of many therapeutic agents. In this study, we demonstrate the utility of multi-omic integration of global transcriptomic, proteomic, and phosphoproteomic profiles of samples from patients diagnosed with either of two B-ALL subtypes - Ph- like (BCR::ABL1-like) and ETV6::RUNX1. Through individual and multi-omic analysis, we recapitulate known transcriptomic findings and identify novel subtype-specific proteomic and phosphoproteomic biomarkers. Our findings suggest a previously undescribed role for calcium-dependent signaling processes in Ph-like B-ALL, which has the potential to serve as a novel avenue for targeted treatments. By integrating multiple omics modalities, we identify not only features of interest but also begin to unravel the regulatory interactions driving subtype-specific mechanisms of leukemogenesis. This integrated analytic approach paves the way for enhanced precision medicine for precise subtyping and treatment selection for pediatric leukemia patients. Mass spectrometry data generated in this study have been deposited in MassIVE under accession MSV000097955.

cancer biology↗

bioRxiv2024

Differential Remodeling of the BRCA1 Interactome by a Unique Minimal Clinical Truncation Mutation

BRCA1, a critical tumor suppressor gene, plays an essential role in maintaining genomic stability through its involvement in DNA double-strand break repair, particularly via homologous recombination. Loss or impairment of BRCA1 function disrupts this repair pathway, resulting in genomic instability and significantly increased susceptibility to breast and ovarian cancers. To elucidate the molecular mechanisms by which BRCA1 mutations contribute to tumorigenesis, we employed quantitative mass spectrometry-based proximity labeling and affinity purification to identify cancer-specific protein-protein interactions (PPIs). Our integrated omics and visualization analysis of interactors revealed that the BRCA1-Y1853ter mutant, through its interaction with BARD1, perturbs the interactome and impacts cellular processes within the cytoplasm and nucleoplasm. Structural data further corroborated these findings, showing enhanced binding between the mutant BRCA1 and specific interactors, suggesting an altered functional profile. Together, these observations raise the hypothesis that the BRCA1-Y1853ter mutant may exhibit gain-of-function characteristics, providing new insights into the molecular and cellular effects of mutations in the BRCA1 C-Terminal (BRCT) domain and their implications for the pathogenesis of breast and ovarian cancers.

cancer biology↗