Integrated Multi-Omic Analysis Reveals Novel Subtype-Specific Regulatory Interactions in Pediatric B-Cell Acute Lymphoblastic Leukemia

TL;DR

This study uses multi-omic analysis to discover new subtype-specific biomarkers in pediatric B-cell leukemia, which could lead to better targeted treatments.

Contribution

The study introduces novel proteomic and phosphoproteomic methods to identify subtype-specific biomarkers in pediatric B-ALL.

Findings

Novel subtype-specific proteomic and phosphoproteomic biomarkers were identified in Ph-like and ETV6::RUNX1 B-ALL subtypes.

Calcium-dependent signaling processes were found to play a previously undescribed role in Ph-like B-ALL.

Abstract

Although children diagnosed with B-cell acute lymphoblastic leukemia (B-ALL) generally respond well to standard treatment regimens, children who do not would benefit from targeted therapies. In order to identify possible novel treatment targets, we profile samples from patients with two specific subtypes of B-ALL using novel proteomic and phosphoproteomic methods. These tools help us identify biomarkers specific to each subtype that were previously unknown and could help determine which treatments a patient is eligible to receive. Further work applying these approaches to a larger patient cohort will lay the groundwork for developing novel treatments, ultimately improving outcomes for children diagnosed with B-ALL.

Background/Objectives: 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. Methods: 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. Conclusions: 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.

Figures