Identification of Molecular Subtypes of B-Cell Acute Lymphoblastic Leukemia in Mexican Children by Whole-Transcriptome Analysis

TL;DR

This study identifies molecular subtypes of B-cell acute lymphoblastic leukemia in Mexican children using RNA sequencing, revealing key mutations and gene fusions for better diagnosis and treatment.

Contribution

The study provides a detailed molecular classification of B-ALL in Mexican pediatric patients using whole-transcriptome analysis.

Findings

High hyperdiploidy was the most common molecular subtype in Mexican B-ALL patients.

RNA-seq successfully detected gene fusions and mutations across various B-ALL subtypes.

Ph-like subtype showed specific mutations and CRLF2 overexpression, while DUX4 had PDGFRa variants.

Abstract

B-lineage acute lymphoblastic leukemia (B-ALL) is classified into more than 20 molecular subtypes, and next-generation sequencing has facilitated the identification of these with high sensitivity. Bulk RNA-seq analysis of bone marrow was realized to identify molecular subtypes in Mexican pediatric patients with B-ALL. High hyperdiploidy (27.3%) was the most frequent molecular subtype, followed by DUX4 (13.6%), TCF3::PBX1 (9.1%), ETV6::RUNX1 (9.1%), Ph-like (9.1%), ETV6::RUNX1-like (9.1%), PAX5alt (4.5%), Ph (4.5%), KMT2A (4.5%), and ZNF384 (4.5%), with one patient presenting both the PAX5alt and low hypodiploidy subtypes (4.5%). The genes TYK2, SEMA6A, FLT3, NRAS, SETD2, JAK2, NT5C2, RAG1, and SPATS2L harbor deleterious missense variants across different B-ALL molecular subtypes. The Ph-like subtype exhibited mutations in STAT2, ADGRF1, TCF3, BCR, JAK2, and NRAS with overexpression of the CRLF2 gene. The DUX4 subtype showed mutually exclusive missense variants in the PDGRFA gene. Here, we have demonstrated the importance of using RNA-seq to facilitate the differential diagnosis of B-ALL with successful detection of gene fusions and mutations. This will aid both patient risk stratification and precision medicine.

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