Identification of prognostic markers in Argentinian acute lymphoblastic leukemia pediatric patients through transcriptome analysis: differential gene expression, mutational status and immune microenvironment

ABBATE MARÍA MERCEDES; RUIZ MARÍA SOL; AVENDAÑO, DANIEL; RICCHERI MARÍA CECILIA; VAZQUEZ ELBA; COTIGNOLA JAVIER

Simposio; 10th Annual Symposium on Global Cancer Research; 2022

Purpose: Acute lymphoblastic leukemia (ALL) isthe most incident pediatric cancer. While considerable progress has been madeon treatment efficacy and survival rates, about 15-30% of patients relapseand/or die. We aimed to identify molecular profiles in leukemic blasts and bonemarrow (BM) microenvironment that could help better predict disease outcome.Methods: We performedRNA-seq on BM samples from pediatric ALL patients at diagnosis (N=37). Patientswere part of a multi-center clinical protocol in Argentina (median follow-up:31 months). We analyzed differential gene expression, gene set variationanalysis, mutations in candidate genes, and fusion genes amongclinico-pathological features. The abundance of immune populations in the BMwas inferred by digital cytometry, and through a ?cytolytic score? based on thegeometric mean of 5 genes expressed in cytotoxic cells.Results: We detected:i)37 differentially expressed genes (DEG) between poor vs good responders toprednisone; ii)71 DEG between high vs standard-risk groups; iii)13 DEG betweenpatients that who died/relapsed vs those who did not; and iv)35 DEG betweenpatients that developed severe therapy-related acute toxicity vs those who didnot (|log2fold-change|>1; p.adj<0.05). Surprisingly, we found that15%-30% of the DEG corresponded to long-non-coding RNAs. We found 6differentially expressed pathways relevant to cancer and ALL biology among riskgroups (p<0.01). We identified 17 mutations in clinically relevant genes and3 fusion genes in 44% of patients; the group of patients harboring pointmutations had lower relapse-free survival (Cox-p-val=0.006). High cytolytic score was associated withactivated CD8+T cells, immune cell trafficking, and BM nichesignaling genesets, suggesting potential candidates for immunotherapies. HigherCD8+T cell/NK at diagnosis could be associated with worse event-free survival(hazard-ratio=5.39; Cox-p-val=0.08).Conclusion:Transcriptomic sequencing allowed the analysis and integration of multiplemolecular features that might improve risk stratification, therapy efficacy andreduce the occurrence of relapse and toxicity.