Bioinformatic characterization of immune cell types and genetic variants in the bone marrow of childhood acute lymphoblastic leukemia patients

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

Workshop; EMBL Course: Cancer genomics; 2021

European Molecular Biology Laboratory

Despite progress on treatment efficacy and survival rates in childhood acute lymphoblastic leukemia (ALL), about 15-30% of patients relapse and/or die. The identification of new biomarkers might improve initial stratification. Immunotherapies are promising as complementary treatments, yet the most relevant therapy targets and patient subsets remain unclear. Aims: To characterize immune cell types in the bone marrow (BM) of ALL using bioinformatic tools and identify genetic variants of clinical relevance in leukemic blasts. Methods:we performed RNA-seq on BM samples collected at ALL diagnosis (N=37) from Argentina. We evaluated SNVs/InDels in 114 genes and 79 fusion genes (RNAmut). The proportion of immune cells was estimated using MIXTURE. A cytolytic score reflectingCD8+cytotoxic T lymphocytes and Natural Killer cells (NK) abundance was calculated as the geometric mean of 5 genes specifically expressed in such cells. Gene set enrichment analysis was performed with GSVA package in R. Results:We found a total of 9,594 variants. After annotation and filtering, we identified 16 SNVs/InDels (n=12) and 3 fusion genes (n=5). The subset of patients with SNVs/InDels showed a higher risk of relapse (risk ratio=1.71; 95%CI:1.06?2.76). Cytolytic score correlated with CD8+T cells and NK proportions (Rho>0.38, p-val<0.05). Higher CD8+T cell/NK could be associated with worse event-freesurvival (hazard ratio=5.39; 95%CI: 0.64-44.98, p-val=0.08). 12.5% of samples had cytolytic Z-score>1, and half of them relapsed/died. Samples with cytolytic Z-score >1 vs. <1 were enriched in genesets related to activation of CD8T cells, immune cell trafficking, and BM niche signaling. The identification ofpatients with increased CD8+T/NK in BM suggests potential candidatesfor immunotherapies. Given the small sample size, these observations should beconfirmed in additional patients.