Deregulation of non-coding rnas is associated with clinical outcome of childhood acute lymphoblastic leukemia.

VAZQUEZ ELBA; COTIGNOLA JAVIER; ABBATE MERCEDES; BRANDANI, JAVIER NAHUEL; GUERON, GERALDINE

Mar del Plata

Congreso; LXIII Reunion Anual de la Sociedad Argentina de Investigacion Clinica; 2018

SAIC

Patients with Acute Lymphoblastic Leukemia (ALL) are stratified into risk groups according to biochemical parameters, cytogenetic and molecular signatures, and early response to therapy. Despite differential treatment, there are some patients that recur in all risk groups. One strategy to better understand the biology of childhood ALL is to study the transcriptome of leukemic cells in order to identify gene expression profiles driving the outcome. In this study, we sought to identify gene expression profiles that could predict childhood ALL outcome and acute therapy-related toxicity. We collected samples by bone marrow aspiration at time of diagnosis and isolated RNA. Then, we performed paired-end transcriptome analysis (RNAseq) from 29 pediatric patients with de-novo ALL. Clinico-pathological characteristics were evaluated and recorded. We performed differential gene expression analysis between risk groups, presence of relapse and acute grade-3/4 toxicity, considering that genes were differentially expressed if the FDR adjusted p-value≤0.05. We performed multivariate analyses including the risk group as a covariate for relapse and toxicity. In all comparisons, we found that several of the Differentially Expressed Genes (DEG) corresponded to non-coding RNAs (ncRNA). The most deregulated gene between high risk and intermediate risk patients was a long intergenic ncRNA (Log2FC=-20, adj.p=0.02). When we compared patients with and without acute grade-3/4 toxicity, 12% of the DEG were ncRNA. Finally, when compared patient with and without relapse we detected 42.5% of the DEG as ncRNA. Among these, we identified two micro-RNAs: miR-6727 (log2FC=5, adj.p=0.02) and miR-4317 (log2FC=-17, adj.p=0.0003). Particularly, miR-4317 has been reported to be also down regulated in biopsies of cutaneous malignant melanoma and gastric cancer. There is now robust emerging evidence that alterations of ncRNAs are highly associated with tumor development and progression. The detection of differential expressed ncRNAs might help to improve childhood ALL prognosis and identify new potential therapeutic targets.