Deregulation of non-coding RNAs is associated with clinical outcome of childhood Acute Lymphoblastic Leukemia

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

Mar del plata

Congreso; LXIII Reunión Científica de la sociedad Argentina de Investigación Clínica; 2018

SAIC-SAI-SAFIS

Patients with Acute Lymphoblastic Leukemia (ALL) are stratified into risk groups according tobiochemical 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 tobetter understand the biology of childhood ALL is to study the transcriptome of leukemic cells inorder to identify gene expression profiles driving the outcome. In this study, we sought to identifygene expression profiles that could predict childhood ALL outcome and acute therapy-relatedtoxicity. 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 performeddifferential gene expression analysis between risk groups, presence of relapse and acute grade-3/4toxicity, considering that genes were differentially expressed if the FDR adjusted p-value≤0.05. Weperformed multivariate analyses including the risk group as a covariate for relapse and toxicity. In allcomparisons, we found that several of the Differentially Expressed Genes (DEG) corresponded tonon-coding RNAs (ncRNA). The most deregulated gene between high risk and intermediate riskpatients was a long intergenic ncRNA (Log2FC=-20, adj.p=0.02). When we compared patients withand without acute grade-3/4 toxicity, 12% of the DEG were ncRNA. Finally, when compared patientwith and without relapse we detected 42.5% of the DEG as ncRNA. Among these, we identified twomicro-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 cutaneousmalignant melanoma and gastric cancer. There is now robust emerging evidence that alterations ofncRNAs are highly associated with tumor development and progression. The detection ofdifferential expressed ncRNAs might help to improve childhood ALL prognosis and identify newpotential therapeutic targets.