Transcriptomic analysis of childhood Acute Lymphoblastic Leukemia at diagnosis and its association with clinical evolution

ORELLANO, LAURA; RICCHERI, CECILIA; GUIÑAZU, KARINA; GUTIERREZ, MARCELA; SCHUTTENBERG, VIRGINIA; VAZQUEZ, ELBA; ABBATE, MERCEDES; ALONSO, MARTA; AVERSA, LUIS; COTIGNOLA, JAVIER

Mar del Plata

Congreso; Reunión Anual de Biociencia 2019; 2019

Sociedad Argentina de Investigación Clínica

The identification of new biomarkers or gene-expression profiles in childhood Acute Lymphoblastic Leukemia (ALL) could help predicting the disease outcome, improving the response to treatment and reducing therapy-related toxicity. For this purpose we collected samples from three hospitals (H.Posadas, H.Gutierrez, H.Ludovica) by bone marrow aspiration and isolated total RNA from 37 pediatric patients with de-novo ALL at time of diagnosis to perform paired-end transcriptome analysis (RNAseq). Clinico-pathological characteristics and disease outcome were evaluated and recorded by trained oncohematologists. We performed differential gene expression analysis between early response to prednisone and occurrence of relapse/death (Event Free Survival, EFS). We considered that genes were differentially expressed if the FDR adjusted p-value≤0.05. We performed multivariate analyses including when necessary, date of transcriptome, gender and risk group as covariates. We found 22 significant differential expressed genes (DEG) for EFS: 12 (54.5%) were protein-coding genes and 10 (45.5%) were non-coding RNA genes. Among the protein-coding genes we found MYLK3 (log2FC=3.9, adj.p=1.2x10-9) and PTPRB (log2FC=3.9, adj.p=2.2x10-5). MYLK3 over-expression was associated with poor prognosis in bladder, liver, colon and gastric cancers. PTPs genes are reported as tumor suppressors but it was also associated with increased risk of colorectal metastasis. In the case of response to prednisone we found 40 DEG (75% protein-coding). Among them we detected the ABCG2 gene (log2FC=3.1, adj.p=1.5x10-3), an ATP Binding protein that functions as a xenobiotic transporter and which may play a major role in multi-drug resistance. In acute myeloid leukemia it was associated with remission failure and shorter disease-free survival. In conclusion, the study of gene expression profiles at diagnosis might help improving risk stratification, therapy efficacy and reducing the occurrence of relapse and toxicity.