Abstract
BackgroundAcute T-cell lymphoblastic leukaemia (T-ALL) is an aggressive disorder derived from immature thymocytes. The variability observed in clinical responses on this type of tumours to treatments, the high toxicity of current protocols and the poor prognosis of patients with relapse or refractory make it urgent to find less toxic and more effective therapies in the context of a personalized medicine of precision.MethodsWhole exome sequencing and RNAseq were performed on DNA and RNA respectively, extracted of a bone marrow sample from a patient diagnosed with tumour primary T-ALL and double negative thymocytes from thymus control samples. We used PanDrugs, a computational resource to propose pharmacological therapies based on our experimental results, including lists of variants and genes. We extend the possible therapeutic options for the patient by taking into account multiple genomic events potentially sensitive to a treatment, the context of the pathway and the pharmacological evidence already known by large-scale experiments.ResultsAs a proof-of-principle we used next-generation-sequencing technologies (Whole Exome Sequencing and RNA-Sequencing) in a case of diagnosed Pro-T acute lymphoblastic leukaemia. We identified 689 disease-causing mutations involving 308 genes, as well as multiple fusion transcript variants, alternative splicing, and 6652 genes with at least one principal isoform significantly deregulated. Only 12 genes, with 27 pathogenic gene variants, were among the most frequently mutated ones in this type of lymphoproliferative disorder. Among them, 5 variants detected in CTCF, FBXW7, JAK1, NOTCH1 and WT1 genes have not yet been reported in T-ALL pathogenesis.ConclusionsPersonalized genomic medicine is a therapeutic approach involving the use of an individual’s information data to tailor drug therapy. Implementing bioinformatics platform PanDrugs enables us to propose a prioritized list of anticancer drugs as the best theoretical therapeutic candidates to treat this patient has been the goal of this article. Of note, most of the proposed drugs are not being yet considered in the clinical practice of this type of cancer opening up the approach of new treatment possibilities.
Highlights
Acute T-cell lymphoblastic leukaemia (T-Acute leukaemia of the lymphoid lineage (ALL)) is an aggressive disorder derived from immature thymocytes
Clinical data evidenced a case of pro-T acute lymphoblastic leukaemia Sixteen years old patient presented with a six weeks progressive cough, asthenia, hyporexia and lose of weight
This paper provided a framework for T-cell acute lymphoblastic (T-ALL) patients based on the use of PanDrugs to integrate whole exome sequencing and Ribonucleic acid (RNA)-Sequencing data into the proposal of a prioritized list of drugs, which could be clinically actionable in the context of a personalized medicine of precision
Summary
Acute T-cell lymphoblastic leukaemia (T-ALL) is an aggressive disorder derived from immature thymocytes. The variability observed in clinical responses on this type of tumours to treatments, the high toxicity of current protocols and the poor prognosis of patients with relapse or refractory make it urgent to find less toxic and more effective therapies in the context of a personalized medicine of precision. The toxicity of intensified chemotherapies treatments, chemotherapy resistance and the outcomes of patients with relapsed or refractory ALL remain poor [1, 3]. It is still necessary develop appropriate strategies to enable us to identify more effective, less toxic treatments taking into account the patient genetic profile. The application of Next-Generation Sequencing (NGS) techniques has produced an unprecedented body of knowledge concerning the molecular pathogenesis of these haematological disorders allowing the discovery of multiple genetic and epigenetic alterations underpinning tumour development
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