Risk stratification of T-cell Acute Lymphoblastic Leukemia patients based on gene expression, mutations and copy number variation

• TCRγδ + T-ALL is a distinct subgroup based on gene expression, CNV and mutations.
• Patients with homozygous deletion of CDKN2A/CDKN2B show inferior DFS.
• TCR clonality along with CDKN2A/CDKN2B CNV can act as prognostic marker in T-ALL.

Gene expression, copy number variations (CNV), mutations and survival were studied to delineate TCRγδ + T-cell acute lymphoblastic leukemia (T-ALL) as a distinct subgroup from TCRαβ + T-ALL. Gene Ontology analysis showed that differential regulation of genes involved in pathways for leukemogenesis, apoptosis, cytokine-cytokine receptor interaction and antigen processing/presentation may offer a survival benefit to TCRγδ + T-ALL patients. Genes involved in disease biology and having equal expression in both the subgroups, were further analysed for mutations and CNV using droplet digital PCR. TCRγδ + T-ALL patients exhibited differential level of mutations for NOTCH1 and IKZF3; however BRAF mutations were detected at equal levels in both the subgroups. Although TCRγδ + T-ALL patients with these mutations demonstrated improved disease-free survival (DFS) as compared TCRαβ + T-ALL patients, it was not statistically significant. Patients with homozygous deletion of CDKN2A/CDKN2B showed poor DFS in each subgroup. TCRγδ + T-ALL patients with wild type/heterozygous deletion of CDKN2A/CDKN2B possess significantly better DFS over TCRαβ + T-ALL patients (p = 0.017 and 0.045, respectively). Thus, the present study has for the first time demonstrated TCRγδ clonality and CDKN2A/CDKN2B CNV together as potential prognostic markers in management of T-ALL. Further understanding the functional significance of differentially regulated genes in T-ALL patients would aid in designing risk based treatment strategies in subset specific manner.