Population-based targeted RNA sequencing reveals novel disease-related gene fusions in pediatric and adult T-ALL.

Background: T-cell acute lymphoblastic leukemia (T-ALL) is a genetically diverse disease characterized by a heterogeneous profile of genetic lesions. Recent transcriptome studies identified a number of new T-ALL-related gene fusions. Novel gene fusions could be employed as disease-specific molecular markers and provide a better understanding of T-ALL biology, proving the need for further omics sequencing studies.

Methods: We performed a population-based analysis of 65 (26 pediatric and 39 adults) Lithuanian T-ALL patients. Targeted RNA sequencing (RNA-seq) was used to detect recurrent and novel T-ALL-related fusion transcripts and gene sequence variants. RT-qPCR was used to calculate the relative gene expression of fusion transcripts.

Results: We identified disease-related gene alterations in 57/65 (87.7%) T-ALL cases, of which four patients harbored gene fusions that affect ABL-class or JAK-STAT signaling pathways. Five novel gene fusions were detected in 4/65 (6.2%) T-ALL cases: CD99::ABL2 and ZEB1::GNAS in the same case, CTCF::ENKD1, DIAPH1::JAK2, and CDK6::NEK1. Novel fusion transcripts encode chimeric proteins that can potentially affect T-cell proliferation, apoptosis, and help to maintain leukemic cells. Importantly, novel fusion transcripts were not detected in the clinical remission samples attributing these fusions to the leukemic compartment.

Conclusions: We report a similar incidence rate of recurrent gene alterations affecting T-ALL-related molecular signaling pathways in both Lithuanian T-ALL patients and other T-ALL studies. Our data suggest that newly identified gene fusions are specific to leukemic T-cells and provide new molecular insights on T-ALL pathogenesis. Further research is needed to confirm these findings.