Characterization of a PRKCE::ETV6 fusion as a potential oncogenic driver in T-cell acute lymphoblastic leukemia

TL;DR

A new gene fusion, PRKCE::ETV6, was found to drive cancer growth in a rare type of T-cell leukemia, offering potential for better diagnosis and treatment.

Contribution

Identification of the novel PRKCE::ETV6 fusion as an oncogenic driver in near-early T-cell progenitor ALL.

Findings

PRKCE::ETV6 fusion promotes leukemia cell proliferation and survival independently of cytokines.

Genomic breakpoints at ETV6 may serve as minimal residual disease markers in ETP-ALL.

Nine rare or previously unrecognized gene fusions were identified in 25% of T-ALL cases.

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy caused by mutation accumulation during hematopoiesis. The characterization of chromosomal abnormalities may provide significant insights into genetic mechanisms of malignant transformation in hematopoietic cells. However, T-ALL is genetically very heterogenous and driving mutations as well as clonal markers for the assessment of minimal residual disease are not always identifiable. Hence, there is a clinical need to further refine the genetic landscape of T-ALL including previously unrecognized fusion partners of commonly translocated genes in T-ALL of childhood.

In this study, we screened n = 229 T-ALL cases by our targeted genomic capture high-throughput sequencing (gc-HTS) approach. In total, we identified n = 60 gene–gene fusions, present in n = 57 (25%) of the patients. Nine rare or even unrecognized translocations were identified and validated. Furthermore, owing to its interesting chromosomal structure, we studied the oncogenic potential of the complex rearrangement of chromosome 2 and 12, found in a near-early T-cell progenitor (ETP) ALL that leads to the fusion events PRKCE::ETV6 and ETV6::INO80D. Exogenous expression of PRKCE::ETV6 in Ba/F3 pro-B and D1 T-cells caused interleukin-independent proliferation and enhanced survival upon interleukin withdrawal, respectively.

Our study underlines the heterogenous mutational landscape in T-ALL. The previously unrecognized PRKCE::ETV6 resulting from a complex rearrangement involving chromosome 2 and 12 demonstrated transforming potential in cytokine-dependent cellular models support the notion of a driver mutation in near ETP-ALL. Our data reconfirm the relevance of ETV6-fusion proteins in the pathogenesis of undifferentiated T-ALL. Importantly, genomic breakpoints at the ETV6 locus represent potentially robust MRD markers for (near) ETP-ALL that lack IG/TR rearrangements.

The online version contains supplementary material available at 10.1186/s40348-025-00208-x.

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