Identification and targeting of extremely high-risk gamma delta T-ALL in children

Acute lymphoblastic leukemia expressing the gamma delta T cell receptor (γδ T-ALL) is an uncommon, poorly understood disease. We studied 200 pediatric γδ T-ALL enrolled on clinical trials to understand the clinical and genetic features of this disease, which showed variation in outcome according to age and genetic driver. γδ T-ALL diagnosed in children under three years of age was extremely high-risk and enriched for genetic alterations leading to both LMO2 activation and STAG2 inactivation. Using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping and results in deregulation of gene expression related to T-cell differentiation. High throughput drug screening identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which was efficaciously targeted by PARP inhibition. These data provide a diagnostic and therapeutic framework for classification and risk stratification of pediatric γδ T-ALL.

Type: Cancer Genomics
Archiver: European Genome-Phenome Archive (EGA)

2 Datasets 1 Publication

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD50000000027	RNA-seq data for 85 patients with acute lymphoblastic leukemia expressing the gamma delta T cell receptor (γδ T-ALL)	Illumina HiSeq 3000	85
EGAD50000000028	Whole genome sequencing data for 61 samples with acute lymphoblastic leukemia expressing the gamma delta T cell receptor (γδ T-ALL) and 29 germline samples	Illumina HiSeq 3000	90

Publications	Citations
Perinatal thymic-derived CD8αβ-expressing γδ T cells are innate IFN-γ producers that expand in IL-7R-STAT5B-driven neoplasms. Sumaria N, Fiala GJ, Inácio D, Curado-Avelar M, Cachucho A, Pinheiro R, Wiesheu R, Kimura S, Courtois L, Blankenhaus B, Darrigues J, Suske T, Almeida ARM, Minguet S, Asnafi V, Lhermitte L, Mullighan CG, Coffelt SB, Moriggl R, Barata JT, Pennington DJ, Silva-Santos B. Nat Immunol 25: 2024 1207-1217	2

Publications

Citations

Perinatal thymic-derived CD8αβ-expressing γδ T cells are innate IFN-γ producers that expand in IL-7R-STAT5B-driven neoplasms.
Sumaria N, Fiala GJ, Inácio D, Curado-Avelar M, Cachucho A, Pinheiro R, Wiesheu R, Kimura S, Courtois L, Blankenhaus B, Darrigues J, Suske T, Almeida ARM, Minguet S, Asnafi V, Lhermitte L, Mullighan CG, Coffelt SB, Moriggl R, Barata JT, Pennington DJ, Silva-Santos B. Nat Immunol 25: 2024 1207-1217