Activation of the LMO2 oncogene through a somatically acquired neomorphic promoter in T-cell acute lymphoblastic leukemia.

Abstract

Somatic mutations within noncoding genomic regions that aberrantly activate oncogenes have remained poorly characterized. Here we describe recurrent activating intronic mutations of LMO2, a prominent oncogene in T-cell acute lymphoblastic leukemia (T-ALL). Heterozygous mutations were identified in PF-382 and DU.528 T-ALL cell lines in addition to 3.7% of pediatric (6 of 160) and 5.5% of adult (9 of 163) T-ALL patient samples. The majority of indels harbor putative de novo MYB, ETS1, or RUNX1 consensus binding sites. Analysis of 5'-capped RNA transcripts in mutant cell lines identified the usage of an intermediate promoter site, with consequential monoallelic LMO2 overexpression. CRISPR/Cas9-mediated disruption of the mutant allele in PF-382 cells markedly downregulated LMO2 expression, establishing clear causality between the mutation and oncogene dysregulation. Furthermore, the spectrum of CRISPR/Cas9-derived mutations provides important insights into the interconnected contributions of functional transcription factor binding. Finally, these mutations occur in the same intron as retroviral integration sites in gene therapy-induced T-ALL, suggesting that such events occur at preferential sites in the noncoding genome.

DOI: 10.1182/blood-2016-09-742148

Cite this paper

@article{Rahman2017ActivationOT, title={Activation of the LMO2 oncogene through a somatically acquired neomorphic promoter in T-cell acute lymphoblastic leukemia.}, author={Sunniyat Rahman and Michael Magnussen and Theresa E Le{\'o}n and Nadine Farah and Zhaodong Li and Brian J Abraham and Krisztina Z Alapi and Rachel J Mitchell and Tom Naughton and Adele K Fielding and Arnold Pizzey and Sophia Bustraan and Christopher Allen and Teodora Popa and Karin Pike-Overzet and Laura Garcia-Perez and Rosemary E Gale and David C Linch and Frank J T Staal and Richard A Young and A Thomas Look and Marc R Mansour}, journal={Blood}, year={2017}, volume={129 24}, pages={3221-3226} }