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

Sunniyat Rahman, Michael Magnussen, Theresa E. León, Nadine Farah, Zhaodong Li, Brian J. Abraham, Krisztina Z. Alapi, Rachel J. Mitchell, Tom Naughton, Adele K. Fielding, Arnold Pizzey, Sophia Bustraan, Christopher Allen, Teodora Popa, Karin Pike-Overzet, Laura Garcia-Perez, Rosemary E. Gale, David C. Linch, Frank J.T. Staal, Richard A. Young, A. Thomas Look and Marc R. Mansour

Key points

  • Recurrent intronic mutations that create probable MYB, ETS1, and RUNX1 binding sites occur at the LMO2 promoter in some T-ALL patients.

  • CRISPR/Cas9-mediated disruption of the mutant MYB site in PF-382 cells markedly downregulates LMO2 expression.


Somatic mutations within non-coding 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% (6/160) of pediatric and 5.5% (9/163) of adult T-ALL patient samples. The majority of indels harbour 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 provide 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 non-coding genome.

  • Submitted September 27, 2016.
  • Accepted February 22, 2017.