Activation of the LMO2 oncogene through a somatically acquired neomorphic promoter in T-cell acute lymphoblastic leukemia
Author(s)Rahman, Sunniyat; Magnussen, Michael; León, Theresa E.; Farah, Nadine; Li, Zhaodong; Alapi, Krisztina Z.; Mitchell, Rachel J.; Naughton, Tom; Fielding, Adele K.; Pizzey, Arnold; Bustraan, Sophia; Popa, Teodora; Pike-Overzet, Karin; Garcia-Perez, Laura; Gale, Rosemary E.; Linch, David C.; Staal, Frank J. T.; Look, A. Thomas; Mansour, Marc R.; Abraham, Brian Joseph; Allen, Christopher D; Young, Richard A; ... Show more Show less
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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.
DepartmentMassachusetts Institute of Technology. Department of Biology
American Society of Hematology
Rahman, Sunniyat, Michael Magnussen, Theresa E. León, Nadine Farah, Zhaodong Li, Brian J. Abraham, Krisztina Z. Alapi, et al. “Activation of the LMO2 Oncogene through a Somatically Acquired Neomorphic Promoter in T-Cell Acute Lymphoblastic Leukemia.” Blood 129, no. 24 (March 7, 2017): 3221–3226.
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