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

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

来源：Blood, 2017, 129(24): 3221-3226.

DOI：10.1182/blood-2016-09-742148

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 oncogenein 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 intronas retroviral integrationsites in gene therapy-inducedT-ALL, suggesting that such events occur at preferential sites in the noncoding genome.

• 出版日期2017-6-15