Activation of the LMO2 oncogene through a somatically acquired neomorphic promoter in T-cell acute lymphoblastic leukemia.
Blood
; 129(24): 3221-3226, 2017 06 15.
Article
in En
| MEDLINE
| ID: mdl-28270453
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.
Full text:
1
Database:
MEDLINE
Main subject:
Proto-Oncogene Proteins
/
Response Elements
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Adaptor Proteins, Signal Transducing
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
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LIM Domain Proteins
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Mutation
Type of study:
Prognostic_studies
Limits:
Adolescent
/
Adult
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Child
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Child, preschool
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Female
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Humans
/
Male
Language:
En
Year:
2017
Type:
Article