Functional analysis of sucrase-isomaltase mutations from chronic lymphocytic leukemia patients

Next-generation sequencing techniques have emerged as powerful tools for the understanding of cancer genomes. In recent years, whole-exome and whole-genome sequencing strategies have enabled the annotation of a comprehensive mutation landscape of chronic lymphocytic leukemia (CLL), the most frequent...

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Bibliographic Details
Published in:Human molecular genetics 2013-06, Vol.22 (11), p.2273-2282
Main Authors: Rodríguez, David, Ramsay, Andrew J, Quesada, Víctor, Garabaya, Cecilia, Campo, Elías, Freije, José M P, López-Otín, Carlos
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Cancer
Cell Line
Cluster Analysis
Gene Expression Profiling
Humans
Intracellular Space - metabolism
Leukemia, Lymphocytic, Chronic, B-Cell - genetics
Leukemia, Lymphocytic, Chronic, B-Cell - metabolism
Metabolic Networks and Pathways
Mutation
Protein Transport
Sequence Alignment
Signal Transduction
Sucrase-Isomaltase Complex - genetics
Sucrase-Isomaltase Complex - metabolism
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Summary:Next-generation sequencing techniques have emerged as powerful tools for the understanding of cancer genomes. In recent years, whole-exome and whole-genome sequencing strategies have enabled the annotation of a comprehensive mutation landscape of chronic lymphocytic leukemia (CLL), the most frequent leukemia in western countries. Several recurrently mutated genes have been identified, with a subset being validated as neoplastic drivers. Still, a main challenge remains for the differentiation between driver and passenger mutations among candidates as well as for the functional description of the newly discovered leukemogenic genes that could be utilized for personalized anti-tumor strategies. In this scenario, we have identified the metabolic enzyme sucrase-isomaltase (SI) as one of the most frequently mutated genes in a cohort of 105 CLL patients. Here, we demonstrate that these SI mutations result in loss of enzyme function by preventing the biosynthesis of catalytically competent SI at the cell surface. Transcriptome analyses of RNA from CLL patients with SI loss-of-function mutations have uncovered gene expression patterns that depict ample metabolic reprogramming, pinpointing SI as a putative player in the cancer-associated metabolic switch. These results highlight SI as a relevant target for clinical evaluation in future CLL studies.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddt078