Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family
| Autor: | Pathak, Anand, Seipel, Katja, Pemov, Alexander, Dewan, Ramita, Brown, Christina, Ravichandran, Sarangan, Luke, Brian T, Malasky, Michael, Suman, Shalabh, Yeager, Meredith, NCI DCEG Cancer Genomics Research Laboratory, NCI DCEG Cancer Sequencing Working Group, Gatti, Richard A, Caporaso, Neil E, Mulvihill, John J, Goldin, Lynn R, Pabst, Thomas, McMaster, Mary L, Stewart, Douglas R |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male Myeloid Genotype Adolescent Protein Conformation NCI DCEG Cancer Sequencing Working Group Immunology Acute Cardiorespiratory Medicine and Haematology Young Adult Rare Diseases Models Clinical Research CCAAT-Enhancer-Binding Protein-alpha Genetics Humans 2.1 Biological and endogenous factors Family Protein Interaction Domains and Motifs Exome Aetiology Child Preschool Germ-Line Mutation Alleles Cancer Leukemic Pediatric Leukemia Human Genome Molecular High-Throughput Nucleotide Sequencing Hematology Middle Aged NCI DCEG Cancer Genomics Research Laboratory Pedigree Gene Expression Regulation Female Protein Multimerization Follow-Up Studies |
| Zdroj: | Haematologica, vol 101, iss 7 |
| Popis: | Familial acute myeloid leukemia is rare and linked to germline mutations in RUNX1, GATA2 or CCAAT/enhancer binding protein-α (CEBPA). We re-evaluated a large family with acute myeloid leukemia originally seen at NIH in 1969. We used whole exome sequencing to study this family, and conducted in silico bioinformatics analysis, protein structural modeling and laboratory experiments to assess the impact of the identified CEBPA Q311P mutation. Unlike most previously identified germline mutations in CEBPA, which were N-terminal frameshift mutations, we identified a novel Q311P variant that was located in the C-terminal bZip domain of C/EBPα. Protein structural modeling suggested that the Q311P mutation alters the ability of the CEBPA dimer to bind DNA. Electrophoretic mobility shift assays showed that the Q311P mu-tant had attenuated binding to DNA, as predicted by the protein modeling. Consistent with these findings, we found that the Q311P mutation has reduced transactivation, consistent with a loss-of-function mutation. From 45 years of follow up, we observed incomplete penetrance (46%) of CEBPA Q311P. This study of a large multi-generational pedigree reveals that a germline mutation in the C-terminal bZip domain can alter the ability of C/EBP-α to bind DNA and reduces transactivation, leading to acute myeloid leukemia. |
| Databáze: | OpenAIRE |
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