@article{3d71058dcc964b0f8b9ea98595ee9e8e,
title = "Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family",
abstract = "Familial acute myeloid leukemia is rare and linked to germline mutations in RUNX1, GATA2 or CCAAT/enhancer binding protein-a (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/EBPa. 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.",
author = "{NCI DCEG Cancer Genomics Research Laboratory} and {NCI DCEG Cancer Sequencing Working Group} and Anand Pathak and Katja Seipel and Alexander Pemov and Ramita Dewan and Christina Brown and Sarangan Ravichandran and Luke, {Brian T.} and Michael Malasky and Shalabh Suman and Meredith Yeager and Gatti, {Richard A.} and Caporaso, {Neil E.} and Mulvihill, {John J.} and Goldin, {Lynn R.} and Thomas Pabst and McMaster, {Mary L.} and Stewart, {Douglas R.} and Bari Ballew and Chanock, {Stephen J.} and Greene, {Mark H.} and Goldstein, {Alisa M.} and Allan Hildesheim and Nan Hu and Landi, {Maria Teresa} and Jennifer Loud and Mai, {Phuong L.} and Lisa Mirabello and Lindsay Morton and Melissa Rotunno and Savage, {Sharon A.} and Taylor, {Philip R.} and Tobias, {Geoffrey S.} and Tucker, {Margaret A.} and Jeannette Wong and Yang, {Xiaohong R.} and Guoqin Yu and Sara Bass and Joseph Boland and Bouk, {Aaron J.} and Maria Brown and Laurie Burdett and Salma Chowdhury and Michael Cullen and Casey Dagnall and Belynda Hicks and Herbert Higson and Hutchinson, {Amy A.} and Kristine Jones and Sally Larson and Kerrie Lashley",
note = "Funding Information: This project has been funded in part with funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. This work was supported by the Division of Cancer Epidemiology and Genetics of the Intramural Research Program of the National Cancer Institute. Publisher Copyright: {\textcopyright} 2016 Ferrata Storti Foundation.",
year = "2016",
doi = "10.3324/haematol.2015.130799",
language = "English (US)",
volume = "101",
pages = "846--852",
journal = "Haematologica",
issn = "0390-6078",
publisher = "Ferrata Storti Foundation",
number = "7",
}