Whole-exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow-up of a large family.

Pathak, Anand; Seipel, Katja; Pemov, Alexander; Dewan, Ramita; Brown, Christina; Ravichandran, Sarangan; Luke, Brian T; Malasky, Michael; Suman, Shalabh; Yeager, Meredith; Cancer GenomicsResearch Laboratory, Nci Dceg; Cancer Sequencing Working Group, Nci Dceg; Parry, Dilys M; Gatti, Richard A; Caporaso, Neil E; Mulvihill, John; Goldin, Lynn R; Pabst, Thomas; McMaster, Mary L and Stewart, Douglas R (2016). Whole-exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow-up of a large family. Haematologica - the hematology journal, 101(7), pp. 846-852. Ferrata-Storti Foundation 10.3324/haematol.2015.130799

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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 utilized 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 mutant 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.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

UniBE Contributor:

Seipel, Katja and Pabst, Thomas


600 Technology > 610 Medicine & health




Ferrata-Storti Foundation




Marianne Zahn

Date Deposited:

02 Mar 2016 15:41

Last Modified:

02 Jul 2016 01:30

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

Acute Myeloid Leukemia; CEBPA; bZip domain; familial; germline



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