Novel Germline CEBPA Sequence Variations in Familial AML and Cytogenetically Normal AML.
Authors: Udani Rupa A. , Parlow Mary , Yin Lihui , Bellissimo Daniel B. 
Published: October 2019

Abstract
Abstract 2566
The CCAAT enhancer binding protein alpha encoded by CEBPA gene is a transcription factors involved in myeloid lineage differentiation. Somatic CEBPA mutations are associated with a favorable prognosis in patients with normal to intermediate karyotype and lacking the internal tandem duplication in the fms-like tyrosine kinase -3 gene (FLT3/ITD) or mutation in the nucleophosmin gene (NPM1). N-terminal CEBPA mutations typically result in a frame shift encoding a truncated form of the 42-kD CEBPα protein and potentially increase translation of the alternative 30-kD isoform. The 30-kD isoform functions as a dominant negative regulator of the full-length 42-kD isoform of the CEBPα protein. C-terminal mutations are generally in-frame insertion/deletions in the DNA binding or the leucine zipper domains that cause alteration of the dimerization domain (bZIP).
Germline mutations in CEBPA gene are recognized as the major cause of familial acute myeloid leukemia (AML). Familial AML is inherited in an autosomal dominant manner with complete penetrance. In contrast to somatic AML, the age onset of familial AML is earlier ranging from 4 to 39 years. The overall survival of the familial AML patients with germline CEBPA mutation is ∼50%–65% better than ∼34%–50% observed with the somatic CEBPA mutations (FLT3/NPM1 negative). In all of the familial AML pedigrees reported, the mutations were frame-shift insertions/deletions in the N-terminal domain resulting in translation of a truncated form of the CEBPα protein.
We have identified four novel germline sequence variants in patients with history of familial AML and unknown karyotypes (cases 1–4). The patients' age ranges from 3 to 32 years. Of the four novel variants, one variant was identified in the C-terminal region of the gene. This is the first reported C-terminal variant detected in the proband of a familial AML pedigree. The variant is out of frame insertion/deletion of ∼401 bp in the C-terminal region of the CEBPA gene (there is a deletion ‘∼171bp then an insertion of 401bp). Another novel C-terminal variation was identified in a patient with cytogenetically normal AML undergoing testing for somatically acquired CEBPA mutations (case 5). The detection of this C-terminal variation in a buccal swab sample confirmed the germline origin of the variation. In two additional cases (cases 6 and 7), we observed that one of the two sequence variations identified was no longer present after treatment, suggesting the remaining variation was germline in origin. Our results demonstrate that germline C-terminal CEBPA mutations can cause familial AML and that germline CEBPA mutations may be identified in cytogenetically normal AML patients. The possibility of germline variants should be considered in AML patients since other family members, who may be possible transplant donors for the patient, may have also inherited the same germline variant.
Case AML Type Sequence variation CEBPA gene region 1 Familial AML c.142delG; p.Ala48fs N terminal 2 c.168C>A; p.Cys56* N terminal 3 c.175G>T; p.Glu59* N terminal 4 c.643_814delins401; p.Thr216fs C terminal 5 Somatic AML c.1073delC; p.Ala358fs C terminal 6 c.68_78del; p.Pro23fs N terminal 7 c. 938T>G; p. Val328G C terminal

Disclosures:
No relevant conflicts of interest to declare.