A Pedigree Harboring a Germ-Line N-Terminal C/EBPα Mutation and Development of Acute Myeloblastic Leukemia with a Somatic C-Terminal C/EBPα Mutation.
Authors: Nanri Tomoko , Uike Naokuni , Kawakita Toshiro , Iwanaga Eisaku , Hoshino Koyu , Mitsuya Hiroaki , Asou Norio 
Published: October 2019

Abstract
Transcription factors involved in myeloid cell differentiation are frequent targets of chromosomal translocations and point mutations in patients with acute myeloblastic leukemia (AML). Familial AML harboring a mutation in a transcription factor should provide an association of clinical features with functions of the transcription factor. Recently, two pedigrees of AML carrying a germ-line mutation in the CEBPA, a gene encoding transcription factor C/EBPα have been reported. As C/EBPα-null mice lack of mature neutrophil and eosinophil granulocytes, C/EBPα is thought to play a central role in regulating the differentiation of granulocytes. We here present clinical and molecular features of a Japanese family in which two individuals developing AML and one healthy individual had an identical CEBPA mutation. Father had received a diagnosis of AML M2 in 1988 at the age of 39 years. Following a relapse 7 years after his first complete remission (CR), he received autologous stem cell transplantation, after which he has been in a lasting CR. His elderly son was diagnosed to have M2Eo in 2004 at the age of 26 years. He has achieved a continuous CR. Bone marrow cells at the time of diagnosis and peripheral blood cells obtained during CR in both patients showed a 4-base pair insertion in the N-terminal region of the CEBPA (350_351insCTAC). The corresponding protein is predicted to terminate prematurely at codon 107 (I68fsX107). Therefore, this heterozygous mutation causes truncation of the 42-kD C/EBPα protein and overproduction of a 30-kD isoform, which lacks a transactivation domain and functions in a dominant negative fashion, causing a decrease in C/EBPα activity. His younger son unaffected by AML aged 21 years also had the same mutation. The N-terminal C/EBPα mutations in sporadic AML patients are associated with FAB M1/M2 subtypes, presence of Auer rods, CD7 expression, normal karyotype, and a favorable prognosis. Familial AMLs with an N-terminal C/EBPα mutation demonstrate links of these unique features to a dominant negative C/EBPα mutation. It is of note that different in-frame insertion mutations in the C-terminal region of C/EBPα were identified in both patients at the time of diagnosis. As these C-terminal CEBPA mutations were not found in peripheral blood cells during CR in both patients, these in-frame insertion mutations in the C/EBPα basic region leucine zipper DNA-binding domain should be somatic mutations. Interestingly, father showed different in-frame insertion mutations in the C-terminal CEBPA at the time of diagnosis and relapse. These N- and C-terminal biallelic mutations in the CEBPA are thought to result in complete loss-of-function of C/EBPα. A recent study using conditional Cebpa knockout mice showed that C/EBPα deficiency in adult mice leads to persistence of immature myeloid blasts in the bone marrow without developing AML. Although the mechanism underlying the development of AML is yet unclear, this study indicates that the N-terminal CEBPA mutation appears to confer an increased risk occurring C-terminal C/EBPα mutations and other mutations as a second and further genetic hits, generating undifferentiated myeloid cells and eventually leading to AML over a long latency.