Mutation of CEBPA in Familial Acute Myeloid Leukaemia.
Authors: Fitzgibbon Jude , Smith Matthew , Cavenagh Jamie , Lister T. Andrew 
Published: October 2019

Abstract
Two siblings (III-1 and III-5) were referred to St Bartholomew’s Hospital for treatment for Acute Myeloid Leukaemia (AML) within the space of 2 weeks. There was a family history of AML (see figure) occurring in their father (II-3). All other family members were alive and well. Patient II-3 was diagnosed with AML in September 1963, aged 10, patient III-1 presented in February 2003, aged 30 and his sister Patient III-5, aged 18 the following week. A diagnosis of AML FAB type M2Eo was made for both III-1 and III-5 and cytogenetic evaluation was normal. Following the diagnosis, patients III-1 and III-5 received 4 courses of combination chemotherapy. Both achieved a complete remission after the first course of therapy and both presented soon after discharge following their final course of therapy with arthralgias, fever and malaise. At that time both patients had raised white counts (28.2 x 109/l and 20.4 x 109/l respectively) in the absence of overt sepsis and off G-CSF. The abnormalities in both patients resolved without medical intervention. At the time of writing, both patients are well with normal blood counts over 17 months from diagnosis. Patient III-1 was shown to have a del (C) mutation in CEBPA at nucleotide 212 in DNA extracted from a peripheral blood sample taken at diagnosis. The corresponding protein, S21fsX158, is predicted to terminate prematurely at codon 158. III-5 was also noted to have an identical del (C) mutation in her diagnostic sample. DNA extracted from their remission peripheral blood samples and germline DNA from buccal swabs, from all 3 affected individuals, further demonstrated the presence of the del(C) 212 mutation. In this family the CEBPA mutation appears to be fully penetrant: AML developed in all carriers of the 212 del(C) mutation, identified. The long latency period (10 years - II-3, 18 years - III-5 and 30 years - III-1) suggests that one or more additional mutations is necessary for the development of overt acute leukaemia. Mutation analysis was extended to include several other genes implicated in the development of AML (KRAS, NRAS, KIT, PTPN11, FLT3 and RUNX1), but no mutations were identified other than a second CEBPA mutation (duplication of nucleotides 1050 to 1085) on the other allele in patient III-1. Direct sequencing of CEBPA from DNA extracted from peripheral blood mononuclear cells from seven healthy family members (including II-1, II-2, III-2 and III-3) confirmed the presence of wild-type sequence in each case. In summary this study describes a family with familial CEBPA mutation associated with AML and having a putative regeneration syndrome following completion of therapy. All 3 affected individuals had been previously well with no prior medical history and no obvious dysmorphism. CEBPA mutation did not therefore appear to be part of a syndrome, such as FPD/AML seen with RUNX1 mutation. However, the resultant leukaemias did appear to be similar with myeloblastic morphology, normal cytogenetics, aberrant CD7 expression and the presence of Auer rods. This observation may enable other kindreds with similar phenotype to be selectably screened for CEBPA mutation.
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