IntroductionAcute myeloid leukemia (AML), according to the WHO classification of hematolymphoid malignancies is mainly divided into two separate groups: AML with defining genetic abnormalities and AML defined by differentiation1-2. The former is genetically diverse consisting of multiple molecular aberrations in the form of fusion genes resulting from chromosomal translocations such as RUNX1::RUNX1T1, PML::RARalpha, CBFB::MYH11, RUNX1::MECOM and/or gene mutations such as FLT3-ITD/TKD, NPM1 and CEBPα, which could occur either in combination with chromosomal abnormality or in cytogenetically normal AML (CN-AML)3-6. These genetic abnormalities help categorize AML patients into favorable, intermediate or poor risk stratification. AML patients with CEBPα mutation (also called CEBPα-mutated AML) belong to the favorable risk group and is a provisional entity in the WHO classification, with the recommendation that all CN-AML be tested for CEBPα mutation7. CEBPα gene mutation testing is part of NGS-based myeloid tumor panel, currently a routine practice in the diagnostic work-up of AML patients.CEBPα (CCAAT enhancer-binding protein alpha, OMIM#116897) gene maps to chromosome 19q13.1, is intronless and the deduced 357-amino acid protein consists of an N-terminal transcription activation domain 1/2 (TAD1/2) and a C-terminal basic leucine zipper (bZIP) domain that recognizes the CCAAT motif in the promoters of target genes8. Two main types of mutations in the CEBPα gene have been reported in AML9. One, nonsense mutations (frameshift) in the TAD1/2 of the N-terminus leading to a dominant negative CEBPα protein, and two, ‘in-frame indels’ in the bZIP of the C-terminus leading to the disruption of dimerization and diminished DNA-binding function of CEBPα protein. Mice with Cebpα-mutation lack granulocytes whereas conditional expression of C/EBPα triggers neutrophilic differentiation indicating an important role of CEBPα mutations in the pathogenesis of AML10.Here, we report a case of AML with two distinct likely pathogenic CEBPα mutations but associated with aggressive disease behavior and poor clinical response. This case contributes to the evolving understanding of CEBPα-mutated AML and highlights the potential need for revised prognostic classification and tailored treatment approaches.
