Emerging role of CEBP‐α mutations in acute myeloid leukemia

Acute myeloid leukemia (AML) is characterized by uncontrolled proliferation of the cells of myeloid origin. It is one of the most aggressive malignancies that, if untreated, carries an abysmal prognosis. Newly diagnosed patients with AML, especially those with so-called cytogenetically normal (CN)AML, are now routinely stratified according to molecular markers that guide long-term prognosis and treatment course. On the other hand, with few exceptions, the initial (induction) treatment of AML lacks individualization (1, 2). Transcription factor CCAAT/enhancer binding protein-a (CEBPA), a gene encoding 42-kD protein, is essential for the differentiation of adipose tissue and granulocytes. CEBPA is expressed abundantly in myeloblasts and continues to be expressed at high levels until the band cell stage. In comparison, the expression of CEBPA is significantly downregulated in mature neutrophils. The role of dominantnegative mutations of CEBPA in AML was first described in 2001. Since then, the presence of mutated CEBPA has generally shown to be associated with a favorable prognosis. Specific mutations in CEBPA leading to changes in CEBPA function are required for leukemogenesis, suggesting that leukemic cells need to maintain CEBPA function crucial for granulopoiesis while dispending the terminal differentiation and growth arrest aspect of its function. Mechanistically, the mutations in CEBPA result in formation of a truncated protein along with increased formation of a 30-kD protein using an alternative initiation codon within the same reading frame. Increased levels of this 30-kD protein interfere with the DNA-binding capacity of the fully functional protein leading to a dominant-negative effect. (3) CEBPA mutations are found in approximately 10% of adult patients with newly diagnosed AML. The current body of literature supports a broad consensus that in patients with cytologically normal (CN)-AML, and those carrying biallelic (bi)-CEBPA mutation have significantly improved survival compared to those with wild-type (wt)-CEBPA or monoallelic (mo)-CEBPA (also known as single mutant or sm-CEBPA). There are, however, few studies suggesting that mo-CEBPA may also confer a favorable survival advantage. These studies differ in their conclusions as to whether the survival advantage from mo-CEBPA is seen only in conjunction with other mutations. It also remains controversial whether survival advantage of bi-CEBPA is limited to those with CN-AML or can be extended to all the patients with AML (2). In this edition of the journal, Li et al. (4) attempt to answer these questions. Their work includes a meta-analysis of ten studies covering more than 6000 patients with AML from Europe and Asia. Their analysis showed no difference in event-free survival (EFS) or overall survival (OS) in the patients with mo-CEBPA compared to wt-CEBPA. However, there was an approximately 60% reduction in the EFS and OS in patients with wt-CEBPA compared to bi-CEBPA. When the analysis was limited to patients with CN-AML only, neither the EFS nor the OS for the patients with mo-CEBPA differed from those with wt-CEBPA. For patients with CN-AML, the presence of wt-CEBPA had approximately 60% and 70% reduction in EFS and OS, respectively, when compared to those with bi-CEBPA. The limitations of this study include those of meta-analyse; studies included in meta-analysis were retrospective and the authors acknowledge searching bias, publication bias, as well as heterogeneity in geography, patient demographics, and therapeutic strategies. This study also does not answer the question of mutations such as fms-like tyrosine kinase-3 (FLT3) or nucleophosmin-1 (NPM1) that coexist with CEBPA. Readers should be cautioned against direct extrapolation of the findings to day-to-day practice as the median age of patients in nine of 10 studies was significantly younger than 60 – a stark contrast with the median age of diagnosis for AML of 67 in the United States. Despite its limitations, the study answers some important questions. The study establishes bi-CEBPA, but not moCEBPA, as a prognostic marker for newly diagnosed patients with AML. There is an emerging consensus that the provisional entity of ‘AML with mutated CEBPA’ should be changed to ‘AML with mutated bi-CEBPA’ in the World Health Organization classification of AML. This study provides an additional piece of evidence in the support for that argument. Another noteworthy finding is that bi-CEBPA could be of favorable prognostic value in all the patients with AML and not just CN-AML as was previously believed. It also Correspondence Mithun Vinod Shah, MD, PhD, Division of Hematol-