CCAAT enhancer binding protein alpha (CEBPA) biallelic acute myeloid leukaemia: cooperating lesions, molecular mechanisms and clinical relevance

Abstract

Recent advances in sequencing technologies have allowed for the identification of recurrent mutations in acute myeloid leukaemia (AML). The transcription factor CCAAT enhancer binding protein alpha (CEBPA) is frequently mutated in AML, and biallelic CEBPA-mutant AML was recognised as a separate disease entity in the recent World Health Organization classification. However, CEBPA mutations are co-occurring with other aberrations in AML, and together these lesions form the clonal hierarchy that comprises the leukaemia in the patient. Here, we aim to review the current understanding of co-occurring mutations in CEBPA-mutated AML and their implications for disease biology and clinical outcome. We will put emphasis on patterns of cooperation, how these lesions cooperate with CEBPA mutations and the underlying potential molecular mechanisms. Finally, we will relate this to patient outcome and future options for personalised medicine.

Keywords: CEBPA biallelic acute myeloid leukaemia; co-occurring mutations; disease modelling; molecular haematology.

Figure 1

Data on mutational co‐occurrence from four large next‐generation sequencing (NGS) based studies with Konstandin et al. (2018) (n = 48) representing cytogenetically normal (CN‐)AML and Papaemmanuil et al. (2016) (n = 66), Su et al. (2018) (n = 81) and Zhang et al. (2019b) (n = 76) representing de novo AML. For comparison, data from the same cohorts representing all cases have been added when available; Metzeler et al., (2016) (n = 664) CN‐AML cases and Papaemmanuil et al. (2016) (n = 1540) de novo AML cases. Data from the individual studies are represented by non‐filled bars. Solid bars represent a calculated average from the studies included (percent of cases with co‐occurring mutations in all samples (left) or in CEBPAbi cases (right).