Identification of novel genetic drivers in the development of acute myeloid leukaemia

Abstract

Genomic profiling has revealed that acute myeloid leukaemias (AMLs) tend to have a relatively low mutation rate, but that many different driver genes may contribute to the development of the disease, complicating efforts to identify similarities between cases. Three AMLs (of whom 2, WEHI-AML-1 and WEHI-AML-2, were siblings) underwent detailed genomic analyses using different molecular techniques supplemented by sequencing data from international databases. The results from the siblings identified a novel inherited predisposition to AML involving the base excision repair protein, MBD4. AMLs deficient in MBD4 have a unique mutational signature characterised by elevated CG>TG mutations and all 3 acquired mutations in driver genes in a conserved order. The importance of MBD4 in maintaining genomic integrity was confirmed in other cancers, through the analysis of large public cancer datasets, and a genetically modified mouse model. The third AML, WEHI-AML-3, had DDX3X-MLLT10, a translocation that has only been reported in T-acute lymphoblastic leukaemias. As expected, analyses of the three AMLs at different clinical timepoints, showed the leukaemias underwent clonal evolution, providing further insight into their disease biology. For example, the leukaemia in WEHI-AML-3 acquired new mutations resulting in mechanisms for therapy resistance and subsequent poor clinical outcome. The results from the 3 AMLs have broader implications for other haematological malignancies and cancers.