This study presents the results of whole-genome sequencing of a cytogenetically normal acute myeloid leukaemia (AML) genome and its matched normal counterpart from the same patient. The sequencing revealed ten genes with acquired mutations, including two previously known mutations associated with tumour progression and eight new mutations present in nearly all tumour cells at diagnosis and relapse. These mutations were found to be present in nearly all tumour cells, suggesting a single dominant clone. The study demonstrates the power of whole-genome sequencing to discover new cancer-associated mutations. The patient had a typical presentation of French-American-British (FAB) subtype M1 AML with normal cytogenetics. The tumour genome was sequenced with 32.7-fold haploid coverage, and the normal skin sample with 13.9-fold coverage. The study identified 8 heterozygous, non-synonymous somatic SNVs in the entire genome, all of which were new. These included mutations in genes such as CDH24, PCLKC, GPR123, EBI2, PTPRT, KNDC1, SLC15A1, and GRINL1B. The study also detected previously described, recurrent somatic insertions in the FLT3 and NPM1 genes. The study highlights the importance of unbiased whole-genome sequencing in identifying mutations that may respond to targeted therapies. It also shows that the tumour genome was essentially diploid, with no somatic copy number changes. The study found that the mutations were present in nearly all tumour cells, suggesting a single dominant clone. The results demonstrate the power of whole-genome sequencing to discover new cancer-associated mutations and provide insights into the molecular pathogenesis of AML. The study also emphasizes the importance of sequencing the normal genome to distinguish inherited variants from somatic mutations. The findings suggest that whole-genome sequencing may be the only effective means for discovering all mutations relevant to AML pathogenesis.This study presents the results of whole-genome sequencing of a cytogenetically normal acute myeloid leukaemia (AML) genome and its matched normal counterpart from the same patient. The sequencing revealed ten genes with acquired mutations, including two previously known mutations associated with tumour progression and eight new mutations present in nearly all tumour cells at diagnosis and relapse. These mutations were found to be present in nearly all tumour cells, suggesting a single dominant clone. The study demonstrates the power of whole-genome sequencing to discover new cancer-associated mutations. The patient had a typical presentation of French-American-British (FAB) subtype M1 AML with normal cytogenetics. The tumour genome was sequenced with 32.7-fold haploid coverage, and the normal skin sample with 13.9-fold coverage. The study identified 8 heterozygous, non-synonymous somatic SNVs in the entire genome, all of which were new. These included mutations in genes such as CDH24, PCLKC, GPR123, EBI2, PTPRT, KNDC1, SLC15A1, and GRINL1B. The study also detected previously described, recurrent somatic insertions in the FLT3 and NPM1 genes. The study highlights the importance of unbiased whole-genome sequencing in identifying mutations that may respond to targeted therapies. It also shows that the tumour genome was essentially diploid, with no somatic copy number changes. The study found that the mutations were present in nearly all tumour cells, suggesting a single dominant clone. The results demonstrate the power of whole-genome sequencing to discover new cancer-associated mutations and provide insights into the molecular pathogenesis of AML. The study also emphasizes the importance of sequencing the normal genome to distinguish inherited variants from somatic mutations. The findings suggest that whole-genome sequencing may be the only effective means for discovering all mutations relevant to AML pathogenesis.