This study presents the results of whole-genome sequencing of a cytogenetically normal acute myeloid leukemia (AML) genome and its matched normal counterpart from the same patient's skin. The researchers sequenced the genomic DNA of tumor and normal skin cells using next-generation sequencing technology. They achieved 32.7-fold haploid coverage for the tumor genome and 13.9-fold coverage for the normal skin sample. Among the 2,647,695 well-supported single nucleotide variants (SNVs) found in the tumor genome, 2,584,418 were also detected in the patient's skin genome, limiting the number of variants requiring further study. The researchers identified ten genes with acquired mutations, two of which were previously described mutations known to contribute to tumor progression, and eight were new mutations present in virtually all tumor cells at presentation and relapse. These findings demonstrate the power of whole-genome sequencing in discovering new cancer-associated mutations and establishing it as an unbiased method for identifying cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies. The study highlights the importance of unbiased whole-genome approaches in uncovering the molecular mechanisms underlying AML pathogenesis.This study presents the results of whole-genome sequencing of a cytogenetically normal acute myeloid leukemia (AML) genome and its matched normal counterpart from the same patient's skin. The researchers sequenced the genomic DNA of tumor and normal skin cells using next-generation sequencing technology. They achieved 32.7-fold haploid coverage for the tumor genome and 13.9-fold coverage for the normal skin sample. Among the 2,647,695 well-supported single nucleotide variants (SNVs) found in the tumor genome, 2,584,418 were also detected in the patient's skin genome, limiting the number of variants requiring further study. The researchers identified ten genes with acquired mutations, two of which were previously described mutations known to contribute to tumor progression, and eight were new mutations present in virtually all tumor cells at presentation and relapse. These findings demonstrate the power of whole-genome sequencing in discovering new cancer-associated mutations and establishing it as an unbiased method for identifying cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies. The study highlights the importance of unbiased whole-genome approaches in uncovering the molecular mechanisms underlying AML pathogenesis.