Cumulative disruption of regulatory genes precedes whole-chromosome gains in acute myeloid leukemia

Whole-chromosome gains occur in a subset of myeloid malignancies, but the genomic context that predisposes cells to these events has been unclear. By analyzing mutation data across three independent AML and MDS cohorts, the authors found that mutations in regulatory genes — including ASXL1, SRSF2, RUNX1, and other transcriptional and epigenetic regulators — are consistently enriched in patients with trisomy. Using single-cell DNA sequencing on the Tapestri platform across 51,000+ cells from 16 AML patients, they resolved the clonal hierarchy in each case and showed that these regulatory mutations typically arise before the chromosome gain, often as multiple co-occurring hits rather than a single lesion. The findings support a model where whole-chromosome gain results from cumulative transcriptional and chromatin dysregulation rather than an abrupt mitotic failure.