Noncoding areas of the genome can experience genetic changes, although it is unclear how these changes affect cancer etiology. Based on whole-genome sequencing analysis of matched tumor and germline samples from 24 patients and epigenetic profiling of 16 patients, researchers constructed a mutational landscape of cis-regulatory regions (CREs) in acute promyelocytic leukemia (APL).

The complex of master transcription factors in APL-bound active enhancers is where CRE mutations occur most often. They discovered a frequently altered area in the third intron of WT1, a crucial regulator of healthy and cancerous hematopoiesis, among considerably enriched mutant CREs. An investigation of 169 APL patients, focusing on noncoding mutations within this WT1 intron, showed that somatic mutations were grouped into a focused hotspot area, with one location being identified as a germline polymorphism contributing to APL risk. Patients with APL and somatic or germline noncoding WT1 mutations showed significantly reduced WT1 expression.

Additionally, biallelic WT1 inactivation, which led to the total loss of WT1, was frequently discovered in APL patients with noncoding WT1 mutations. The high frequency of biallelic inactivation showed that WT1 in APL functions as a tumor suppressor. By destroying the formation of chromatin loops, noncoding WT1 variants suppressed the enhancer activity and WT1 expression and mechanically disrupted MYB binding on chromatin.

The study emphasized the crucial part noncoding variations play in the leukemogenesis of APL.