Recurrent noncoding somatic and germline WT1 variants converge to disrupt MYB binding in acute promyelocytic leukemia

Abstract

Genetic alternations can occur at non-coding regions, but how they contribute to cancer pathogenesis is poorly understood. Here we established a mutational landscape of cis-regulatory regions (CREs) in acute promyelocytic leukemia (APL) based on whole-genome sequencing analysis of paired tumor and germline samples from 24 patients and epigenetic profiling of 16 patients. Mutations occurring in CREs occur preferentially in active enhancers bound by the complex of master transcription factors in APL. Among significantly enriched mutated CREs, we found a recurrently mutated region located within the third intron of WT1, an essential regulator of normal and malignant hematopoiesis. Focusing on non-coding mutations within this WT1 intron, an analysis on 169 APL patients revealed that somatic mutations were clustered into a focal hotspot region, including one site identified as a germline polymorphism contributing to APL risk. Significantly decreased WT1 expression was observed in APL patients bearing somatic and/or germline non-coding WT1 variants. Furthermore, biallelic WT1 inactivation was recurrently found in APL patients with non-coding WT1 variants, which resulted in the complete loss of WT1. The high incidence of biallelic inactivation suggested the tumor suppressor activity of WT1 in APL. Mechanistically, non-coding WT1 variants disrupted MYB binding on chromatin and suppressed the enhancer activity and WT1 expression through destroying the chromatin looping formation. Our study highlights the essential role of non-coding variants in the leukemogenesis of APL.

A machine learning model identifies M3-like subtype in AML based on PML/RARα targets

“…WT1 has been found to be an important regulator of normal and malignant hematopoiesis, which is usually inactivated in APL patients and results in the complete loss of WT1’s inhibitory function on APL tumor cells. 36 We also observed higher expression of GATA2 in M3 and M3-like subtypes, which has been demonstrated as a prognosis factor in AML. 21 The combination of KDM1A inhibitor and ATRA can promote the induction and differentiation of leukemia cells by ATRA.…”

Transcription Factor MYB as Therapeutic Target: Current Developments

“…Other studies identified genomic alterations creating a MYB-dependent promoter in an intron of the LMO2 gene [ 40 ] or a MYB-dependent neo-enhancer downstream of TAL1 [ 41 ]. Adding complexity to the idea that non-coding mutations can impact MYB binding sites and contribute to cancer, mutations in a cis-acting element in an intron of the WT1 gene were found to destroy MYB binding and downregulate the tumor suppressor gene WT1 in acute promyelocytic leukemia [ 42 ].…”

The Promise of Retinoids in the Treatment of Cancer: Neither Burnt Out Nor Fading Away

“…An epidemiological study implying a single rate-limiting event in APL based on the constant incidence over life [49] and leukemia development in PML-RARa transgenic mice [50,51] suggests that the PML-RARa translocation is necessary and sufficient for triggering leukemogenesis. APL cells have remarkably stable genomes with co-occurring mutations in only a handful of genes involved in cell signaling and proliferation, including FLT3, WT1, NRAS, and KRAS, and noncoding regions within the intron of WT1 [52][53][54].…”