Wilms Tumor–Associated ENL Mutants Cause Target-Gene Overexpression

Recurrent hotspot mutations in the histone acetylation–reading YEATS domain of the eleven-nineteen leukemia protein (ENL) have been linked to Wilms tumor, a form of kidney cancer that almost exclusively affects children. However, whether the development of Wilms tumor is directly caused by these mutations, which consistently involve small in-frame insertions or deletions, is not known. In experiments using human kidney cell lines, Wan and colleagues found that these mutations in ENL's YEATS domain led to an apparent gain of function, increasing the transcription of ENL's target genes, some of which, such as HOXA genes, are involved in development. Experiments employing a three-dimensional model of nephrogenesis demonstrated that these mutations caused aberrant nephron development, increasing the abundance of undifferentiated structures that resemble the blastema components of Wilms tumors. Mechanistically, mutant ENL largely bound the same target genes as wild-type ENL, but mutant ENL's occupancy—as well as the occupancy of the larger protein complex ENL joins to activate transcription—was increased at some of those genes, including the HOXA cluster. Interestingly, like wild-type ENL, tumor-associated ENL mutants required the protein's reader function to drive localization to target genes, but the ENL mutants did not appear to have greater affinity for acetylated (or otherwise acylated) histone peptides, implying that increased binding strength did not explain the mutants' increased occupancy at these genes. Instead, tumor-associated ENL mutants exhibited greater self-association at target sequences, which may explain the increased expression of target genes caused by mutant ENL. This self-association–induced gene activation appeared to be driven not only by the mutant YEATS domain, but also by ENL's ANC1 homology domain and a predicted intrinsically disordered region. Collectively, these findings provide preliminary evidence for a causative role of tumor-associated ENL mutations and Wilms tumor, elucidate the mechanism by which these mutations may trigger dysfunctional development, and adds further evidence illustrating the importance of readers of histone modifications in disease.

Wan L, Chong S, Xuan F, Liang A, Cui X, Gates L, et al. Impaired cell fate through gain-of-function mutations in a chromatin reader. Nature 2020;577:121–6.

• ©2020 American Association for Cancer Research.