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Mutated ENL Proteins and Pediatric Kidney Cancer

By: Kayci Reyer
Posted: Thursday, January 9, 2020

Dysregulation of chromatin-mediated mechanisms, such as reader proteins, may cause normal cells to turn into malignant cells during the development of a human embryo, according to research published in Nature. This process may in turn lead to the development of Wilms tumor, the most common pediatric kidney cancer.

“We have never seen this type of mechanism before,” noted Liling Wan, PhD, of The Rockefeller University, in an institutional press release. “It raises the question whether this type of molecular mechanism is also hijacked in other cancer types.”

The investigators focused on a reader protein called ENL, which is known to activate oncogenes in leukemia. Because some patients with Wilms tumor have a mutation in the gene that codes for ENL, that same mutation was inserted into some embryonic mouse stem cells that grew into kidneys in a lab setting. A structure similar to a tumor developed in the growing kidney—not unlike what has been observed in the development of Wilms tumor in humans.

Neither cells with the ENL mutations nor those without experienced a disruption in their ability to identify the correct gene expression. Each had ENL proteins attach to the same genomic sites. However, the mutated proteins formed masses at these locations, which resulted in constant RNA transcription. This unending transcription caused cells to overproliferate and remain in their early stages instead of differentiating into mature kidney cells. This process eventually resulted in the formation of a tumor.

“So far, we have proof of concept that intervening in any stage of this process can stabilize the gene-expression levels and allow the cells to develop normally,” Dr. Wan proposed.

Disclosure: For full disclosures of the study authors, visit nature.com.



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