Researchers have discovered a gene – found on the male-only Y chromosome – that protects against the development of acute myeloid leukemia (AML). This research was published in Nature Genetics.
The study initially focused on UTX, a gene which has been established as an important player in cancer and is known to be mutated in several tumor types.
UTX codes for the histone H3 Lys27-specific demethylase known as UTX (or KDM6A), more specifically, UTX catalyzes the removal of d- and tri- methyl groups on histone H3 Lys27 which promotes gene activation in its ‘functioning’ form and UTX is known to be a tumor suppressor.
Dysregulation of UTX is linked to oncogenesis in various tissue types making it an attractive therapeutic target. UTY is a closely-related to UTX, but, this gene is exclusively present on the male-only Y chromosome.
The researchers investigated the association between loss of UTX and increased development of AML. Interestingly, they found that UTY protected male mice lacking UTX from developing AML. The team were then able to confirm that the tumor suppressing properties of UTY extended to many other cancer types – not just AML, and that a loss of UTX is accompanied by a loss of UTY.
It was originally thought that the genetic information on the Y chromosome was specifically related to male sexual characteristics - this study highlights that these genes may indeed have other roles.
In a recent press release the study’s first author, Dr Malgorzata Gozdecka, from the Wellcome Trust Sanger Institute, explained:
“This is the first Y chromosome-specific gene that protects against AML. Previously it had been suggested that the only function of the Y chromosome is in creating male sexual characteristics, but our results indicate that the Y chromosome could also protect against AML and other cancers.”
Study findings also indicated that, as well as UTX, UTY was also a tumor suppressor. In addition, the researchers revealed that it was in fact the noncatalytic functions of UTX/UTY that were the leading mediators of tumor suppression. The team identified that UTX acts as a sort of scaffold that unites several key regulatory proteins. These proteins govern access to DNA and gene expression – a task UTY is also capable of carrying out. When both UTX and UTY are missing, gene expression cannot be adequately regulated which can promote oncogenesis.
Prof. Brian Huntly, senior author of the paper, elaborated on the impact of their findings:
“It is known that men often lose the Y chromosome from their cells as they age, however the significance of this was unclear. Our study strengthens the argument that loss of the Y chromosome can increase the risk of cancer and describes a mechanism for how this may happen.”
Dr George Vassiliou, joint project leader added:
“Treatments for AML have not changed in decades and there is a large unmet need for new therapies. This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukemia-causing processes. We hope this study will enable new lines of research for the development of previously unforeseen treatments and improve the lives of patients with AML.”
This research provides a clearer picture of the genetic changes involved in the development of AML and several other cancers. This new understanding will hopefully lead to the creation of novel targeted drugs for cancer.
Meulen, Joni Van Der, et al. “The H3K27me3 Demethylase UTX in Normal Development and Disease.” Epigenetics, vol. 9, no. 5, 2014, pp. 658–668., DOI:10.4161/epi.28298.
Malgorzata Gozdecka et al. (2018) UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs. Nature Genetics. DOI: 10.1038/s41588-018-0114-z