Research led by the Wellcome Trust Sanger Institute has revealed the long-mysterious molecular underpinnings of an important anti-cancer gene located on the X chromosome and suggests that a complementary gene on the Y chromosome, known as the UTY gene, can protect against an aggressive blood cancer called acute myeloid leukemia (AML). Women have two X chromosomes while men have an X and a Y, so the UTY gene is only present in men.
The study, published in Nature Genetics, initially sought to determine the role of the UTX gene, which is found on the X chromosome, in AML development following past research that indicated mutated UTX sequences are present in many types of tumors and that reintroducing a functional copy into cancerous cells quells their dangerous activity.
Unlike many other genes on the X-chromosome, UTX does not undergo X inactivation, an early embryonic process where one copy of the X chromosome is essentially silenced, preventing gene expression. UTX’s ability to avoid inactivation explains why blood cancers such as AML occur more frequently in males than females – females have two copies of UTX, so if only one version is mutated, the other can step in to do the tumor-suppressing work. Males whose sole copy is mutated appeared to be out of luck.
The investigation involved a series of experiments in mice who had undergone genome editing to inactivate one or both copies of the UTX gene in their red blood cell lines.
First, the mouse results illuminated how UTX acts as a sort of anti-cancer supervisor by regulating other tumor-suppressing genes. It appears to help mediate healthy cell processes by acting as a “scaffold” that represses production of certain proteins involved in possibly cancer-causing pathways and promotes production of proteins that circumvent cancerous behavior.
Yet amazingly, none of the male mice with a dysfunctional UTX gene developed any type of blood cancer, and molecular analyses confirmed that the rescuing agent was the UTY gene. Until now, it was thought that UTY could not act like UTX, despite similarities, because it has no catalytic activity.
To explain why males still develop AML and other cancers despite the newly discovered properties of UTY, the team analyzed a variety of UTX-mediated human cancer cell lines. This portion of the study showed that in many instances, mutations in the UTX gene are accompanied by deletions in the UTY gene.
“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," said first author Dr Malgorzata Gozdecka in a statement.
"Treatments for AML have not changed in decades and there is a large unmet need for new therapies,” added joint project leader Dr George Vassiliou. “This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukaemia-causing processes."