Protective role of Y chromosome gene in leukaemia, discovered

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Acute myeloid leukaemia (AML): protective role of a gene carried on the Y chromosome discovered. Image Credit:Jonathan Bailey, National Human Genome Research Institute, NIH and Paulo Henrique Orlandi Mourao, Wikimedia Commons
Acute myeloid leukaemia (AML): protective role of a gene carried on the Y chromosome discovered. Image Credit:Jonathan Bailey, National Human Genome Research Institute, NIH and Paulo Henrique Orlandi Mourao, Wikimedia Commons

Scientists have discovered the first leukemia-protective gene that is specific to the male-only Y chromosome.

Researchers at the Wellcome Sanger Institute and the University of Cambridge have found that this gene present on the Y-chromosome, protects against the development of Acute Myeloid Leukaemia (AML) and other cancers.

Acute myeloid leukaemia is an aggressive blood cancer that affects people of all ages. It develops in cells in the bone marrow and leads to life-threatening infections and bleeding. There has been no change in the mainstream AML treatment for decades now.

Main findings

The study, published in Nature Genetics, investigated how loss of the X-chromosome gene UTX, which is known to be mutated in many tumors, hastens the development of AML. However, they found that UTY, a related gene on the Y chromosome, protected male mice lacking UTX from developing AML.

The authors then show that in AML and in several other human cancer types, loss of UTX is accompanied by loss of UTY, confirming that the cancer-suppressing role of UTY extends beyond AML.

Women possess two X chromosomes whereas men have one X and one Y chromosome. The X and Y chromosomes share many genes, but a small number of genes, including UTY, are only found on the Y chromosome.

Until now, these Y-specific genes were thought to contain the genetic information required for male sexual characteristics but were not known to have other roles. The discovery of this new role changes the way the Y chromosome is viewed and improves understanding of how AML and other cancers develop.

Says Dr Malgorzata Gozdecka, the first author on the study from the Wellcome Sanger Institute, “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.” 

This discovery also throws possible clues on why and how men are more prone to cancer, as they age.

Says Professor Brian Huntly, joint project leader from Cambridge University and Consultant Haematologist, at Cambridge University Hospitals NHS Trust,

“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.”

Role of UTX in cancer development

In their study, researchers studied the UTX gene in human cells and in mice to try to understand its role in AML. In addition to their discovery that UTY acts as a tumour suppressor gene, the scientists found a new mechanism for how loss of UTX leads to AML.

They discovered that UTX acts as a common scaffold, bringing together a large number of regulatory proteins that control access to DNA and gene expression, a function that can also be carried out by UTY. When UTX/UTY are missing, these proteins can’t regulate gene expression correctly and cancer growth becomes more likely.

“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, says Dr George Vassiliou, joint project leader from the Wellcome Sanger Institute and Consultant Haematologist at Cambridge University Hospitals NHS Trust”

The original paper can be accessed here:

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

Source: Wellcome Sanger Institute