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Acute Myeloid Leukemia Protection Provided by Y Chromosome Gene

NEW YORK (GenomeWeb) – An international team led by investigators in the UK has identified a role for the Y chromosome gene UTY in protecting against acute myeloid leukemia (AML) risk. 

As they reported online today in Nature Genetics, the researchers initially used mouse knockout experiments to delve into the role of the X-linked gene UTX in myeloid blood cancer development, based on past studies uncovering UTX loss-of-function mutations in leukemia and other cancer types. Results from those experiments support the notion that UTX — which encodes a histone H3 Lys27-specific demethylase— can protect against leukemia development.

That protective effect does not appear to be a consequence of the UTX gene product's enzymatic activity, though, since a related, catalytically inactive Y chromosome gene called UTY showed protective activity in UTX knockout mice. Indeed, the team's subsequent proteomic and genomic experiments on mouse models and human cell lines from men with AML suggest that both the X chromosome gene UTX and the Y chromosome gene UTY can dial down AML risk.

"It is known that men often lose the Y chromosome from their cells as they age, however the significance of this was unclear," co-senior author Brian Huntly, a stem cell and hematology researcher at the University of Cambridge, said in a statement. "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."

For their analyses, Huntly and colleagues used exome sequencing and other approaches to follow leukemia development in conditional knockout male and female mice missing one or both copies of the UTX gene.

In other cancer types, such as T-cell acute lymphoblastic leukemia, the authors explained, mutations in the catalytic domain of UTX appear to be important. "UTX mutations in T-ALL are found almost exclusively in males, reflecting the fact that the gene is X-linked and escapes X inactivation, such that females (but not males) with single-allele loss-of-function UTX mutations retain UTX expression."

In the mouse model experiments for AML, the team found that the Y chromosome gene UTY, despite the lack of catalytic activity of its protein, could mitigate leukemia risk. Meanwhile, available exome sequence data led to a handful of AML cell lines containing both UTX mutations and UTY microdeletions, consistent with the prior finding that UTX mutations in AML do not show the same sex bias described for T-ALL forms of leukemia.

With the help of RNA sequencing, chromatin immunoprecipitation sequencing, ATAC-seq, and other approaches, the researchers took a closer look at the nature of this interaction in hematopoietic stem and progenitor cells from UTX knockout and wild type mice. They also turned to CRISPR/Cas9 gene editing to lop out genes with rising expression in UTX and UTY double-mutants.

These and other experiments highlighted the catalytic activity-independent nature of UTX's tumor suppression. Their results revealed ties between UTX loss and changes in chromatin accessibility and other regulatory changes that augment cancer-promoting activity of the ETS transcription factors and repress tumor suppressive genes regulated by GATA transcription factors — a tumor suppressor role mirrored by the Y chromosome gene UTY in AML.

"This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukemia-causing processes," co-senior author George Vassiliou, a hematological cancer genetics researcher affiliated with the Wellcome Trust Sanger Institute and the University of Cambridge, said in a statement. "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."