Researchers in Japan find that B-cell acute lymphoblastic leukemia with NUTM1 gene rearrangements is a unique form of the disease, with a distinct pattern of gene activity and gene regulation that is highly sensitive to chemotherapy
Osaka, Japan – Despite a host of checks and balances that usually prevent harmful genetic mutations, sometimes mistakes happen, with serious consequences. Now, researchers from Japan elucidate how a common mutation underlying a common childhood cancer also makes it highly treatable.
In a study published in March in
Blood, researchers from The University of Osaka, Institute of Science Tokyo, and The University of Tokyo revealed that infant B-cell acute lymphoblastic leukemia (B-ALL) caused by
NUTM1 gene rearrangements is distinct from other forms of B-ALL and responds better to treatment.
Genomic rearrangements, which happen when genes are “cut and pasted” into the wrong locations, resulting in the production of abnormal proteins, are the cause of many cancers. The
NUTM1 gene is rearranged in a large percentage of infant B-ALL cases, and it is especially common for this to result in fusion with the
BRD9 gene, which encodes a bromodomain protein.
“Bromodomain family proteins are frequently implicated in cancers that involve
NUTM1 rearrangement,” says co-first author of the study Koutarou Nishimura. “However, it was unclear how the
BRD9-NUTM1 fusion leads to the development of infant B-ALL.”
To address this, the researchers performed comprehensive analyses of genomic and clinical data from patients with B-ALL. In addition, they investigated the effects of the
BRD9-NUTM1 fusion in mice and in precursor cell lines that develop into blood cells.
“The results were very striking,” explains Daichi Inoue, corresponding author. “We found that, unlike other forms of B-ALL caused by different mutations, those with
NUTM1 rearrangements shown a unique pattern of gene activity and gene regulation, especially decreased DNA methylation—a chemical tag that helps control how genes are turned on and off—throughout the genome.”
Furthermore, the researcher team found that
NUTM1 fusion genes drive leukemia development by triggering B-cell differentiation (i.e. the maturation of immune cells into B cells) and increasing the lifespan of blood cells. Importantly, leukemias with the
BRD9-NUTM1 fusion were extremely sensitive to chemotherapy, in contrast to leukemias with other common gene rearrangements.
“Our study shows that leukemias with
NUTM1 rearrangements have unique molecular profiles that make them vulnerable to treatment and are associated with improved clinical outcomes,” says Nishimura.
The findings from this study will help optimize treatment for infants with this type of B-ALL, as they are likely to respond to lower treatment intensities. Exploring the functional effects of the protein encoded by the
BRD9-NUTM1 fusion could also help identify additional treatment targets in the future.
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The article, “Comprehensive Molecular and Functional Analysis of NUTM1-Rearranged Leukemia,” will be published in
Blood at DOI:
https://doi.org/10.1182/blood.2024026928
About The University of Osaka
The University of Osaka was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world. Now, The University of Osaka is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.
Website:
https://resou.osaka-u.ac.jp/en