NUTM1 Rearrangements Linked to Treatable Infant Leukemia

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.

Notes