US investigators believe that they have identified a mutation that could result in the development of targeted therapies for patients with a form of lymphoma that currently has a poor cure rate, reports Nature

Three subtypes of diffuse large B cell lymphoma, a type of non-Hodgkin's lymphoma, exist, of which the activated B cell like (ABC) form is known to have the worst outcomes, with a three year survival rates of just 40%. Louis Staudt and colleagues from the National Cancer Institute (Bethesda, MD) set out to identify proteins that play a role in the development of the ABC subtype, reasoning that they might provide new targets for therapy.

First, investigators undertook a genetic screen in which thousands of genes were inactivated. They discovered that that ABC lymphoma cells were killed when they inactivated genes encoding MYD88, a protein that is crucial for the normal immune response and IRAK1, another cell signalling protein that works with MYD88.

Next, the team sequenced the MYD88 gene in 382 lymphoma biopsy samples, revealing that 29% of ABC lymphoma samples harboured the same amino acid substitution, L265P. In other lymphoma subtypes this mutation was found to be rare or absent.

The investigators proved that mutant forms of MYD88 sustained survival of ABC lymphoma cells, while the non-mutated version did not, suggesting that mutations in the MYD88 gene play an important role in the development of this cancer.

They went on to discover that the mutant form of MYD88 spontaneously assembled a protein complex that included IRAK1 (a cell signalling protein identified in the first screen) and a related protein IRAK4. IRAK4, they discovered, functions as an enzyme to modify IRAK1, and that this crucial step is required for the mutant MYD88 protein to promote lymphoma survival. IRAK4 inhibitors, which are currently in development for inflammatory and autoimmune diseases, thereby have the potential to provide a new therapy for ABC lymphoma.

"We believe the results of this study may provide a method to identify patients with the ABC subtype of diffuse large B cell lymphoma whose tumours may depend upon MYD88 signalling and who may therefore benefit from therapies targeting IRAk4 alone or in combination with agents targeting other regulatory pathways that sustain the survival of these lymphoma cells," said Staudt.

Reference

V Ngo, R Young, R Schmitz et al Oncogenically active MYD88 mutations in human lymphoma Nature Doi: 10.1038/nature09671