Overlooked Molecular Machine in Cell Nucleus May Hold Key to Treating Aggressive AML

Published May 2019 | Nature Cell Biology

Inhibiting a hyperactive form of the protein IRAK4 effectively targeted acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells, a finding that supports hunting for medications that can effectively inhibit the same pathway in people with these aggressive forms of cancer.

The study, conducted by a multinational team of scientists led by Daniel Starczynowski, PhD, focused on a long-overlooked part of a leukemic cell’s internal machinery called the spliceosome. The spliceosome edits out unnecessary snippets of RNA coding called introns or exons. It then splices the loose ends of RNA back together to support correct protein function.

But in AML and MDS cells, mutations in the gene U2AF1 result in RNA splicing errors that produce an IRAK4 protein with extra coding sequences called IRAK4-L (or long). This in turn triggers oncogenesis in myeloid blood cells.

In mice, an experimental treatment significantly reduced production of leukemic cells. If this approach can be extended to humans, Starczynowski says IRAK4-inhibiting drugs could affect about 20 percent of AML patients.

Now the researchers are testing existing drugs—and developing a prospective one—that can target hyperactive IRAK4 in leukemia cells. They hope to be ready to start clinical trials within a few years.

Success could be a significant benefit to AML and MDS patients who currently have few long-lasting treatment options.

“There is very little we can do for these patients. Even new drugs now getting fast-tracked through the development process may only produce another six months of survival,” Starczynowski says.

“The curative option is a bone marrow transplant, but most of these patients don’t qualify.”