Proteins called NUP98 fusions are known to form clusters that contribute to causing blood cancers such as acute myeloid leukemia and T-cell acute lymphoblastic leukemia. Patients who have these clusters in their blood cells tend to have worse clinical outcomes and show less response to therapies.
But scientists haven’t known exactly how these clusters or “foci” contribute to the development of cancer.
Now, research led by Greg Wang, PhD, professor of pharmacology and cancer biology at Duke University School of Medicine, shows exactly how these clusters disrupt gene expression to turn normal blood cells into leukemia cells. The study was published in February in the journal Molecular Cell.
“This paper proposes a new model, in which these foci act like factories eliciting oncogenic signaling, making normal cells into fast-growing cancer cells,” Wang said.
“We found that specific patterns in the amino acid sequence of the NUP98 onco-proteins not only establish protein-protein interactions among themselves but also establish interactions with a suite of functional partners,” he said.
Together, these interactions form the clusters seen in blood cancer cells.
Wang collaborated with Benjamin Sabari, PhD, an assistant professor at University of Texas Southwestern Medical Center, and Ling Cai, PhD, an assistant professor of pathology at Duke, to conduct integrated analyses using several methods, including mutagenesis, proteomics, genomics, and condensate reconstitution.
The work will help researchers develop new treatments for blood cancers, including treatments that block the protein interactions the team discovered, Wang said. The discovery could potentially be applied to other types of cancers in which disease-causing proteins form clusters, he said.
The work was funded by the Cancer Prevention and Research Institute of Texas, The Welch Foundation, the Leukemia and Lymphoma Society, and private funds of Duke University. It was made possible by use of core facilities of the Duke Cancer Institute, which are funded in part by the National Institutes of Health.