Binding partners and cooperating mutations define NUP98 leukemia subtypes

Genomic rearrangements involving the NUP98 gene (NUP98r) have been linked to a wide spectrum of hematologic malignancies. These include acute myeloid leukemias, T–acute lymphoblastic leukemia, and myelodysplastic neoplasms (MDS). How NUP98 fusion oncoproteins lead to such a broad range of leukemias remains poorly understood. Published in Blood, a team led by corresponding author Jeffery Klco, MD, PhD, St. Jude Department of Pathology, studied how the disease types of leukemia with NUP98 rearrangements are determined.

By studying the genomic background of NUP98r leukemias, the team found that cooperating mutations are linked to specific disease types. The team then established disease models of NUP98r and showed that each NUP98 fusion oncoprotein induces hematopoietic lineages differentially, whereas cooperating alterations promote survival of cells or block differentiation at distinct stages.

This work has implications for potential treatments. Menin inhibitors are promising drugs for acute myeloid leukemia subtypes, including those with NUP98r, but the models showed that cells with cooperating mutations may become less sensitive to Menin inhibitors. 

“We came to believe that cooperating mutations provide an additional mechanism to determine the heterogeneity of the diseases,” said first author Masayuki Umeda, MD, PhD. “These findings indicate a need to view Menin inhibitor effects through the lens of differentiation or cooperating mutations, to identify patients who are less likely to respond and guide alternative therapeutic strategies.”

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