Researchers have reported a new potential route for targeting paediatric acute myeloid leukaemia (AML) driven by fusion proteins involving NUP98 – which may improve the treatment for this aggressive cancer.
A US study has unearthed a protein complex that supports the expression of cancer promoting genes in NUP98-rearranged AML. The complex involves the histone acetyltransferases KAT6A and KAT7.
They say it is possible to target this complex with existing drugs – and that laboratory studies in cells and mouse models suggest this may significantly improve patient survival.
The study was led by researchers at St Jude Children's Research Hospital in Memphis and the Dana-Farber Cancer Institute in Boston, and findings have been reported in the journal Cancer Discovery.
Menin inhibitors are already being used to treat NUP98-rearranged AML, but they are not curative, and often cancers eventually develop resistance to them.
The research team found that an inhibitor that blocks KAT6A and KAT7 works synergistically with a menin inhibitor. In patient-derived xenograft mouse models of NUP89-rearranged AML, the combination prolonged survival.
Dr Charles Mullighan, one of the co-leaders of the research, said their study was a “major advance” in understanding of NUP98-rearranged leukaemias.
He said: “We found NUP98 fusions drive leukaemia by assembling these proteins in a complex to switch on the expression of genes that turn normal cells into leukaemia cells.
“We showed these inhibitors can stop the assembly of the switch, preventing activation of these cancer-driving genes, which may be a novel therapeutic vulnerability in AML.”
He added: “With such encouraging results, this combination should be evaluated clinically, especially in patients whose cancer is resistant to menin inhibition.”
Source:
Michmerhuizen NL, Heikamp EB, Iacobucci I, Umeda M, Arthur B, Mishra V, Park CS, Di Giacomo D, Hiltenbrand R, Gao Q, Radko-Juettner S, Lott J, Martucci C, Subramanyam V, Hatton C, Wenge DV, Baviskar P, Portola P, Claquin A, Chandra B, Baggett DW, Khalighifar A, Huang H, Zhou P, Long L, Shi H, Sun Y, Papachristou EK, Sekhar Reddy Chilamakuri C, de Luna Vitorino FN, Gongora JM, Wu H, Pounds SB, Janke LJ, Kentsis A, D'Santos CS, Garcia BA, Kriwacki RW, Chi H, Klco JM, Armstrong SA, Mullighan CG. (2025) “KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia.” Cancer Discovery, 19 June 2025, doi: 10.1158/2159-8290.CD-24-1772.
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