"We have made a major advance in our understanding of these difficult-to-treat leukemias," said senior co-corresponding author Charles Mullighan, MBBS, MD, St. Jude Department of Pathology. "We used that knowledge to provide a strong clinical rationale to try this combined approach that had striking results."
The scientists combined a drug that stops menin, a protein involved in controlling leukemic gene expression, with one that targets the acetyltransferases MOZ/KAT6A and HBO1/KAT7, the complex they found interacts with NUP98 fusions. The drug targeting the complex alone greatly increased survival in patient-derived mouse models, but the combination therapy had an even larger effect.
"We found this complex is targetable with an inhibitor that interacts synergistically with menin inhibition, even in relapsed disease," Mullighan said. "With such encouraging results, this combination should be evaluated clinically, especially in patients whose cancer is resistant to menin inhibition."
Finding vulnerabilities in pediatric AML driven by NUP98 fusions has been challenging. A fusion oncoprotein comprises a pair of fused proteins, usually due to chromosomal rearrangements, often giving the hybrid new functions that can promote cancer-driving genes. Because the two original proteins still exist in the body and may have essential functions, targeting them directly can cause adverse side effects. Scientists have looked for a workaround, targeting the proteins that fusions interact with instead.
Previous research found that targeting menin, a molecule that NUP98 fusions use to promote oncogenes, is helpful - but not curative - in NUP98-rearranged leukemia. Therefore, the researchers systematically looked at proteins interacting with NUP98 fusions and DNA in AML models to find another vulnerability. After identifying the proteins interacting with NUP98 fusion proteins, they used genome editing to inactivate each gene and determine which ones the cancer depends on. In this case, they identified MOZ/KAT6A and HBO1/KAT7, which help form a complex that activates pro-cancer gene expression.
"We found NUP98 fusions drive leukemia by assembling these proteins in a complex to switch on the expression of genes that turn normal cells into leukemia cells," Mullighan said. "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."
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.
KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia.
Cancer Discov. 2025 Jun 19. doi: 10.1158/2159-8290.CD-24-1772