A recent study has revealed promising targets for treating childhood acute myeloid leukaemia (AML) driven by NUP98 fusion oncoproteins (FOs), a genetic hallmark of this aggressive cancer.
Researchers discovered that proteins from the MYST family of histone acetyltransferases (HATs), including KAT6A (MOZ), KAT7 (HBO1), and their partner BRPF1, play a critical role in maintaining the cancerous state in NUP98-rearranged (NUP98-r) AML. These HAT proteins interact closely with NUP98 fusion proteins on chromatin and within phase-separated condensates—structures that regulate gene activity at key stem cell genes.
By either genetically disabling or pharmacologically inhibiting KAT6A and KAT7, scientists observed impaired growth and survival of NUP98-r AML cells. Treatment reduced levels of the histone modification H3K23ac, displaced the NUP98::HOXA9 fusion protein from chromatin at important gene sites, and triggered differentiation of the cancerous cells into more mature, less harmful myeloid cells.
Importantly, inhibiting KAT6A/7 decreased the leukaemic burden in mouse models and worked synergistically with Menin inhibitors, a current therapeutic approach. It also proved effective against cells resistant to Menin inhibitors.
This study highlights MYST family HATs as actionable therapeutic targets in NUP98-r AML, offering new hope for improved treatments in children affected by this challenging form of leukaemia.
Reference
Michmerhuizen NL et al. KAT6A and KAT7 histone acetyltransferase complexes are molecular dependencies and therapeutic targets in NUP98-rearranged acute myeloid leukemia. Cancer Discov. 2025; doi: 10.1158/2159-8290.CD-24-1772.
