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UBTF tandem duplication acute myeloid leukemias are sensitive to menin inhibition [Cut&Run]

ABSTRACT: UBTF tandem duplications (TD) have recently emerged as a subtype-defining alteration in pediatric acute myeloid leukemia (pAML), which is characterized by HOXB gene dysregulation and a poor response to conventional chemotherapy. Here, we use protein-protein interaction studies to show that UBTF-TD maintains interactions with components of the RNA pol I complex, while also engaging with a network of unique protein interactors specific to UBTF-TD, like KMT2A. These data suggest that UBTF- TD both preserves canonical UBTF functions and demonstrates gain of function activities. Furthermore, we show that UBTF-TD and KMT2A co-localize to key genomic targets dysregulated in UBTF-TD myeloid malignancies, like HOXB gene clusters and MEIS1. Using a protein degradation system, we show that stemness, proliferation, and the HOXB molecular signature are dependent on sustained UBTF-TD localization to chromatin. Finally, we show UBTF-TD leukemias are sensitive to menin inhibition—providing a viable therapeutic strategy for children with this high-risk AML subtype.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229664 | GEO | 2024/02/12

REPOSITORIES: GEO

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