Acute myeloid leukemias with UBTF tandem duplications are sensitive to Menin inhibitors

Juan Martin Barajas, Milad Rasouli, Masayuki Umeda, Ryan Lea Hiltenbrand, Sherif Abdelhamed, Rebecca Mohnani, Bright Arthur, Tamara Westover, Melvin E Thomas, Minoo Ashtiani, Laura J Janke, Beisi Xu, Ti-Cheng Chang, Wojciech Rosikiewicz, Emily Xiong, Chandra Rolle, Jonathan Low, Reethu Krishnan, Guangchun Song, Michael P WalshJing J Ma, Jeffrey E Rubnitz, Ilaria Iacobucci, Taosheng Chen, Anja Krippner-Heidenreich, Christian Michel Zwaan, Olaf Heidenreich, Jeffery M Klco

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

UBTF tandem duplications (UBTF-TDs) have recently emerged as a recurrent alteration in pediatric and adult acute myeloid leukemia (AML). UBTF-TD leukemias are characterized by a poor response to conventional chemotherapy and a transcriptional signature that mirrors NUP98-rearranged and NPM1-mutant AMLs, including HOX gene dysregulation. However, the mechanism of how UBTF-TD drives leukemogenesis remains unknown. In this study, we investigated the genomic occupancy of UBTF-TD in transformed cord-blood CD34+ (cbCD34+) cells and patient-derived xenograft models. We found that UBTF-TD protein maintained genomic occupancy at ribosomal DNA (rDNA) loci while also occupying genomic targets commonly dysregulated in UBTF-TD myeloid malignancies, such as the HOXA/HOXB gene clusters and MEIS1. These data suggest that UBTF-TD is a gain-of-function alteration that results in mislocalization to genomic loci dysregulated in UBTF-TD leukemias. UBTF-TD also co-occupies key genomic loci with KMT2A and Menin, which are known to be key partners involved in HOX-dysregulated leukemias. Using a protein degradation system, we showed that stemness, proliferation, and transcriptional signatures are dependent on sustained UBTF-TD localization to chromatin. Finally, we demonstrate that primary cells from UBTF-TD leukemias are sensitive to the Menin inhibitor SNDX-5613, resulting in markedly reduced in vitro and in vivo tumor growth, myeloid differentiation, and abrogation of the UBTF-TD leukemic expression signature. These findings provide a viable therapeutic strategy for patients with this high-risk AML subtype.

Originele taal-2Engels
TijdschriftBlood
DOI's
StatusE-publicatie vóór gedrukte publicatie - 27 okt. 2023

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