TY - JOUR
T1 - Acute myeloid leukemias with UBTF tandem duplications are sensitive to Menin inhibitors
AU - Barajas, Juan Martin
AU - Rasouli, Milad
AU - Umeda, Masayuki
AU - Hiltenbrand, Ryan Lea
AU - Abdelhamed, Sherif
AU - Mohnani, Rebecca
AU - Arthur, Bright
AU - Westover, Tamara
AU - Thomas, Melvin E
AU - Ashtiani, Minoo
AU - Janke, Laura J
AU - Xu, Beisi
AU - Chang, Ti-Cheng
AU - Rosikiewicz, Wojciech
AU - Xiong, Emily
AU - Rolle, Chandra
AU - Low, Jonathan
AU - Krishnan, Reethu
AU - Song, Guangchun
AU - Walsh, Michael P
AU - Ma, Jing J
AU - Rubnitz, Jeffrey E
AU - Iacobucci, Ilaria
AU - Chen, Taosheng
AU - Krippner-Heidenreich, Anja
AU - Zwaan, Christian Michel
AU - Heidenreich, Olaf
AU - Klco, Jeffery M
N1 - Copyright © 2023 American Society of Hematology.
PY - 2023/10/27
Y1 - 2023/10/27
N2 - 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.
AB - 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.
U2 - 10.1182/blood.2023021359
DO - 10.1182/blood.2023021359
M3 - Article
C2 - 37890156
SN - 0006-4971
JO - Blood
JF - Blood
ER -