1. Academic Validation
  2. Acute myeloid leukemias with UBTF tandem duplications are sensitive to Menin inhibitors

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

  • Blood. 2023 Oct 27:blood.2023021359. doi: 10.1182/blood.2023021359.
Juan Martin Barajas 1 Milad Rasouli 2 Masayuki Umeda 2 Ryan Lea Hiltenbrand 1 Sherif Abdelhamed 3 Rebecca Mohnani 4 Bright Arthur 5 Tamara Westover 3 Melvin E Thomas 3rd 1 Minoo Ashtiani 4 Laura J Janke 1 Beisi Xu 6 Ti-Cheng Chang 1 Wojciech Rosikiewicz 1 Emily Xiong 1 Chandra Rolle 3 Jonathan Low 1 Reethu Krishnan 1 Guangchun Song 3 Michael P Walsh 7 Jing J Ma 3 Jeffrey E Rubnitz 1 Ilaria Iacobucci 1 Taosheng Chen 1 Anja Krippner-Heidenreich 8 Christian Michel Zwaan 2 Olaf Heidenreich 2 Jeffery M Klco 3


  • 1 St. Jude Children's Research Hospital, Memphis, Tennessee, United States.
  • 2 Erasmus MC-Sophia Children's Hospital, Netherlands.
  • 3 St Jude Children's Research Hospital, Memphis, Tennessee, United States.
  • 4 Princess Maxima Centrum for Pediatric Oncology, Utrecht, Netherlands.
  • 5 St Jude children's hospital, Memphis, Tennessee, United States.
  • 6 St. Jude Children Research Hospital, Memphis, Tennessee, United States.
  • 7 St. Jude Children's Research Hospital.
  • 8 Princes Maxima Centrum voor Kinderoncologie, Utrecht, Netherlands.

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.