Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia

Jennifer L. Kamens, Stephanie Nance, Cary Koss, Beisi Xu, Anitria Cotton, Jeannie W. Lam, Elizabeth A. R. Garfinkle, Pratima Nallagatla, Amelia M. R. Smith, Sharnise Mitchell, Jing Ma, Duane Currier, William C. Wright, Kanisha Kavdia, Vishwajeeth R. Pagala, Wonil Kim, LaShanale M. Wallace, Ji-Hoon Cho, Yiping Fan, Aman Seth, Nathaniel Twarog, John K. Choi, Esther A. Obeng, Mark E. Hatley, Monika L. Metzger, Hiroto Inaba, Sima Jeha, Jeffrey E. Rubnitz, Junmin Peng, Taosheng Chen, Anang A. Shelat, R. Kiplin Guy and Tanja A. Gruber ()
Additional contact information
Jennifer L. Kamens: Department of Pediatrics, Stanford University School of Medicine
Stephanie Nance: Department of Oncology, St. Jude Children’s Research Hospital
Cary Koss: Department of Oncology, St. Jude Children’s Research Hospital
Beisi Xu: Department of Computational Biology, St. Jude Children’s Research Hospital
Anitria Cotton: Department of Oncology, St. Jude Children’s Research Hospital
Jeannie W. Lam: Department of Pediatrics, Stanford University School of Medicine
Elizabeth A. R. Garfinkle: The University of Tennessee Health Science Center
Pratima Nallagatla: Department of Pediatrics, Stanford University School of Medicine
Amelia M. R. Smith: Department of Pediatrics, Stanford University School of Medicine
Sharnise Mitchell: Department of Oncology, St. Jude Children’s Research Hospital
Jing Ma: Department of Pathology, St. Jude Children’s Research Hospital
Duane Currier: Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital
William C. Wright: Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital
Kanisha Kavdia: St. Jude Children’s Research Hospital
Vishwajeeth R. Pagala: St. Jude Children’s Research Hospital
Wonil Kim: Department of Oncology, St. Jude Children’s Research Hospital
LaShanale M. Wallace: Department of Oncology, St. Jude Children’s Research Hospital
Ji-Hoon Cho: St. Jude Children’s Research Hospital
Yiping Fan: Department of Computational Biology, St. Jude Children’s Research Hospital
Aman Seth: Department of Pathology, St. Jude Children’s Research Hospital
Nathaniel Twarog: Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital
John K. Choi: Department of Pathology, University of Alabama School of Medicine
Esther A. Obeng: Department of Oncology, St. Jude Children’s Research Hospital
Mark E. Hatley: Department of Oncology, St. Jude Children’s Research Hospital
Monika L. Metzger: Department of Oncology, St. Jude Children’s Research Hospital
Hiroto Inaba: Department of Oncology, St. Jude Children’s Research Hospital
Sima Jeha: Department of Oncology, St. Jude Children’s Research Hospital
Jeffrey E. Rubnitz: Department of Oncology, St. Jude Children’s Research Hospital
Junmin Peng: St. Jude Children’s Research Hospital
Taosheng Chen: Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital
Anang A. Shelat: Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital
R. Kiplin Guy: Department of Pharmaceutical Sciences, University of Kentucky
Tanja A. Gruber: Department of Pediatrics, Stanford University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Rearrangments in Histone-lysine-N-methyltransferase 2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis with an event-free-survival of 38%. Herein we evaluate 1116 FDA approved compounds in primary KMT2Ar infant ALL specimens and identify a sensitivity to proteasome inhibition. Upon exposure to this class of agents, cells demonstrate a depletion of histone H2B monoubiquitination (H2Bub1) and histone H3 lysine 79 dimethylation (H3K79me2) at KMT2A target genes in addition to a downregulation of the KMT2A gene expression signature, providing evidence that it targets the KMT2A transcriptional complex and alters the epigenome. A cohort of relapsed/refractory KMT2Ar patients treated with this approach on a compassionate basis had an overall response rate of 90%. In conclusion, we report on a high throughput drug screen in primary pediatric leukemia specimens whose results translate into clinically meaningful responses. This innovative treatment approach is now being evaluated in a multi-institutional upfront trial for infants with newly diagnosed ALL.

Date: 2023
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DOI: 10.1038/s41467-023-36370-x

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