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Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia

Author

Listed:
  • 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
    St. Jude Children’s Research Hospital
    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
    Stanford University School of Medicine)

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.

Suggested Citation

  • 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 & Duan, 2023. "Proteasome inhibition targets the KMT2A transcriptional complex in acute lymphoblastic leukemia," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36370-x
    DOI: 10.1038/s41467-023-36370-x
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