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 SethNathaniel 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, Tanja A Gruber

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish
Pages (from-to)809
JournalNature Communications
Volume14
Issue number1
DOIs
StatePublished - Feb 13 2023

Bibliographical note

© 2023. The Author(s).

Keywords

  • Infant
  • Adult
  • Humans
  • Child
  • Proteasome Endopeptidase Complex/genetics
  • Lysine/genetics
  • Myeloid-Lymphoid Leukemia Protein/genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
  • Transcriptome

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