Proteasome Inhibition Targets the KMT2A Transcriptional Complex in Acute Lymphoblastic Leukemia

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Feb 13

PMID 36781850

Authors

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

Tanja A Gruber

Affiliations

Soon will be listed here.

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.

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