Effective Therapy for AML With RUNX1 Mutation by Cotreatment With Inhibitors of Protein Translation and BCL2

Authors

Christopher P Mill
Warren Fiskus
Courtney D DiNardo
Christine Birdwell
John A Davis
Tapan M Kadia
Koichi Takahashi
Nicholas Short
Naval Daver
Maro Ohanian
Gautam Borthakur
Steven M Kornblau
Michael R Green
Yuan Qi
Xiaoping Su
Joseph D Khoury
Kapil N Bhalla

Publication Date

2-10-2022

Journal

Blood

Abstract

The majority of RUNX1 mutations in acute myeloid leukemia (AML) are missense or deletion-truncation and behave as loss-of-function mutations. Following standard therapy, AML patients expressing mtRUNX1 exhibit inferior clinical outcome than those without mutant RUNX1. Studies presented here demonstrate that as compared with AML cells lacking mtRUNX1, their isogenic counterparts harboring mtRUNX1 display impaired ribosomal biogenesis and differentiation, as well as exhibit reduced levels of wild-type RUNX1, PU.1, and c-Myc. Compared with AML cells with only wild-type RUNX1, AML cells expressing mtRUNX1 were also more sensitive to the protein translation inhibitor homoharringtonine (omacetaxine) and BCL2 inhibitor venetoclax. Homoharringtonine treatment repressed enhancers and their BRD4 occupancy and was associated with reduced levels of c-Myc, c-Myb, MCL1, and Bcl-xL. Consistent with this, cotreatment with omacetaxine and venetoclax or BET inhibitor induced synergistic in vitro lethality in AML expressing mtRUNX1. Compared with each agent alone, cotreatment with omacetaxine and venetoclax or BET inhibitor also displayed improved in vivo anti-AML efficacy, associated with improved survival of immune-depleted mice engrafted with AML cells harboring mtRUNX1. These findings highlight superior efficacy of omacetaxine-based combination therapies for AML harboring mtRUNX1.

Keywords

Antineoplastic Agents, Bridged Bicyclo Compounds, Heterocyclic, Cell Line, Tumor, Core Binding Factor Alpha 2 Subunit, Drug Synergism, Homoharringtonine, Humans, Leukemia, Myeloid, Acute, Mutation, Protein Synthesis Inhibitors, Proto-Oncogene Proteins c-bcl-2, Sulfonamides

DOI

10.1182/blood.2021013156

PMID

34601571

PMCID

PMC8832475

PubMedCentral® Posted Date

2-10-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes