Effective therapy for AML with RUNX1 mutation by cotreatment with inhibitors of protein translation and BCL2
Autor: | Maro Ohanian, Warren Fiskus, Nicholas J. Short, Koichi Takahashi, Steven M. Kornblau, John A. Davis, Xiaoping Su, Yuan Qi, Joseph D. Khoury, Tapan M. Kadia, Michael R. Green, Courtney D. DiNardo, Kapil N. Bhalla, Christine Birdwell, Naval Daver, Gautam Borthakur, Christopher P. Mill |
---|---|
Jazyk: | angličtina |
Rok vydání: | 2022 |
Předmět: |
BRD4
Immunology Antineoplastic Agents medicine.disease_cause Biochemistry BET inhibitor chemistry.chemical_compound Cell Line Tumor hemic and lymphatic diseases Medicine Humans MCL1 neoplasms Protein Synthesis Inhibitors Sulfonamides Mutation Myeloid Neoplasia business.industry Venetoclax Drug Synergism Cell Biology Hematology Bridged Bicyclo Compounds Heterocyclic In vitro Leukemia Myeloid Acute Proto-Oncogene Proteins c-bcl-2 RUNX1 chemistry Homoharringtonine Core Binding Factor Alpha 2 Subunit Cancer research Weapons business |
Zdroj: | Blood |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |