TY - JOUR
T1 - Effective therapy for AML with RUNX1 mutation by cotreatment with inhibitors of protein translation and BCL2
AU - Mill, Christopher P.
AU - Fiskus, Warren
AU - DiNardo, Courtney D.
AU - Birdwell, Christine
AU - Davis, John A.
AU - Kadia, Tapan M.
AU - Takahashi, Koichi
AU - Short, Nicholas
AU - Daver, Naval
AU - Ohanian, Maro
AU - Borthakur, Gautam
AU - Kornblau, Steven M.
AU - Green, Michael R.
AU - Qi, Yuan
AU - Su, Xiaoping
AU - Khoury, Joseph D.
AU - Bhalla, Kapil N.
N1 - Funding Information:
The authors thank the Sequencing and Microarray Core Facility and the Flow Cytometry and Cellular Imaging (FCCI) Core Facility, which are supported by the Anderson Cancer Center Support Grant 5 P30 CA016672-40. K.N.B. was supported by a grant from the N.I.H (R01 CA255721). This research is supported in part by the Anderson Cancer Center Leukemia SPORE (P50 CA100632).
Publisher Copyright:
© 2022 American Society of Hematology
PY - 2022/2/10
Y1 - 2022/2/10
N2 - 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.
AB - 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.
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U2 - 10.1182/blood.2021013156
DO - 10.1182/blood.2021013156
M3 - Article
C2 - 34601571
AN - SCOPUS:85124206566
SN - 0006-4971
VL - 139
SP - 907
EP - 921
JO - Blood
JF - Blood
IS - 6
ER -