期刊
BLOOD
卷 134, 期 1, 页码 59-73出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2018893982
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- M.D. Anderson Cancer Center from the National Institutes of Health (NIH), National Cancer Institute (NCI) [5 P30 CA016672-40]
- NIH/NCI (Anderson TCGA Genome Data Analysis Center) [CA143883, CA083639]
- Mary K. Chapman Foundation
- Michael & Susan Dell Foundation
- M.D. Anderson Cancer Center [NIH/NCI P30CA016672]
- CPRIT [RP170295]
- Baylor College of Medicine
- NIH/NCI [P30 CA125123, R35 CA197589]
- CPRIT Proteomics and Metabolomics Core Facility [RP170005]
- NCI
- Arvinas
- M.D. Anderson Cancer Center Leukemia Specialized Program of Research Excellence [P50 CA100632]
RUNX1 transcription factor regulates normal and malignant hematopoiesis. Somatic or germline mutant RUNX1 (mtRUNX1) is associated with poorer outcome in acute myeloid leukemia (AML). Knockdown or inhibition of RUNX1 induced more apoptosis of AML expressing mtRUNX1 versus wild-type RUNX1 and improved survival of mice engrafted with mtRUNX1-expressing AML. CRISPR/Cas9-mediated editing-out of RUNX1 enhancer (eR1) within its intragenic super-enhancer, or BET protein BRD4 depletion by short hairpin RNA, repressed RUNX1, inhibited cell growth, and induced cell lethality in AML cells expressing mtRUNX1. Moreover, treatment with BET protein inhibitor or degrader (BET-proteolysis targeting chimera) repressed RUNX1 and its targets, inducing apoptosis and improving survival of mice engrafted with AML expressing mtRUNX1. Library of Integrated Network-based Cellular Signatures 1000-connectivity mapping data sets queried with messenger RNA signature of RUNX1 knockdown identified novel expression-mimickers (EMs), which repressed RUNX1 and exerted in vitro and in vivo efficacy against AML cells expressing mtRUNX1. In addition, the EMs cinobufagin, anisomycin, and narciclasine induced more lethality in hematopoietic progenitor cells (HPCs) expressing germline mtRUNX1 from patients with AML compared with HPCs from patients with familial platelet disorder (FPD), or normal untransformed HPCs. These findings highlight novel therapeutic agents for AML expressing somatic or germline mtRUNX1.
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