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Blood. 2019 Jul 4;134(1):59-73. doi: 10.1182/blood.2018893982. Epub 2019 Apr 25.

RUNX1-targeted therapy for AML expressing somatic or germline mutation in RUNX1.

Author information

The University of Texas M.D. Anderson Cancer Center, Houston, TX.
Arvinas, Inc., New Haven, CT.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX.
Department of Molecular Physiology and Biological Physics and Chemistry, University of Virginia, Charlottesville, VA; and.
Department of Molecular, Cellular, and Developmental Biology.
Department of Chemistry, and.
Department of Pharmacology, Yale University, New Haven, CT.


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.

[Available on 2020-07-04]

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