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Blood. 2019 Apr 25. pii: blood.2018893982. doi: 10.1182/blood.2018893982. [Epub ahead of print]

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

Author information

1
MD Anderson Cancer Center, United States.
2
Leukemia, MD Anderson Cancer Center, United States.
3
Leukemia, UT MD Anderson Cancer Center, United States.
4
Accutar Biotechnology, Inc., United States.
5
Arvinas, LLC, Japan.
6
Mol & Cell Biology-Mol.Regulation, Baylor College of Medicine, United States.
7
Baylor College of Medicine, United States.
8
Molecular and Computational Biology, Baylor College of Medicine, United States.
9
Hematopathology, The University of Texas M.D. Anderson Cancer Center, United States.
10
Leukemia, University of Texas MD Anderson Cancer Center, United States.
11
Molecular Biology and Biological Physics, University of Virginia, United States.
12
Department of Leukemia, The University of Texas MD Anderson Cancer Center, United States.
13
Department of Molecular Hematology and Therap, University of Texas M. D. Anderson Cancer Center, United States.
14
Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, United States.
15
MD Anderson Cancer Center.
16
Molecular Physiology and Biological Physics, University of Virginia, United States.
17
Department of Chemistry, Yale University, United States.
18
Leukemia, MD Anderson Cancer Center, United States kbhalla@mdanderson.org.

Abstract

RUNX1 transcription factor regulates normal and malignant hematopoiesis. Somatic or germline mutant (mt) RUNX1 is associated with poorer outcome in AML. Knockdown or inhibition of RUNX1 induced more apoptosis of AML expressing mutant versus wild-type (wt) 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 shRNA, repressed RUNX1, inhibited cell growth and induced cell lethality in AML cells expressing mtRUNX1. Moreover, treatment with BET protein inhibitor (BETi) or degrader (BET-PROTAC) repressed RUNX1 and its targets, inducing apoptosis, and improving survival of mice engrafted with AML expressing mtRUNX1. LINCS1000-CMap datasets queried with mRNA 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. Additionally, the EMs cinobufagin, anisomycin and narciclasine induced more lethality in hematopoietic progenitor cells (HPCs) expressing germ-line mtRUNX1 from patients with AML as compared to 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.

PMID:
31023702
DOI:
10.1182/blood.2018893982

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