RUNX1-targeted therapy for AML expressing somatic or germline mutation in RUNX1.
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
Core Binding Factor Alpha 2 Subunit
/ antagonists & inhibitors
Gene Knockdown Techniques
Germ-Line Mutation
Hematopoietic Stem Cells
/ drug effects
Humans
Leukemia, Myeloid, Acute
/ genetics
Mice
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
04 07 2019
04 07 2019
Historique:
received:
25
12
2018
accepted:
16
04
2019
pubmed:
27
4
2019
medline:
10
1
2020
entrez:
27
4
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31023702
pii: S0006-4971(20)42439-5
doi: 10.1182/blood.2018893982
pmc: PMC6609954
doi:
Substances chimiques
Antineoplastic Agents
0
Core Binding Factor Alpha 2 Subunit
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
59-73Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA100632
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197589
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA083639
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA234478
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA143883
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA262636
Pays : United States
Informations de copyright
© 2019 by The American Society of Hematology.
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