Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem- and progenitor cells in acute myeloid leukemia AML

Herrmann, H., Blatt, K., Shi, J., Gleixner, K. V., Cerny-Reiterer, S., Mullauer, L., Vakoc, C. R., Sperr, W. R., Horny, H. P., Bradner, J. E., Zuber, J., Valent, P. (December 2012) Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem- and progenitor cells in acute myeloid leukemia AML. Oncotarget, 3 (12). pp. 1588-99. ISSN 1949-2553

URL: http://www.ncbi.nlm.nih.gov/pubmed/23249862

Abstract

Acute myeloid leukemia (AML) is a life-threatening stem cell disease characterized by uncontrolled proliferation and accumulation of myeloblasts. Using an advanced RNAi screen-approach in an AML mouse model we have recently identified the epigenetic 'reader' BRD4 as a promising target in AML. In the current study, we asked whether inhibition of BRD4 by a small-molecule inhibitor, JQ1, leads to growth-inhibition and apoptosis in primary human AML stem- and progenitor cells. Primary cell samples were obtained from 37 patients with freshly diagnosed AML (n=23) or refractory AML (n=14). BRD4 was found to be expressed at the mRNA and protein level in unfractionated AML cells as well as in highly enriched CD34(+)/CD38(-) and CD34(+)/CD38(+) stem- and progenitor cells in all patients examined. In unfractionated leukemic cells, submicromolar concentrations of JQ1 induced major growth-inhibitory effects (IC(5)(0) 0.05-0.5 microM) in most samples, including cells derived from relapsed or refractory patients. In addition, JQ1 was found to induce apoptosis in CD34+/CD38(-) and CD34(+)/CD38(+) stem- and progenitor cells in all donors examined as evidenced by combined surface/Annexin-V staining. Moreover, we were able to show that JQ1 synergizes with ARA-C in inducing growth inhibition in AML cells. Together, the BRD4-targeting drug JQ1 exerts major anti-leukemic effects in a broad range of human AML subtypes, including relapsed and refractory patients and all relevant stem- and progenitor cell compartments, including CD34(+)/CD38(-) and CD34(+)/CD38(+) AML cells. These results characterize BRD4-inhibition as a promising new therapeutic approach in AML which should be further investigated in clinical trials.

Item Type: Paper
Uncontrolled Keywords: Adult Aged Aged, 80 and over Antigens, CD34/metabolism Antigens, CD38/metabolism Antimetabolites, Antineoplastic/pharmacology Antineoplastic Agents/*pharmacology Antineoplastic Combined Chemotherapy Protocols/pharmacology Apoptosis Azepines/*pharmacology Cell Proliferation/drug effects Cytarabine/pharmacology Dose-Response Relationship, Drug Drug Resistance, Neoplasm Drug Synergism Female HL-60 Cells Humans Inhibitory Concentration 50 Leukemia, Myeloid, Acute/genetics/immunology/*metabolism/pathology Male Membrane Glycoproteins/metabolism Middle Aged *Molecular Targeted Therapy Neoplastic Stem Cells/*drug effects/immunology/metabolism/pathology Nuclear Proteins/*antagonists & inhibitors/genetics/metabolism RNA, Messenger/metabolism Transcription Factors/*antagonists & inhibitors/genetics/metabolism Triazoles/*pharmacology Tumor Cells, Cultured U937 Cells Young Adult
Subjects: diseases & disorders > cancer
diseases & disorders > cancer > drugs and therapies
diseases & disorders > cancer > cancer types > leukemia
bioinformatics > genomics and proteomics > small molecules
CSHL Authors:
Communities: CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > Microscopy Service
CSHL labs > Vakoc lab
CSHL Cancer Center Program > Gene Regulation and Cell Proliferation
Depositing User: Matt Covey
Date: December 2012
Date Deposited: 07 Mar 2014 20:40
Last Modified: 13 Oct 2015 14:29
PMCID: PMC3681497
Related URLs:
URI: http://repository.cshl.edu/id/eprint/29574

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