Oncotarget

Research Papers:

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

Harald Herrmann, Katharina Blatt, Junwei Shi, Karoline V. Gleixner, Sabine Cerny-Reiterer, Leonhard Müllauer, Christopher R. Vakoc, Wolfgang R. Sperr, Hans-Peter Horny, James E. Bradner, Johannes Zuber and Peter Valent _

PDF  |  HTML  |  How to cite  |  Order a Reprint

Oncotarget. 2012; 3:1588-1599. https://doi.org/10.18632/oncotarget.733

Metrics: PDF 3272 views  |   HTML 2376 views  |   ?  


Abstract

Harald Herrmann1, Katharina Blatt2, Junwei Shi3, Karoline V. Gleixner2, Sabine Cerny-Reiterer1, Leonhard Müllauer4, Christopher R. Vakoc3, Wolfgang R. Sperr1,2, Hans-Peter Horny6, James E. Bradner5, Johannes Zuber3,7, Peter Valent1,2

1 Ludwig Boltzmann Cluster Oncology, Vienna, Austria;

2 Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria;

3 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA;

4 Department of Pathology, Medical University of Vienna, Austria;

5 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA;

6 Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany; and

7 Research Institute of Molecular Pathology (IMP), Vienna, Austria.

Correspondence:

Peter Valent, email:

Keywords: AML, leukemic stem cells, BRD4, JQ1, targeted therapy

Received: November 02, 2012, Accepted: November 26, 2012, Published: November 27, 2012

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 (IC50 0.05-0.5 µM) 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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 733