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.