Showing papers by "Junwei Shi published in 2012"

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

Abstract: // Harald Herrmann 1 , Katharina Blatt 2 , Junwei Shi 3 , Karoline V. Gleixner 2 , Sabine Cerny-Reiterer 1 , Leonhard Mullauer 4 , Christopher R. Vakoc 3 , Wolfgang R. Sperr 1,2 , Hans-Peter Horny 6 , James E. Bradner 5 , Johannes Zuber 3,7 , Peter Valent 1,2 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 (IC 50 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.