Marina Konopleva, MD, PhD
My major interest is the regulation of apoptosis in normal and leukemic stem cells, in the context of bone marrow microenvironment. Our findings indicate overexpression of the anti-apoptotic genes Bcl-2 and Bcl-XL in quiescent leukemic but not in normal progenitor cells, and the ability of bone marrow stromal cells to induce Bcl-2 expression. We explore strategies of sensitization to chemotherapy by inhibition of these genes, such as antisense oligonucleotides and recently small molecule inhibitors and this concept is now being tested in clinical trials. We have further identified Raf/MEK/ERK and PI3K/AKT/ILK signaling pathways as pro-survival pathways abnormally activated in AML cells, and are currently investigating the role of leukemia microenvironment in chemoresistance of leukemias mediated by activation of these pathways. We investigated the role of stroma-derived factor (SDF-1alpha) and its cognate receptor CXCR4 in normal and leukemic progenitors, and propose strategies to inhibit CXCR4 with the goal to improve the antileukemia effect of chemotherapy and stem cell transplantation. These pre-clinical studies have translated into clinical trials for enhancement of chemosensitivity of leukemias. Having gained considerable success in the laboratory-based research years under the mentorship of Dr. Michael Andreeff, I have successfully moved to an independent clinical appointment in 2007. My goals are to excel in laboratory and clinical research and to translate my lab-bench discoveries into the novel treatment modalities for patients with leukemia. My major scientific focus is characterization of the molecular mechanisms of chemoresistance of leukemia conferred by the bone marrow microenvironment.