Dr. Marina Konopleva
The University of Texas MD Anderson Cancer Center
Department of Leukemia
- molecular biology
- hematopoietic stem cells
- acute and chronic leukemias
My major interest is the regulation of apoptosis in normal and leukemic stem cells in the context of the bone marrow microenvironment. Our findings have indicated overexpression of the antiapoptotic genes Bcl-2 and Bcl-XL in quiescent leukemic cells but not in normal progenitor cells and the ability of bone marrow stromal cells induce Bcl-2 expression. We have explored strategies of sensitization to chemotherapy by inhibition of these genes, such as antisense oligonucleotides and small molecule inhibitors. 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 the leukemia microenvironment in the chemoresistance of leukemias mediated by activation of these pathways. Presently, my laboratory is interested in further delineating the role that bone marrow microenvironment plays in the chemoresistance of leukemic cells. We have demonstrated that interactions between stroma-secreted SDF-1 and CXCR4 prevent chemotherapy-induced apoptosis in CLL and in AML.
A tutorial in my laboratory would allow the students to learn basic stem cell biology/isolation/culture, culture human cells (primary cultures and cell lines), learn basic flow cytometry and microscopy and provide experience in the molecular biology and biochemistry of signal transduction related to leukemia resistance, signaling and programmed cell death.
Konopleva M, Contractor R, Tsao T, Samudo I, Ruvolo PP, Kitada S, Deng X, Zhai D, Shi YX, Sneed T, Verhaegen M, Soengas M, Ruvolo VR, McQueen T, Schober WD, Watt JC, Jiffar T, Ling X, Marini FC, Harris D, Dietrich M, Estrov Z, McCubrey J, May WS, Reed JC, Andreeff M. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 10:375-88, 11/2006.
Tabe Y, Jin L, Tsutsumi-Ishii Y, Xu Y, McQueen T, Priebe W, Mills GB, Ohsaka A, Nagaoka I, Andreeff M, Konopleva M (2007) Activation of integrin-linked kinase is a critical pro-survival pathway induced in leukemia cells by bone marrow-derived stromal cells. Cancer Res, 67(2):684-94.
Zeng Z, Sarbassov DD, Samudio IJ, Yee KW, Munsell MF, Jackson Ce, Giles FJ, Sabatini DM, Andreeff M, Konopleva M (2007) Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood, 109:3509-12.
Zeng Z, Shi YX, Samudio IJ, Wang RY, Ling X, Frolova O, Levis M, Rubin JB, Negrin RR, Estey EH, Konoplev S, Andreeff M, Konopleva M (2008) Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML. Blood, 2008 Oct 27. [Epub ahead of print]