Research in our laboratory is focused on the contribution of failure of normal growth regulatory controls to the development of hematologic malignancies. Alterations in the balance of apoptosis and proliferation may lead to chronic leukemic states such as B cell chronic lymphocytic leukemia (B-CLL). Consistent genetic defects have been difficult to identify in B-CLL; hence our focus has been on alterations in cytokine networks which may affect the cellular environment of the malignant clone. We showed that TGFbeta, a potent immunosuppressive cytokine which can induce apoptosis and inhibit proliferation, is overproduced in mice and humans with B- CLL, but the leukemic B cells fail to respond to the apoptotic signals provided by TGFbeta. This defect in TGFbeta responsiveness is not due to a lack of expression of TGF receptors, but appears to be a failure in the signal transduction pathway for this cytokine. In addition to TGFbeta, we have investigated the role of T cell produced cytokines (IL4 and IFNg) in regulating the apoptotic process in CLL B cells.
We found a predominance of IFNg producing T cells in these patients as compared to normals, and that the leukemic B cells express higher levels of IFNg receptors. Interestingly, this cytokine has an extremely anti-apoptotic effect on the B cells. Thus, the leukemic B cell is producing a cytokine that can cause potent immunosuppression (and apoptosis) of other cells while being itself resistant and appears to be overly responsive to the anti-apoptotic effects of IFNg. Taken together, these aberrations could contribute to the survival and expansion of the malignant B cell. Current investigations are focused on the role of other cytokines in the control of hematologic malignancies, using both human and murine models, with the intent of identifying potent targets for therapy.
The laboratory is also involved in the development of new flow cytometric applications for research and clinical use. This includes basic and translational studies on applications for monitoring receptor/ligand binding, multiparameter functional studies, minimal residual disease detection, stem cell isolation and identification, and transplantation monitoring.
Peter Nowell, M.D. Pathology
Bruce Rosengard, M.D , Surgery
Alain Rook, M.D., Dermatology
M Mizus, R Schretzenmair, L Zhang, L Holzman, E Mohler, J Moore: Measurement of Extracellular Vesicles in the Urine of Patients with Kidney Diseases J : 2015.
Takeshita J, Mohler E, Krishnamoorthy P, Moore J, Rogers W, Zhang L, Gelfand J, Mehta N.: Endothelial Cell-, Platelet-, and Monocyte/Macrophage-Derived Microparticles are Elevated in Psoriasis Beyond Cardiometabolic Risk Factors. J Am Heart Association : 2014.
Kurtzman N, Zhang L, French B, Jonas R, Bantly A, Rogers WT, Moore JS, Rickels M, Mohler ER III: Personalized cytomic assessment of vascular health: Evaluation of the vascular health profile in diabetes mellitus. Cytometry Part B: Clinical Cytometry in press : 2013.
Urtishak KA, Edwards AY, Wang LS, Hudome A, Robinson BW, Barrett JS, Cao K, Cory L, Moore JS, Bantly AD, Yu QC, Chen IM, Atlas SR, Willman CL, Kundu M, Carroll AJ, Heerema NA, Devidas M, Hilden JM, Dreyer ZE, Hunger SP, Reaman GH, Felix CA: Potent Obatoclax cytotoxicity and activation of triple death mode killing across infant acute lymphoblastic leukemia. Blood 121(14): 2689-2703 Blood 121 (14): 2689-2703,2013.
Curtis A.M., Edelberg J., Jonas R., Rogers W.T., Moore J.S., Wajihuddin S., Mohler E.R. III: Endothelial Microparticles; Sophisticated Vesicles Modulating Vascular Function Vascular Medicine in press : 2013.
Tario Jr., J. D., Humphrey, K., Bantly, A. D., Muirhead, K. A., Moore, J. S., Wallace, P. K: Optimized Staining and Proliferation Modeling Methods for Cell Division Monitoring using Cell Tracking Dyes J. Vis. Exp. 70 : e4287,2012.
Mehta NN, Li RC, Takeshita J, Zhang L, VanVoorhees A, Rogers W, Wilcox M, Raper A, Moore J, Gelfand JM, Mohler ER: Elevated endothelial cell, platelet and T-cell micro particles in psoriasis may provide novel link to atherosclerosis free Journal of the American College of Cardiology 59 (13sI): E2055,2012.
Mohler ER III, Zhang L, Medenilla E, Rogers W, French B, Bantly A, Moore JS, Huan Y, Murashima M, Berns JS: Effect of darbepoetin alfa on endothelial progenitor cells and vascular reactivity in chronic kidney disease. Vascular Medicine 16 (13): 183-189,2011.
Baker JF, Zhang L, Imadojemu S, Sharpe A, Patil S, Moore JS, Mohler ER 3rd, Von Feldt J.: Circulating endothelial progenitor cells are reduced in SLE in the absence of coronary artery calcification. Rheumatol Int. : 2011.
Curtis AM, Zhang L, Medenilla E, Gui M, Wilkinson PF, Hu E, Giri J, Doraiswamy V, Gunda S, Burgert M, Moore JS, Edelberg JM, MohlerER III: Relationship of microparticles to progenitor cells as a measure of vascular health in a diabetic population Cytometry Part B (Clinical Cytometry) : 2010.
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