Amittha Wickrema, Ph.D.

Signaling Pathways Regulating Normal and Malignant Hematopoiesis

Research Summary

The overall goal of my laboratory is to understand signaling pathways regulating normal and malignant hematopoiesis. In the area of normal hematopoiesis we are currently focused on understanding the signal transduction pathways guiding lineage commitment and terminal differentiation of erythroid cells. We are using a primary human cellular model system where early stem cells and stem cells progenitors commit to erythroid lineage, differentiate and enucleate into reticulocytes during in vitro culture. Using this model we have been able to define the signaling pathways that are vital for erythroid cell viability, proliferation and differentiation. Currently we are focused on identifying specific signaling molecules and transcription factors that guide the terminal events including cytoskeletal remodeling and enucleation.

The second major project in the laboratory is focused on growth control of myeloma cells. Multiple myeloma is an incurable disease that affects the plasma B cells. Secretion of Interleukin-6 by autocrine and paracrine mechanisms plays a major role in the pathobiology of the disease. We have identified several signaling cascades that are inactivated in myeloma cells contributing to suppression of cell cycle arrest and apoptosis. Current studies are focused on identifying small molecule compounds capable of reactivating these pathways in order to induce apoptosis and/or cell cycle arrest of malignant cells. These studies include identification and selection of candidate small molecule compounds, screening them for effectiveness in modulating the activity of serine/threonine and tyrosine kinases and using a mouse myeloma model to test the efficacy in vivo.

Selected Papers

Wickrema A, Krantz SB, Winkelmann JC, Bondurant MC. (1992). Differentiation and erythropoietin receptor gene expression in human erythroid progenitor cells. Blood, 80:1940-1949.

Muta K, Krantz SB, Bondurant M, Wickrema A. (1994). Distinct roles of erythropoietin, insulin-like growth factor 1, and stem cell factor in the development of erythroid progenitor cells. Journal of Clinical Investigation, 94:34-43.

Gazitt Y, Reading CC, Hoffman R, Wickrema A, Vesole DH, Jaganath S, Condino J, Lee B, Barlogie B, Tricolt G. (1995). Purified CD34+Lin-Thy+ stem cells do not contain clonal myeloma cells. Blood, 86:381-389.

Jacobs-Helber SM, Wickrema A, Lawson A, Sun Z, Sawyer ST. (1998). AP1 regulation of proliferation and initiation of apoptosis in erythroid cells. Opposing roles of Cjun and JunB. Molecular Cell Biology, 18:3699-3707.

Wickrema A, Uddin S, Sharma A, Chen F, Alsayed Y, Ahmad S, Sawyer St, Krystal G, Yi T, Nishada K, Hibi M, Hirano T, Platanias LC. (1999). Engagement of Gab1 and Gab2 in erythropoietin signaling. J Biol Chem, 274:24469-24474.

Mahmood D, Amlak M-G, Deb D., Platanias LC, Uddin S, Wickrema A. (2002). Association and acetylation of forkhead transcription factor, FKHRL1 by p300 co-activator during erythropoietin starvation in primary erythroid cells. Oncogene, 21: 1556-1562.

Verma A, Sassano A, Deb D, Kambhampati S, Wickrema A, Uddin S, van Besien K, Platanias LC. (2002). Activation of the p38 Map kinase signaling pathway mediates cytokine-induced hematopoietic suppression in aplastic anemia. J. Immunology, 168:5984-5988.

Jacobs-Helber, Roh K-H, Bailey D, Dessypris E, Ryan JJ, Chen J, Wickrema A, Barber D, Dent P, Sawyer ST. (2003). Tumor necrosis factor-alpha expressed constitutively in erythroid cells or induced by erythropoietin has negative and stimulatory roles in normal erythropoiesis and erythroleukemia Blood, 101: 524-531.

Hoffman JF, Joiner W, Nehrke K, Potapova O, Foye K, Wickrema A. (2003). The hsk4 (KCNN4) isoform is the Ca++ - activated K+ channel in human red blood cells. Proc. Natl. Acad. Sci., 100: 7366-7371.

Uddin S., Kang J-H, Ulaszek J, Mamood D, Wickrema A. (2004). Differentiation-stage specific activation of p38 isoforms in primary erythroid cells, Proc. Natl. Acad. Sci. 1:146-149.