Role of the microenvironment in protection of cancer cells
Signal transduction
Regulation of macrophage polarization
Involvement of Bcr and Abr as negative regulators of the small GTPase Rac in sepsis, asthma and pulmonary hypertension
MOLECULAR CARCINOGENESIS RESEARCH OVERVIEW
The Molecular Carcinogenesis Laboratory is interested in studying the cell types that are part of our immune system. We study their normal function under circumstances of inflammation and also how they behave when they have become cancer cells.
As an example, our lab is interested in understanding why acute lymphoblastic leukemia cells, which are the malignant counterparts of a specific type of immune cells, become resistant to drug treatment.
Between 1981 and 1987, our work resulted in the discovery that two genes, BCR and ABL, become fused in Philadelphia-chromosome positive leukemias including Ph-positive ALL and chronic myeloid leukemia (CML). We cloned the breakpoints of these genes, and showed that a chimeric transcript is made. This results in the generation of a hybrid protein with abnormal tyrosine kinase activity. The discovery later led to the development of the first targeted anti-cancer drug: Imatinib (STI571, Gleevec) and significantly improved survival of patients with CML.
We created a transgenic mouse model for the P190 Bcr/Abl protein found in Ph-positive ALL and showed that this oncoprotein is directly responsible for the development of leukemia.
We generated mice lacking a functional Bcr gene, and mice lacking a related gene called Abr. These animals have innate immune cells that are easily activated, leading to increased susceptibility to sepsis.
KEY AREAS OF RESEARCH
We study interactions of acute lymphoblastic leukemia cells with other cells in their environment and how these interactions, such as those promoted by the SDF1a-CXCR4 axis, protect them against chemotherapy. We recently showed that the inhibition of this axis can make the leukemia cells more sensitive to drug treatment.
We aim to identify cell surface molecules on acute lymphoblastic leukemia cells that can be used to more effectively treat this type of leukemia. We were the first to identify the BAFF-R on acute lymphoblastic leukemia cells.
We conduct experiments to understand how specific carbohydrate modifications and carbohydrate-binding proteins affect acute lymphoblastic leukemia cell survival and drug resistance.
We are interested in discovering how cells of the innate immune system are regulated during inflammatory processes.
Mechanisms and targets for Childhood Acute Lymphoblastic leukemia.
We are supported by the William Lawrence and Blanche Hughes Foundation to identify new therapies for pediatric acute lymphoblastic leukemia (ALL) that can be rapidly translated into clinical trials.
Li A, Xing Y, Chan B, Heisterkamp N, Groffen J, Borok Z, Minoo P, Li C. Cell type-specific expression of adenomatous polyposis coli in lung development, injury, and repair. Dev Dyn. 239:2288-2297, 2010.
Yun J.P., Behan, J.W., Heisterkamp, N., Butturini, A., Klemm, L., Ji, L., Groffen, J., Muschen, M., and Mittelman, S.D. Diet-induced obesity accelerates acute lymphoblastic leukemia progression in two murine models. Cancer Prev Res. 3:1259-1264, 2010.
Oh,D., Han, S., Seo, J., Lee, J-R., Choi, J., Groffen, J., Kim, K., Cho, Y. S., Choi, H-S., Shin,H., Woo, J., Won,H., Park, S. K., Kim, S-Y., Jo, J., Whitcomb, D.J., Cho, K., Kim,H., Bae, Y.C., Heisterkamp, N., Choi, S-Y., and Eunjoon Kim, E. Regulation of synaptic Rac1 activity, LTP maintenance, and learning and memory by BCR and ABR Rac GTPase-activating proteins. J Neurosc. 30:14134-44, 2010.
Yu M., Jiang E., Parameswaran R., Stoddart S, Fei F, Muschen M, Park E, Hsieh Y-T, Martinelli G, Hofmann W-K, Yang AS, Groffen J, Heisterkamp N, Kim Y-m. AMD3100 sensitizes acute lymphoblastic leukemia cells to chemotherapy in vivo. Blood Cancer J. 1:e14, 2011.
