What are the effects of AML1-ETO expression on the self-renewal and differentiation properties of human HSC?
We are analyzing HSC expansion and differentiation in well-defined in vitro systems that can identify the specific effects that AML1-ETO has on HSC biology. AML1-ETO-transduced HSC are able to proliferate in cytokine-supplemented cultures for up to 8 months and retain many characteristics of stem cells, including telomerase activity, multi-potential differentiation capacity (B lymphoid as well as myeloid), CD34 expression and the ability to engraft NOD/SCID mice. Sorting experiments have shown that the surface marker expression of the cells corresponds to the expected phenotype, morphology and functional ability of the different hematopoietic lineages (Figure 1). These cultures represent a unique system for studying the effects of a leukemia-associated protein in a normal, primary cell background. Cooperating oncogenes (and "knock-down" of suspected tumor suppressor genes by siRNA technology) that may allow cells to grow in a cytokine-independent manner and/or for prolonged periods (immortalization) will be tested in this model.
Related Publications
Where possible, article titles are linked to an abstract of the article. Selected citations may also be linked to PDFs of the article available on a Journal's site. Depending on the Journal's publishing policy, you may need a subscription to download the PDF.
Mulloy, J.C., Jankovic V, Wunderlich M, Delwel R, Cammenga J, Krejci O, Zhao H, Valk PJ, Lowenberg B, Nimer SD. AML1-ETO fusion protein up-regulates TRKA mRNA expression in human CD34+ cells, allowing nerve growth factor-induced expansion. PNAS, 102(11):4016-21, 2005.
Wunderlich, M., Krejci, O., Wei, J., and Mulloy, J.C. Human CD34+ cells expressing the inv(16) fusion protein exhibit a myelomonocytic phenotype with greatly enhanced proliferative ability. Blood, 108(5)1690-1697, 2006.
Krejci, O., Wunderlich, M., Geiger, H., Schleimer, D., Jansen, M., Andreassen, P.R. and Mulloy, J.C. p53 signaling in response to increased DNA damage sensitizes AML1-ETO cells to stress-induced death. Blood. 111(4): 2190-2199, 2008.
Mulloy, J. C., Cammenga, J., MacKenzie, K. L., Berguido, F. J., Moore, M. A. and Nimer, S. D.:The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells. Blood 99, 15-23, 2002.
Mulloy, J.C., Cammenga, J., Berguido, F.J., Wu, K., Zhou, P., Comenzo, R.L., Jhanwar, S., Moore, M.A.S., and Nimer, S.D.:
Maintaining the self-renewal and differentiation potential of human CD34+ hematopoietic cells using a single genetic element.
Blood, 102(13)4369-4376, 2003.
Contact Us
For additional information, please contact
Dr. James Mulloy, Division of Experimental Hematology, at 513-636-1844. Dr. Mulloy's office can be found in room S7.603.
