What are the target genes of AML1-ETO that are essential for the leukemic phenotype?
We have expressed an AML1-ETO retrovirus and a control retrovirus in human HSC by retroviral transduction and used the transduced cells for hybridization screening of high-density microarrays. Differentially expressed "target" genes have been identified, and we are currently testing the contribution of the identified genes to the AML1-ETO phenotype outlined in Aim 1. The cell cultures described in Aim 1 have also been analyzed using microarray technology and compared to normal human CD34+ cells, and many of the genes identified using the transient system are also found to be differentially regulated in these long-term AML1-ETO cultures. We hope to identify the mechanism by which AML1-ETO induces the long-term self-renewal of human HSC. These signals may represent the "normal" way in which HSC self-renew, and it may be possible to modulate these pathways using soluble factors and in this way expand normal human HSC without introduction of an oncogene.
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.
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., Jankovic, V., Wunderlich, M., Valk, P.J.M., Cammenga, J., Krejci, O., Viales, A., Delwel, R., Lowenberg, B., and Nimer, S.D.: AML1-ETO upregulates TrkA expression in human CD34+ cells allowing NGF-induced expansion. PNAS, 102(11)4016-4021, 2005.
Cammenga, J., Mulloy, J.C., Berguido, F.J., MacGrogan, D., Viale, A., and Nimer, S.D..: Induction of C/EBP activity alters gene expression and differentiation of human CD34+ cells. Blood, 101(6)2206-2214, 2003.
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Dr. James Mulloy, Division of Experimental Hematology, at 513-636-1844. Dr. Mulloy's office can be found in room S7.603.
