Dr. Zeleznik-Le’s research interest is focused on the MLL protein, and on MLL fusion proteins that cause leukemia.  MLL is involved in the proper maintenance of expression of downstream target genes, including genes of the HOX cluster.  How MLL functions to help maintain proper expression of target genes is not well understood, but it is thought to involve epigenetic mechanisms acting at the level of chromatin.  One focus of her work is to identify chromatin changes that are mediated by MLL and MLL fusion proteins.  This also includes studies to understand how proteins that interact with MLL compete and /or synergize to mediate these effects, and the role of post-translational modifications of MLL on its function.  Another main focus of her research utilizes in vitro and in vivo murine models of MLL leukemia to dissect critical functions required for immortalization and leukemogenesis.  Questions addressed concern hematopoietic cell lineage commitment, and specificity of MLL and partner gene functional domains for immortalization capability.

Dr. Zeleznik-Le has been involved in the cloning of several MLL fusion genes from patient leukemia samples, including the MLL-CBP fusion.  She has developed murine models of MLL leukemia that recapitulate the human disease.  Her laboratory has identified proteins that interact with MLL, including those with chromatin modifying capability. 

Current Publications:

Lavau, C., Du, C., Thirman, M., and Zeleznik-Le, N.J. Chromatin related properties of CBP fused to MLL generate an MDS-like syndrome that evolves into myeloid leukemias. EMBO J 19: 4655-4664, 2000.

Liedman, D. and Zeleznik-Le, NJ. Retroviral transduction model of mixed lineage leukemia fused to CREB binding protein. Curr. Opin. Hematology 8: 218-223, 2001.

 Xia, Z-B., Anderson, M., Diaz, M.O., and Zeleznik-Le, N.J. MLL repression domain activity is mediated by histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor CtBP. Proc. Nat’l Acad. Sci, USA 100:8342-8347, 2003.

Mujtaba, S., He, Y., Zeng, L., Yan, S., Plotnikova, O., Sanchez, R., Zeleznik-Le, N.J., Ronai, Z., Zhou, M.M. Structural mechanism of the bromodomain of coactivator CBP in p53 transcriptional activation. Mol. Cell. 13:251-263, 2004.

Popovic, R., Zeleznik-Le, N.J.  MLL: how complex does it get? J. Cell. Biochem. 95:234-242, 2005.

Zia, Z-B., Popovic, R., Chen, J., Theisler, C., Lorenz, T., Santillan, D.A., Erfurth, F., Diaz, M.O., Zeleznik-Le, N.J.  The MLL fusion gene, MLL-AF4, regulates cyclin-dependent kinase inhibitor CDKN1B (P27kip1) expression.  Proc. Natl. Acad. Sci. USA, in press, 2005.