Associate Professor
Ph.D. University of Missouri, 1993
A primary focus of my lab is to utilize Affymetrix gene chip technology to identify candidate IFN-stimulated genes (ISGs) and dsRNA-stimulated genes that regulate cellular apoptotic or antiviral responses. Recent Affymetrix studies (Leaman et al., 2003; Sun and Leaman, 2004) identified novel induced genes whose protein products are known or hypothesized to regulate apoptotic processes, including TNF-Related Apoptosis Inducing Ligand (TRAIL), XIAP-associated factor-1 (XAF1) and Noxa. Work is currently in progress to assess the functions of these and other gene products in the biological effects of IFNs (see recent publications, below).
XAF1: XAF1 is a newly identified protein that interacts with a particular IAP family member, XIAP (X-linked IAP). We have demonstrated that XAF1 mRNA and protein are potently upregulated by IFN-beta in apoptosis-sensitive cells but not in apoptosis resistant cells (Leaman et al., 2002). A role for XAF1 in TRAIL-induced apoptosis has been demonstrated by overexpressing XAF1 in cells otherwise resistant to TRAIL as a single agent. Structural studies aimed at identifying XAF1 functional motifs are in progress (Leaman et al., 2002). We have also recently identified a novel XAF1-interacting protein that is undergoing functional characterization. This protein, tentatively called XIRP (XAF-1 interacting RING finger protein) has very interesting effects on cellular sensitivity to virus or other innate immune system stimuli when over expressed.
Additional novel IFN-stimulated genes: Other genes with potential importance in regulating IFN-beta-induced apoptosis or antiviral effects in melanoma have been identified in these same studies and confirmed as ISGs (Leaman et al., 2003). Analyses of several of these genes and the roles of their protein products in IFN responses are underway. In particular, we are actively pursuing the function of the protein encoded by the ISG12 gene, which is highly induced in expression following IFN stimulation. Furthermore, work with another mitochondrial protein, Noxa, that is regulated by IFNs has revealed an interesting role in virus-induced apoptosis (Sun and Leaman, 2005).
Leaman, D.W. (2008) Recent advances in Oligonucleotide Therapeutics: antisense to aptamers. Expert Opinion Drug Discovery 3:997-1009.
Rosebeck, S.R. and D.W. Leaman. (2008) Mitochondrial localization of the Interferon-inducible protein ISG12a Apoptosis. 13:562-572.
Sairyo, K., A. Biyani, V. K. Goel, D.W. Leaman, R. Booth Jr., J. Thomas, N. A. Ebraheim, I.A. Cowgill and S.E. Mohan. (2007) Lumbar ligamentum flavum hypertrophy is due to accumulation of inflammation related scar tissue. SPINE 32:2805-2811.
J.M. Paranjape, D. Xu, D.M. Kushner, J. Okicki, D. Lindner, H. Cramer, R.H. Silverman, and D.W. Leaman. (2006) Assessing human telomerase RNA degradation by 2-5A- antisense chimeras in a cell-free system, tumor cells and murine xenografts. Oligonucleotides, 16:225-240.
Reu, F., Bae, S., Cherkassky, L., Leaman, D.W., Beauliieu, N., Macleod, R., and E. Borden. (2006). Overcoming resistance to interferon-induced apoptosis of renal cancer and melanoma cells by DNA demethylation. J. Clin. Oncol. (Epub Jun 2006).
Reu, F., D.W. Leaman, Ratan Maitra, Soo In Bae, Leonid Cherkassky, Mark W. Fox, Donald R. Repinski, Normand Beaulieu, Mamta Chawla-Sarkar, A. Robert MacLeod, Ernest C. Borden. (2006) Expression of RASSF1A, an epigenetically silenced tumor suppressor, overcomes resistance to apoptosis induction by interferons. Cancer Res. 66:2785-2793.
Mohammad, M.K., B. Slotterbeck, M. Morran, D.W. Leaman, H. von Grafenstein, S-C. Hong, M.F. McInerney. (2006) Dysregulated Toll Like Receptors in Bone Marrow Derived Macrophages at the Onset of Diabetes in the Nonobese Diabetic Mouse. Int. Immunol. 18:1101-1113.
Taylor KL, RK Oates, R Grane, D.W. Leaman, EC Borden, and DJ Lindner. (2006) IFN-alpha1,8 Inhibits Tumor-Induced Angiogenesis in Murine Angiosarcomas. J Interferon Cytokine Res. 26:353-361.
Leaman, D.W., S. Rosebeck and E.C. Borden. (2005) Biological and Clinical Properties of Type I Interferons. In “Immunotherapy of Cancer”, Humana Press. pp 365-396.
Leaman, D.W. (2005). 2-5A Antisense Treatment of Respiratory Syncytial Virus. Current Opinions in Pharmacology, 5:502-507.
Sun, Y. and D.W. Leaman. (2005) Involvement of Noxa in cellular apoptotic responses to interferon, double-stranded RNA and virus infection. J. Biol. Chem. 280:15561-15568.
Sairyo, K., Biyani, A., Goel, V., Leaman, D.W., Booth Jr., R., Thomas, J., Gehling, D., Vishnubhotla, S., Long, R. and N. Ebraheim. (2005). Pathomechanism of ligamentum flavum hypertrophy: A multidisciplinary investigation based on clinical, biochemical, histological and biological assessments. SPINE, 30:2649-2656.
Sun, Y and D.W. Leaman. (2004) Ectopic expression of Toll-like receptor 3 (TLR3) overcomes the double-stranded RNA (dsRNA) signaling defects of P2.1 cells. J. IFN Cytokine Res. 24:350-361.
Sarkar, S., D. W. Leaman, S. Gupta, P. Sil, D. Young, A. Morehead, D. Mukherjee, Y. Sun, N. Ratliff, M. Rayborn, J. Hollyfield, and S. Sen. (2004) Cardiac Over-expression of Myotrophin Triggers Myocardial Hypertrophy and Heart Failure in Transgenic Mice. J. Biol. Chem. 279:20422-20434.
P. Madasamy, R. V. Sairam, R. Myers, H. Weirich, B. Smith, D.W. Leaman, S.L. Goldman. (2004) Microarray Analysis of Nitric Oxide Responsive Transcripts in Arabidopsis. Plant Biotechnology J. 2:359-366.
Leaman, D.W., M. Chawla-Sarkar, B. Jacobs, K. Vyas, Y. Sun, A. Ozdemir, T. Yi, B. Williams and E.C. Borden. (2003) Novel Growth and Death Related Interferon Stimulated Genes (ISGs) in Melanoma: Greater Potency of IFN-beta compared with IFN-alpha. J. IFN and Cytokine Res. 23:745-756
Vyas, K, D. L. Brassard, M. M. Y. Sun, M. J. Grace, E. C. Borden and D.W. Leaman. (2003). Biologic activity of polyethylene glycol12000-IFN- alpha 2b (PEG-IFN- alpha 2b) compared to IFN-alpha2b: Gene modulatory and anti-growth effects in tumor cells. J. Immunother. 26:202-211.
Leaman, D.W., M. Chawla-Sarkar, K. Vyas, M. Reheman, S. Toji, K Tamai and E.C. Borden. (2002). Identification of X-linked Inhibitor of Apoptosis-Associated Factor-1 (XAF1) as an Interferon-stimulated gene that augments TRAIL/Apo2L-induced apoptosis. J. Biol. Chem. 277:28504-28511.
Chawla-Sarkar, M., D. W. Leaman, B. S. Jacobs and E.C. Borden. (2002) IFN-b pretreatment sensitizes human melanoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) induced apoptosis. J. Immunol. 169:847-855.