Mathias G. Lichtenheld, M.D.

Associate Professor of Microbiology and Immunology
Director Interdisciplinary Biomedical Graduate Studies
Room 738 (office), Room 708 (lab)
Batchelor Children's Research Institute
1580 NW 10th Avenue
Telephone: 305-243-3301
Fax: 305- 243-7211
Email: mlichten@med.miami.edu

Research Interests:

Overview:
The goal of our laboratory is to identify novel drug targets that can be used to promote tumor rejection and lysis of virally infected cells through immunological and pharmacological strategies. To that end, we primarily characterize the molecular controls of cytotoxic immune responses against cancer and viral infections. We also investigate how drugs that are already available induce immune cell activation and cell death of cancer. We pursue these questions at the basic science level in order to provide answers that will be necessary for molecular medicine, the future of translational research. Thus, we employ state-of-the-art molecular biology approaches and develop our own strategies where needed.

How do the Transcriptional Territories of the Lymphocyte’s Killer Genes Function? Cytotoxic lymphocytes carry self-contained killer molecules to defeat viral infections and tumors. Accordingly, the expression of the channel forming perforin and the pro-apoptotic granzymes is orchestrated elaborately.

Genes are controlled by multiple regulatory domains with different functions that together make up their transcriptional territory. In our most recent landmark study, we discovered all regulatory domains of the human perforin gene. We began this work several years ago with one major goal in mind. We wanted to see all the switches controlling the gene. Using innovative approaches and techniques, we showed where the transcriptional territory of perforin began, where it ended and where its neighbor began. More specifically, perforin’s regulatory domains are spread over 150,000 bp and include a powerful essential control region with locus control region activity (LCR). The cartoon symbolizes the linear localization of the regulatory domains and proposes a three-dimensional model in which they can interact with each other in an active chromatin hub (ACH) but not with the domains of the neighboring genes. Using our unique line of strategies, we have begun to work out the regulation of granzyme B at the same level of coherence.

Which Molecules Control the Expression of Perforin and Granzymes?
Now that we know the regulatory domains, we are able link the cytotoxic effector genes in the nucleus through transcription factors and signaling molecules to specific cell receptors and their ligands. These investigations may discover functionally unique molecules that comprise excellent drug targets to control cytotoxicity. We have shown that one such molecule is Stat5, and we are continuing to establish its key role for cytotoxic lymphocytes using gene transfer of constitutively active and dominant-negative molecules by nucleofection and pseudotyped lentiviral vectors. These experiments have told us that Stat5 targets yet another transcription factor that we believe to be the “holy grail” for cytotoxic lymphocytes.

Direct Tumor Killing and Immune Stimulation of Killer Lymphocytes by Novel Compounds
Perhaps one of the scientifically most interesting malignancies is multiple myeloma (MM) because certain drugs can directly kill the tumor cell and at the same time stimulate the immune system to clear the malignancy as well. Our previous focus was on compounds that inactivate Ras, because it is often dysregulated in multiple myeloma. Surprisingly, we found that they can kill diverse MM cell lines and primary isolates without the necessity of blocking Ras signaling. Our current investigations focus on the compounds that simultaneously stimulate the immune system and we have identified several transcription factors that become rapidly activated in this process. Identification of the drug targets in MM and in lymphocytes should provide us with the Achilles tendon of MM.

Selected Publications:
Pipkin, M.E., Ljutic, B., Cruz-Guilloty, F., Nouzova, M., Rao, A., Zúñiga-Pflücker, J.C. and M.G. Lichtenheld. Chromosome transfer activates and delineates a locus control region for perforin. Immunity 26:1-13, 2007.

Pipkin, M., and M.G. Lichtenheld. 2006. A reliable method to display authentic DNase I hypersensitive sites at long-ranges in single-copy genes from large genomes. Nucleic Acids Res. e34:1-11, 2006.

Beaupre, D.M., Cepero, E., Obeng, E.A., Boise, L.H., and M.G. Lichtenheld. R115777 induces Ras independent apoptosis of myeloma cells via multiple pathways. Mol. Cancer Ther. 3:179-186, 2004.

M.G. Lichtenheld. Control of perforin gene expression: A paradigm for understanding cytotoxic lymphocytes? In: Cytotoxic Cells: Basic Mechanisms and Medical Applications ed. M.V. Sitkovsky and P.A. Henkart. (Philadelphia: Lippincott Williams & Wilkins) pp.123-145, 2000.

Zang, J., Scordi, I., Smyth, M.J. and M.G. Lichtenheld. Interleukin 2 receptor signaling regulates the perforin gene through signal transducer and activator of transcription (Stat)5 activation of two enhancers. J. Exp. Med. 190:1297-1307, 1999.