1.18 Hillman Cancer Center
5117 Centre Avenue
Pittsburgh, PA 15213
NF-κB is a family of transcription factors that control expression of numerous genes involved in diverse biological processes, including inflammation, immune response, and cell growth. NF-κB activity is normally inhibited by IκBs (Inhibitors of NF-κB) or IκB-like protein p100. Accordingly, NF-κB activation requires IκB degradation or p100 processing to selectively degrade its C-terminal IκB-like domain. The IκB degradation depends on an IκB kinase (IKK) complex, which consists of two catalytic subunits IKKα (IKK1) and IKKβ (IKK2), and one regulatory subunit IKKγ (NEMO), while the p100 processing is specifically mediated by IKKα and its upstream kinase NIK, NF-κB-inducing kinase. These two major mechanisms leading to NF-κB activation are now termed canonical and non-canonical NF-κB signaling pathways, respectively.
Activation of the NF-κB signaling pathways, particularly the canonical signaling pathway, is tightly regulated and rapidly curtailed following the initial activating stimulus. Transient activation of NF-κB is physiologically important because persistent activation of either pathway can result in deleterious or even fatal conditions, such as septic shock, inflammatory diseases, autoimmune diseases, and cancers. Although the molecular mechanisms by which NF-κB is induced under physiological conditions have been well defined, how NF-κB is aberrantly activated for human pathogenesis remains largely unclear. Given the fact that it is unfeasible to block NF-κB activation for disease therapy using ‘classical’ NF-κB inhibitors because of the physiological importance of NF-κB in humans, it is of interest and importance to address the difference in the pathogenic and physiological activation of NF-κB, which is important for the development of novel approaches to specifically target pathogenic NF-κB activation for disease prevention and treatment. Currently, we are energetically studying how NF-κB is constitutively activated for the pathogenesis and therapy resistance of the following diseases and translating this knowledge into clinical settings.
A. Viral Oncogenesis. We are focusing on two NF-κB-dependent oncogenic viruses: human T-cell leukemia virus type I (HTLV-I) and Kaposi's sarcoma herpesvirus/human herpesvirus-8 (KSHV/HHV8). While HTLV-I is the etiologic agent of adult T-cell leukemia/lymphoma (ATL), KSHV causes Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). Interestingly, both HTLV-I and KSHV are often detected in individuals infected with HIV. In fact, KS is the most prevalent malignancy among patients with AIDS. Currently, no effective therapies exist for these fatal diseases.
B. Cellular Oncogenesis. We study the top three deadliest tumors-lung, breast and colon, which account for approximately 241,000 deaths every year in the United States alone. We are investigating how NF-κB is deregulated in tumor cells and tumor microenvironment, particularly tumor-associated inflammatory cells, as well as how deregulated NF-κB promotes the formation, progression, metastasis and chemoradioresistance of these solid tumors. We are also actively investigating human leukemia/lymphomas associated with somatic mutations of the nf-κb2 gene and one hematologic malignancy termed early T-cell precursor acute lymphoblastic leukemia (ETP-ALL), a newly identified type of highly lethal pediatric leukemia with no known cause or cure. Recently, we have established the first reproducible and the only available in vivo model for studying this aggressive childhood leukemia.
2. Inflammatory and Autoimmune Diseases. In addition to tumors, we are also interested in chronic obstructive pulmonary disease (COPD), colitis, multiple sclerosis (MS) and rheumatoid arthritis (RA). In particular, we are investigating the molecular and cellular mechanisms by which NF-κB is able to promote COPD and colitis for the development of lung and colon cancers, but NF-κB-driven MS and RA are not associated with tumorigenesis.
3. Graft-Versus-Host Disease (GVHD). Hematopoietic stem cell transplantation (HSCT) is an effective therapy for patients with a broad range of hematologic malignancies, and is the only potential option for several types of leukemia that no effective therapy exists, such as ATL and EPT-ALL. However, allogeneic HSCT (alloSCT) causes GVHD in approximately 30-70% of patients, increasing morbidity and mortality as well as the cost of care. Given the role of NF-κB in inflammation and inflammation-associated diseases, it is interesting to investigate whether and how NF-κB contributes to the development of GVHD and more importantly to target NF-κB for the prevention of GVHD.
Lei Han - Postdoctoral Associate