Wasif Khan, Ph.D.
Professor of Microbiology & Immunology
Description of Research
The primary focus of Dr. Khan's research is to understand molecular control of B-lymphocyte homeostasis in health and disease. His major interest in cancer research is to advance knowledge as to how intracellular signaling contributes to initiation and maintenance of B lymphoma cells. Three B-cell surface receptors, BCR, Baff-R and TLRs, play an indispensable role in maintaining and/or inducing intracellular signaling that regulates B cell survival and proliferation. The regulation of B cell proliferation and survival is necessary for immune responses. Dysregulation of these processes contribute to B cell-associated autoimmune diseases such as type 1 diabetes (T1D) and systemic lupus erythematosus (SLE or Lupus) and B-cell malignancies.
The overall hypothesis is that understanding molecular mechanisms of these key signaling pathways and their cross-talk hold the key to developing novel therapeutic approaches to treat non-Hodgkin's B cell lymphoma and autoimmune diseases. Indeed, Dr. Khan's findings suggest that BCR and BAFF-R mediate signaling that endow B cells resistance to apoptosis and promote proliferation. One of Dr. Khan's lab's recent findings is that BCR and BAFF-R signaling cross-talk is mediated by Btk, and that this kinase also activates transcription factor NF-kB downstream of both receptors. This laid the foundation for the use of Btk as a therapeutic target for B cell lymphomas and autoimmune diseases. Currently, Btk inhibitors are under clinical trial for the treatment of autoimmune diseases as well as B cell lymphomas.
- Discovered that Bruton’s tyrosine kinase (Btk) provides a molecular link between B cell antigen receptor (BCR) and transcription factor NF-kB
- Discovered that Btk mediated activation of NF-kB involves Btk-dependent activation of phospholipase C-gamma2, lipid second messengers (DAG and CA2+) and I kappaB kinase (IKK) complex
- Discovered that Btk couples BAFF-R signaling to the activation of the classical NF-kB pathway and indirectly diminishes the alternative NF-kB pathway
- Identified c-Rel as a key transcription factor to regulate BAFF-R and p100 gene expression and provides a central mechanism for late transitional B cell (T2) survival and maturation, but not in the apoptosis sensitive early transitional (T1) B cells that are subject to negative selection
Selected Cancer-Related Publications
- Tassi I, Cella M, Castro I, Gilfillan S, Khan WN, Colonna M. Requirement of phospholipase C-gamma2 (PLCgamma2) for Dectin-1-induced antigen presentation and induction of TH1/TH17 polarization. Eur J Immunol 39:1369-78, 2009. Read more »
- Castro I, Wright JA, Damdinsuren B, Hoek KL, Carlesso G, Shinners NP, Gerstein RM, Woodland RT, Sen R, Khan WN. B cell receptor-mediated sustained c-Rel activation facilitates late transitional B cell survival through control of B cell activating factor receptor and NF-kappaB2. J Immunol 182:7729-37, 2009. Read more »
- Zuo Y, Yancey P, Castro I, Khan W, Motojima M, Ichikawa I, Fogo AB, Linton MF, Fazio S, Kon V. Renal dysfunction potentiates foam cell formation by repressing ABCA1. Arterioscler Thromb Vasc Biol 29:1277-82,2009. Read more »
- Khan WN. B cell receptor and BAFF receptor signaling regulation of B cell homeostasis. J Immunol 183:3561-7,2009. Read more »
Collaborating in the Multidisciplinary Research Program(s):