Department of Cell Biology
Chanin Bldg., Room 302C
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||Transcription Regulation and Cell Signaling Control in Normal and Lymphoma B cells
Molecular pathogenesis of lymphomas situates at the crossroad of B cell differentiation, cancer genetics, transcription regulation, and cell signaling. Thus, we constantly draw upon the most recent advances in these perspective fields to address the mechanisms responsible for lymphoma initiation and development. As each lymphoma entity often corresponds to a specific lymphocyte activation/differentiation state that is phenotypically “frozen” by the malignant transformation process, our lymphoma-related studies also provide valuable insights to the regulatory mechanisms that goven the normal immune system. Our research has three major goals: to better understand mature B cell development in molecular terms, to decipher how this process is perturbed during lymphomagenesis, and to help develop better lymphoma therapy.
The germinal center (GC) response is a T-cell dependent B cell activation, expansion, and maturation process that has the unique property of generating high affinity antibodies and B cell memory. Because dysregulated GC responses contribute to the development of B cell lymphomas and autoimmune diseases, in-depth understanding of the control mechanisms governing the GC response has both immunological and clinical implications. GCs are dynamic and specialized structures in the secondary lymphoid organs where the B cell genome is subject to two types of genetic alterations catalyzed by AID (activation induced cytidine deaminase), e.g. Ig class switch recombination and somatic hypermutation. Prior to their GC exit, B cells bearing mutated surface Ig molecules undergo positive and negative selections through interaction with two other types of cells in the GC, e.g. follicular dendritic cells and follicular T helper cells. As a result, only those B cells with the proper Ig specificity and affinity are allowed to escape the fate of apoptosis or anergy, gaining license to terminally differentiate into memory or plasma cells. At the single cell level, the acquisition and termination of GC phenotype is the coordinated transcriptional response to various extracellular and intracellular stimuli; yet the precise sequence and nature of events that orchestrate this process is incompletely understood. We are particularly interested in the roles played by two transcriptional factors, BCL6 and STAT3. BCL6 coordinates the initiation of GC response and maintains the GC phenotype by regulating an extensive gene expression program which restricts B cell responsiveness to activation signals, genotoxic stress, and terminal differentiation potential. In the late phase of GC response, BCL6 downregulation triggers the rise of STAT3 expression and activity, which then collaborate with IRF4 to control the commitment step to the plasma cell fate.
Non-Hodgkin’s lymphoma (NHL) is the 5th most common type of cancer in the U.S. Many NHLs have a B cell phenotype and are transformed from normal GC B cells. It is well-documented that not only is AID responsible for Ig CSR and SHM, but its mutagenic action in non-Ig loci can cause tumorigenic mutations and chromosomal translocations in many B cell lymphomas. BCL6, in fact, was initially cloned through its involvement in lymphoma-associated chromosomal translocations and is the most frequently targeted proto-oncogene in NHL. Another important characteristic of mature B cell lymphomas is its heterogeneity. We are particularly interested in diffuse large B cell lymphoma (DLBCL), a heterogeneous type of NHL that accounts for 30-40% of newly diagnosed NHL cases in the U.S. Based upon their gene expression similarities to either normal GC B cells or in vitro activated peripheral blood B cells, DLBCLs are subdivided into 3 groups: the GCB-DLBCL, ABC-DLBCL and an unclassified type III. In general, the GCB group expresses high levels of BCL6 and tends to respond better to conventional chemotherapy, while the ABC group has lower levels of BCL6, constitutively activated NF-kB and STAT3, and tends to be refractory to chemotherapeutic treatment. The distinct immunophenotypic and cell signaling properties of the two DLBCL subtypes have important implications in understanding their transformation pathways as well as facilitating development of biology-based, targeted lymphoma therapies. Our recent studies have focused on the role of STAT3 in post-GC plasma cell differentiation and novel roles in ABC-DLBCL pathogenesis and therapeutic response.
Ongoing studies are designed to address the following questions:
1. What are the cause and consequence of constitutively activated STAT3 in the ABC type of diffuse large B-cell lymphomas (DLBCL)?
2. What is the mechanistic basis underlying the survival disparity between the two major DLBCL subtypes (GCB and ABC)? Can a better understanding here lead to improved treatment strategies for ABC-DLBCL patients?
3. How is the expression and activity of BCL6 fine-tuned by the B cell differentiation process?
4. Can the PAK family kinases be targeted for improved treatment of adult T-cell leukemia/lymphomas (ATLL)?
5. Does Bcl6 play a role outside of the immune system? The current focus here is the role of Bcl6 as a metabolic regulator in the liver.