Department of Cell Biology

B. Hilda Ye, PhD -- Research Interest

Hilda Ye


Associate Professor
Department of Cell Biology
Chanin Bldg., Room 302C
718.430.3339

Hilda.ye@einstein.yu.edu

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   Transcription Regulation and Cell Signaling Control
in Normal and Transformed Germinal Center B cells

 
Molecular pathogenesis of lymphomas situates at the crossroad of B cell differentiation, cancer genetics, transcription regulation, and cell signaling. Thus, to address the questions of how and why various lymphomas initiate and develop in vivo, we constantly draw upon the most recent advances in these perspective filelds, testing and integrating new paradims in our investigations. As each lymphoma entity often corresponds to a specific lymphocyte activation/differentiation state that is phenotypically “frozen” by the malignant transformtion process, our work also provides valuable insights to the regulatory mechanisms that goven the normal immune system. There are three general goals of our research: 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.

BCL6 and the germinal center reaction:

After their first antigen encounter, mature naïve B cells follow one of the two distinct developmental paths: to rapidly differentiate into short-lived plasma cells without T cell help, or to participate in a T-cell dependent process called the germinal center (GC) response which allows some of their selected progenies to become either memory B cells or plasma cells (both short and long term) that produce high affintiy antibodies. GCs are dynamic and specialized structures in the secondary lymphoid organs composed of mostly B cells undergoing rapid clonal expansion. Within GC, the B cell genome is subject to two types of genetic alterations, e.g. Ig class switch recombination (CSR; IgH only) and somatic hypermutation (SHM; both IgH and IgL). Both of these processes are aimed to increase Ig diversity and are dependent upon the mutator enzyme AID (activation induced cytidine deaminase). 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 moment, the sequence and nature of events that coordinate the initiation and termination of GC response is not well understood. Among the few well established facts is the observation that the onset and maintenance of GC reaction critically require the transcription repressor, BCL6. Widely considered to be the master regulator of the GC response, BCL6 maintains the GC-specific gene expression program by silencing genes involved in B cell activation (CD69, CD80, NF-kappaB1), response to DNA damage (p53, ATR), cell-cycle regulation (cyclin D2, p21WAF, p27KIP) and plasma cell differentiation (STAT3, IRF4, and Blimp-1). Thus, neither the memory nor the plasma cell differentiation program can be initiated until BCL6 expression is extinguished by GC exit signals. One of our main interests lies in the functional interplay between BCL6 and STAT3 in late GC reaction and lymphoma B cells.

B cell Non-Hodgkin's lymphoma:

Non-Hodgkin’s lymphoma (NHL) is the 5th most common type of cancer in the U.S. Most of these tumors have a B cell phenotype and are derived from GC B cells. From the genetic point of view, NHL is distinct from non-hematophoietic cancers in that most lymphomas carry recurrent chromosomal translocations while microsatellite instability or genome-wide chromosomal instability is rare. To some extent, this phenomenon is explained by the unique mutagenic cellular environment of GC B cells featuring AID activity. Evidence is accumulating that not only is AID responsible for Ig CSR and SHM, but its mutagenic action can also be targeted to other loci in the genome leading to somatic mutations and chromosomal translocations that underlie many mature 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. There are 3 most common forms of NHL: follicular lymphomas (FL) which carry the hallmark BCL2 translocations, Burkitt’s lymphomas (BL) which are invariably associated with c-Myc translocations, and diffuse large B cell lymphomas (DLBCL) which in nearly half of the case carry translocations or activating mutations deregulating BCL6 expression.

DLBCL accounts for 30-40% of newly NHL cases in the United States and yet up to 80% of NHL mortality due to transformation of FL to DLBCL. 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-kappaB and STAT3, and tends to be refractory to chemotherapeutic treatment. In normal B cells, NF-kappaB activation can be triggered by CD40-CD40L interaction or BCR signaling while STAT3 works downstream of a number of cytokines promoting plasma cell differentiation. In addition, both NF-kappaB and STAT3 are well-known oncogenes with a variety of cancer promoting properties (enhance proliferation, survival, angiogenesis and metastasis). Therefore, the distinct gene expression and cell signaling properties between the two DLBCL subtypes have very important implications in understanding their transformation pathways as well as facilitating development of biology-based, targeted lymphoma therapies.

Ongoing studies are designed to address the following questions:

1. How is the expression status of BCL6 coupled to B cell differentiation control?

2. During late stage GC response, how does cell signaling coordinate the transistion from the BCL6 governed GC program to a Blimp-1-directed plasma cell program?

3. What are the cause and consequences of a constitutively activated STAT3 pathway in ABC-DLBCL?

 
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