Associate Professor, Department of Cell Biology
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?
Huang, X., Meng, B., Iqbal, J., Ding, B.B., Perry, A.M., Cao, W., Smith, L.M., Bi, C., Jiang, C., Greiner, T.C., Weisenburger, D., Rimsza, L., Rosenwald, A., Ott, G., Delabie, J., Campo, E., Braziel, R., Gascoyne, R., Cook, J., Tubbs, R., Jaffe, E., Armitage, J., Vose, J., Staudt, L., McKeithan, T.W., Chan, W., Ye, B.H.*, Fu, K*. Activation of the STAT3 signaling pathway is associated with poor survival in diffuse large B-cell lymphoma patients treated with R-CHOP. (J Clin Oncol., in press, 2013. * Equal contribution authors)
Ye, B.H., Mai, Y. A Bach2 Link between Pre-B Cell Receptor Checkpoint and Pre-B Cell ALL. Cancer Cell. 2013 24(3):282-4. [PDF Full Text]
Ding, B.B., Bi, E., Chen, H., Yu, J.J. and Ye, B.H. IL-21/STAT3 and CD40L/NF-kappaB synergistically promote plasma cell differentiation through upregulation of Blimp-1. J Immunol. 190(4):1827-36, 2013. [PDF Full Text]
Will, B., Zhou, L., Vogler, T.O., Ben-Neriah, S., Schinke, C.,Tamari, R., Yu, Y., Bhagat, T., Bhattacharya, S., Barreyro, L., Heuck, C., Mo, Y., Parekh, S., McMahon, C., Pellagatti, A., Boultwood, J., Montagna, C., Silverman, L., Maciejewski, J., Greally, J.M., Ye, B.H., List, A.F., Steidl, C., Steidl, U., Verma, A, Stem and progenitor cells in myelodysplastic syndromes show aberrant stage specific expansion and harbor genetic and epigenetic alterations. Blood, 120:2076-86, 2012. [PDF Full Text]
Petrich, A., Leshchenko, V., Kuo, P.-Y., Xia, B., Thirukonda, V.K., Ulahannan, N., Gordon, S., Fazzari, M.J., Ye, B.H., Sparano, J., Parekh, S. Akt Inhibitors MK-2206 and Nelfinavir overcome mTOR inhibitor resistance in DLBCL. Clin Cancer Res. 18:2534-44, 2012. [PDF Full Text]
Nahar R, Ramezani-Rad P, Mossner M, Duy C, Cerchietti L, Geng H, Dovat S, Jumaa H, Ye BH, Melnick A, Müschen M. Pre-B cell receptor-mediated activation of BCL6 induces pre-B cell quiescence through transcriptional repression of MYC. Blood. 118:4174-8, 2011. [PDF Full Text]
Hurtz, C., Hatzi, K., Cerchietti, L., Braig, M., Park, E., Kim, Y-M., Herzog, S., Ramezani-Rad, P., Jumaa, H., Müller, M. C., Hofmann, W-K., Hochhaus, A., Ye, B. H., Agarwal, A., Druker, B. J., Shah, N. P., Melnick A. M. and Müschen, M. BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia. J Exp Med. 208:2163-74, 2011. [PDF Full Text]
Duy, C., Hurtz, C., Shojaee, S., Cerchietti, L., Geng, H., Swaminathan, S., Klemm, L., Kweon, S-M., Nahar, R., Braig, M., Park, E., Kim, Y-M., Hofmann, W-K., Herzog, S., Jumaa, H., Koeffler, H. P., Yu, J.J., Heisterkamp, N., Graeber, T. G., Wu, H., Ye, B. H., Melnick, A., & Müschen, M. BCL6 enables survival of Ph+ acute lymphoblastic leukemia cells upon BCR-ABL1 kinase inhibition. Nature, 473:384-388, 2011. [PDF Full Text]
Peled, J.U., Yu, J.J., Venkatesh, J., Bi, E., Ding, B.B., Krupski-Downs, M., Shaknovich, R., Sicinski, P., Diamond, B., Scharff, M.D., Ye, B.H. Requirement for cyclin D3 in germinal center formation and function. Cell Research 20:631-646, 2010.
Duy, C., Yu, J.J., Nahar, R., Swaminathan, S., Kweon, S.-M., Polo, J.M., Valls, E., Klemm, L., Shojaee, S., Cerchietti, L., Schuh, W., Jack, H.-M., Hurtz, C., Ramezani-Rad, P., Herzog, S., Jumaa, H., Koeffler, H.P., de Alborán, I.M., Melnick, A.M., Ye, B.H. and Müschen, M. BCL6 is critical for the development of a diverse primary B cell repertoire. J Exp Med., 207:1209-21, 2010.
Mendez, L.M., Polo, J., Krupski, M., Yu, J.J., Melnick, A., Ye, B.H. CtBP1 is an essential corepressor for BCL6 autoregulation. Mol. Cell. Biol., 28:2175-2186, 2008.
Ding, B.B., Yu, J.J., Yu, Y.-L.R., Mendez, L.M., Shaknovich, R., Zhang, Y, Cattoretti, G., and Ye, B.H. Constitutively activated STAT3 promotes cell proliferation and survival in the activated B cell subtype of diffuse large B-cell lymphoma. Blood 111:1515-1523, 2008.
Wang, X., Ding, B.B., Mendez, L.M., Papetti, M., and Ye, B.H. Re: Torlakovic et al. PU.1 protein expression has a positive linear association with protein expression of germinal centre B cell genes including BCL-6, CD10, CD20 and CD22: identification of PU.1 putative binding sites in the BCL-6 promotor. J Pathol210: 130-131, 2006.
Pixley, F.J., Xiong, Y., Yu, Y.-L.R., Sahai, E., Stanley, E.R., and Ye, B.H. BCL-6 suppresses RhoA activity to alter macrophage morphology and motility. J. Cell Science. 118:1873-1883, 2005.
Li, Z.P., Wang, X., Yu, Y.-L. R., Ding, B.B., Yu, J.J., Dai, X.-M., Naganuma, A., Stanley, E.R., and Ye, B.H. BCL-6 negatively regulates expression of the NF-kB1 p105/p50 subunit. J. Immunol. 174: 205-214, 2005.
Yu, Y.-L.R., Wang, X., Pixley, F.J., Yu, J.J., Dent, A.L., Broxmeyer, H.E., Stanley, E.R., and Ye, B.H. BCL-6 negatively regulates macrophage proliferation by suppressing autocrine IL-6 production. Blood. 105:1111-1784, 2005.
Pasqualucci, L., Migliazza, A., Ye, B. H., Dalla-Favera, R. Transcriptional Deregulation of Mutated BCL6 Alleles by Loss of Negative Autoregulation in Diffuse Large B Cell Lymphoma.Ann NY Acad Sci, 987: 314-315, 2003.
Wang, X., Li, Z.-P., Naganuma, A., Ye, B.H. Negative autoregulation of BCL - 6 is bypassed by genetic alterations in diffuse large B cell lymphoma. Proc Natl Acad Sci U S A. 99:15018-23, 2002.
Ye, B.H. The Role of BCL-6 in normal lymphoid system and non-Hodgkin’s lymphomas. In: Normal and malignant development of blood cells. Ravid, K. and Licht J. (eds) Wiley-Liss, Inc. 2001.
Toney, L.M., Cattoretti, G., Merghoub, T., Pandolfi, P.-P., Dalla-Favera, R., Ye, B.H., Dent, A.L. BCL-6 regulates chemokine gene transcription in macrophages. Nature Imm. 1:214-220, 2000.
Qi, C., Hori. M., Coleman, A.E., Torrey, T.A., Taddesse-Heath, L., Ye, B.H., Chattopadhyay, S.K., Hartley, J.W., Morse, H.C. 3rd. Genomic organisation and expression of BCL6 in murine B-cell lymphomas. Leuk Res. 24:719-732, 2000. [MEDLINE]
Ye, B.H. Role of BCL-6 in the pathogenesis of non-Hodgkin’s lymphoma. Cancer Invest. 18:356-365, 2000. [MEDLINE]
Harris, M.B., Chang, C.C., Berton, M.T., Danial, N.N., Zhang, J., Kuehner, D., Ye, B.H., Kvatyuk, M., Pandolfi, P.P., Cattoretti, G., Dalla-Favera, R., Rothman, P.B. Transcriptional Repression of Stat6-Dependent Interleukin-4-Induced Genes by BCL-6: Specific Regulation of Iε Transcription and Immunoglobulin E Switching. Mol. Cell. Biol.19:7264-7275, 1999.
Niu H., Ye B. H., Dalla-Favera R. Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. Genes Dev. 12:1953-1961, 1998.
Ye, B. H., Cattoretti, G., Zhang, J., Hawe, N., Shen, Q., de Waard, R., Orazi, A., Nouri-Shirazi, M., Chaganti, R.S.K., Rothman, P., Stall, A. M., Pandolfi P.-P., and Dalla-Favera, R. The BCL-6 proto-oncogene controls germinal-center formation and Th2-type inflammation. Nature Genet. 16:611-620, 1997.
Flenghi, L, Bigerna, B., Fizzotti, M., Venturi, S., Pasqualucci, L., Pileri, S., Ye, B. H., Gambacorta, M., Pacini, R., Baroni, C. D., Pescarmona, E., Anagnostopoulos, I., Stein, H., Asdrubali, G., Martelli, M. F., Pelicci, P. G., Dalla-Favera, R., and Falini, B. Monoclonal antibodies PG-B6a and PG-B6p recognize, respectively, a highly conserved and a formol-resistant epitope on the human BCL-6 protein amino-terminal region. Am. J. Pathol. 148:1543-55, 1996.
Chang C.-C., Ye, B. H., Chaganti, RSK., and Dalla-Favera, R. BCL-6, a POZ/Zinc-finger protein, is a sequence specific transcription repressor. Proc. Natl. Acad. Sci. USA. 93:6947-6952, 1996.
Dalla-Favera, R., Ye, B. H., Cattoretti, G., Lo Coco, F., Chang, C.-C., Zhang, J., Migliazza, A., Cechova, K., Niu, H., Chaganti, S., Chen, W., Louie, D. C., Offit, K., and Chaganti, RSK. BCL-6 in diffuse large-cell lymphomas. In: Important Advances in Oncology 1996. DeVita, V. T., Hellman, S., and Rosenberg, S. A. (eds) Lippincott-Raven Publishers, Philadelphia, pp. 139-148, 1996.
Ye, B. H., Chaganti, S., Chang, C.-C., Niu, H., Corradini, P., Chaganti, RSK., and Dalla-Favera, R. Chromosomal translocations cause deregulated BCL6 expression by promoter substitution in B cell lymphoma. EMBO J. 14:6209-6217, 1995.
Ye, B. H., Lo Coco, F., Chang, C.-C., Zhang, J., Migliazza, A., Cechova, K., Knowles, D. M., Offit, K., Chaganti, R.S., and Dalla-Favera, R. Alterations of the BCL-6 gene in diffuse large-cell lymphoma. In: Current Topics in Microbiology & Immunology. M, Potter (ed), 194:101-8, 1995.
Cechova, K., Gu, W., Ye, B. H., Lo Coco, F., Chang, C-C., Zhang, J., Migliazza, A., Mellado, W., Niu, H., and Dalla-Favera, R. Advances in the understanding of the molecular pathogenesis of aggressive B cell lymphomas. In: Normal and Malignant Hematopoiesis: New Advances, Mihichm, E., Metcalf, D. (eds) Plenum Press, pp. 131-154, 1995.
Migliazza, A., Martinotti, S., Chen, W., Fusco, C., Ye, B. H., Knowles, D. M., Offit, K., Chaganti, R.S.K., and Dalla-Favera, R. Frequent somatic hypermutation of the 5' non-coding region of the BCL-6 gene in B-cell lymphoma. Proc. Natl. Acad. Sci. USA. 92:12520-12524, 1995.
Flenghi, L., Ye, B. H., Fizzotti, M., Bigerna, B., Cattoretti, G., Venturi, S., Pacini, R., Pileri, S., Lo Coco, F., Pescarmona, E., Pelicci, P-G., Dalla-Favera, R., and Falini, B. A specific monoclonal antibody (PG-B6) detects expression of the BCL-6 Protein in germinal center B cells. Am. J. Pathol. 147:405-411, 1995.
Cattoretti, G., Chang, C-C., Cechova, K., Zhang, J., Ye, B. H., Falini, B., Louie, C. C., Offit, K., Chaganti, R.S.K., and Dalla-Favera, R. The BCL-6 protein is expressed in germinal center B-cells. Blood86:45-53, 1995.
Offit, K., Lo Coco, F., Louie, D. C., Parsa, N. Z., Leong, D., Portlock, C., Ye, B. H., Lista, F., Filippa, D. A., Rosenbaum, A., Ladanyi, M., Dalla-Favera, R., and Chaganti, R.S.K. Rearrangement of the BCL-6 gene as a prognostic marker in diffuse large cell lymphoma. N.Engl. J. Med. 331:74-80, 1994. [MEDLINE]
Gaidano, G., Lo Coco, F., Ye, B. H., Shibata, D., Levine, A. M., Knowles, D. M., and Dalla-Favera, R. Rearrangements of the BCL-6 gene in acquired immunodeficiency syndrome- associated non-Hodgkin's lymphoma: association with diffuse large-cell subtype. Blood 84:397-402, 1994.
Lo Coco, F., Ye, B. H., Lista, F., Corradini, P., Offit, K., Knowles, D. M., Chaganti, R.S.K., and Dalla-Favera, R. Rearrangements of the BCL-6 gene in diffuse large-cell non Hodgkin's lymphoma. Blood 83:1757-1759, 1994.
Dalla-Favera, R., Ye, B. H., Lo Coco, F., Chang, C-C.,Cechova, K., Zhang, J., Migliazza, A., Mellado, W., Niu, H., Chaganti, S., Chen, W., Offit, K., and Chaganti, R.S.K. BCL-6 and the molecular pathogenesis of B Cell lymphoma. In: Molecular Genetics of Cancer, CSH Symposia on Quantitative Biology, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, Vol. 59, pp. 117-123, 1994.
Dalla-Favera, R., Ye, B. H., Lo Coco, F., Gaidano, G., Lista, F., Knowles, D. M., Louie, D. C., Offit, K., and Chaganti, R.S.K. Identification of genetic lesions associated with diffuse large-cell lymphoma. In: Annals of Oncology 5 (Suppl. 1):S55-60, 1994.
Ye, B. H., Lista, F., Lo Coco, F., Knowles, D. M., Offit, O., Chaganti, R.S.K., and Dalla-Favera, R. Alterations of a zinc-finger encoding gene, BCL-6, in diffuse large-cell lymphoma. Science 262:747-750, 1993.
Ye, B. H., Rao, P. H., Chaganti, R.S.K., and Dalla-Favera, R. Cloning of BCL-6, the locus involved in chromosomal translocations affecting Band 3q27 in B-cell lymphoma. Cancer Res. 53:2732-35, 1993.
More Information About Dr. B. Hilda Ye
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Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Chanin Building, Room 302C
Bronx, NY 10461