Associate Professor, Department of Cell Biology
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 filelds to address the mechanims 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 transformtion 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 ABC-DLBCL?
2. What is the mechanistic basis underlying the survival disparity between the two DLBCL subtypes? Can a better understanding here lead to improved treatment strategies for ABC-DLBCL patients?
3. How is the expression status of BCL6 coupled to B cell differentiation control?
4. The role of Bcl6 as a mechatoblic regulator in the liver.
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