Jianguo Tao

Moffitt Cancer Center, Tampa, Florida, United States

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Publications (32)252.68 Total impact

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    ABSTRACT: APCs are critical in T cell activation and in the induction of T cell tolerance. Epigenetic modifications of specific genes in the APC play a key role in this process, and among them histone deacetylases (HDACs) have emerged as key participants. HDAC6, one of the members of this family of enzymes, has been shown to be involved in regulation of inflammatory and immune responses. In this study, to our knowledge we show for the first time that genetic or pharmacologic disruption of HDAC6 in macrophages and dendritic cells results in diminished production of the immunosuppressive cytokine IL-10 and induction of inflammatory APCs that effectively activate Ag-specific naive T cells and restore the responsiveness of anergic CD4(+) T cells. Mechanistically, we have found that HDAC6 forms a previously unknown molecular complex with STAT3, association that was detected in both the cytoplasmic and nuclear compartments of the APC. By using HDAC6 recombinant mutants we identified the domain comprising amino acids 503-840 as being required for HDAC6 interaction with STAT3. Furthermore, by re-chromatin immunoprecipitation we confirmed that HDAC6 and STAT3 are both recruited to the same DNA sequence within the Il10 gene promoter. Of note, disruption of this complex by knocking down HDAC6 resulted in decreased STAT3 phosphorylation-but no changes in STAT3 acetylation-as well as diminished recruitment of STAT3 to the Il10 gene promoter region. The additional demonstration that a selective HDAC6 inhibitor disrupts this STAT3/IL-10 tolerogenic axis points to HDAC6 as a novel molecular target in APCs to overcome immune tolerance and tips the balance toward T cell immunity.
    The Journal of Immunology 08/2014; · 5.36 Impact Factor
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    ABSTRACT: Wnt/β-catenin signaling underlies the pathogenesis of a broad range of human cancers, including the deadly plasma cell cancer multiple myeloma. In this study, we report that downregulation of the tumor suppressor microRNA miR-30-5p is a frequent pathogenetic event in multiple myeloma. Evidence was developed that miR-30-5p downregulation occurs as a result of interaction between multiple myeloma cells and bone marrow stromal cells, which in turn enhances expression of BCL9, a transcriptional coactivator of the Wnt signaling pathway known to promote multiple myeloma cell proliferation, survival, migration, drug resistance, and formation of multiple myeloma cancer stem cells. The potential for clinical translation of strategies to re-express miR-30-5p as a therapeutic approach was further encouraged by the capacity of miR-30c and miR-30 mix to reduce tumor burden and metastatic potential in vivo in three murine xenograft models of human multiple myeloma without adversely affecting associated bone disease. Together, our findings offer a preclinical rationale to explore miR-30-5p delivery as an effective therapeutic strategy to eradicate multiple myeloma cells in vivo. Cancer Res; 74(6); 1-13. ©2014 AACR.
    Cancer Research 03/2014; · 9.28 Impact Factor
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    ABSTRACT: MYC (c-Myc) deregulation has been frequently associated with aggressive lymphomas and adverse clinical outcome in B-cell malignancies. MYC has been implicated in controlling the expression of miRNAs, and MYC-regulated miRNAs affect virtually all aspects of the hallmarks of MYC-driven lymphomas. Increasing evidence has indicated that there is significant cross-talk between MYC and miRNAs, with MYC regulating expression of a number of miRNAs, resulting in widespread repression of miRNA and, at the same time, MYC being subjected to regulation by miRNAs, leading to sustained MYC activity and the corresponding MYC downstream pathways. Thus, these combined effects of MYC overexpression and downregulation of miRNAs play a central regulatory role in the MYC oncogenic pathways and MYC-driven lymphomagenesis. Here, we provide biological insight on the function of MYC-regulated miRNAs, the mechanisms of MYC-induced miRNA repression, and the complicated feedback circuitry underlying lymphoma progression, as well as potential therapeutic targets in aggressive B-cell lymphomas.
    Cell cycle (Georgetown, Tex.) 01/2014; 13(2). · 5.24 Impact Factor
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    Xiaohong Zhao, Xinwei Zhang, Jianguo Tao
    Oncotarget 11/2013; · 6.63 Impact Factor
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    ABSTRACT: A dynamic interaction occurs between the lymphoma cell and its microenvironment, with each profoundly influencing the behavior of the other. Here, using a clonogenic coculture growth system and a xenograft mouse model, we demonstrated that adhesion of mantle cell lymphoma (MCL) and other non-Hodgkin lymphoma cells to lymphoma stromal cells confers drug resistance, clonogenicity, and induction of histone deacetylase 6 (HDAC6). Furthermore, stroma triggered a c-Myc/miR-548m feed-forward loop, linking sustained c-Myc activation, miR-548m downregulation, and subsequent HDAC6 upregulation and stroma-mediated cell survival and lymphoma progression in lymphoma cell lines, primary MCL and other B cell lymphoma cell lines. Treatment with an HDAC6-selective inhibitor alone or in synergy with a c-Myc inhibitor enhanced cell death, abolished cell adhesion-mediated drug resistance, and suppressed clonogenicity and lymphoma growth ex vivo and in vivo. Together, these data suggest that the lymphoma-stroma interaction in the lymphoma microenvironment directly impacts the biology of lymphoma through genetic and epigenetic regulation, with HDAC6 and c-Myc as potential therapeutic targets.
    The Journal of clinical investigation 10/2013; · 15.39 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):4944-4944. · 9.28 Impact Factor
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    ABSTRACT: c-MYC (hereafter MYC) overexpression has been recognized in aggressive B-cell lymphomas and linked to adverse prognosis. MYC activation results in widespread repression of miRNA expression and associated lymphoma aggressive progression. Our recent study identified a MYC-miRNAs-EZH2 feed-forward loop linking over-expression of MYC, EZH2, and miRNA repression. Here, using a novel small-molecule BET bromodomain inhibitor, JQ1 and the EZH2 inhibitor, DZNep, we demonstrated that combined treatment of JQ1 and DZNep cooperatively disrupted MYC activation, resulting in a greater restoration of miR-26a expression and synergistically suppressed lymphoma growth and clonogenicity in aggressive lymphoma cells. Furthermore, CHIP assay demonstrated that MYC recruited EZH2 to miR-26a promoter and cooperatively repressed miR-26a expression in aggressive lymphoma cell lines as well as primary lymphoma cells. Loss or gain-of-function approaches revealed that miR-26a functioned as a tumor suppressor miRNA and mediated the combinatorial effects of JQ1 and DZNep. These findings represent a novel promising approach for silencing MYC-miRNA-EZH2 amplification loop for combinatorial therapy of aggressive B-cell lymphomas.Leukemia accepted article preview online, 29 March 2013; doi:10.1038/leu.2013.94.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 03/2013; · 10.16 Impact Factor
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    Yizhuo Zhang, Xiaohong Zhao, Jianguo Tao
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    ABSTRACT: Functional identification of Myc activation mechanisms and its interplay with other survival pathways such as BCR will allow to gain insight into lymphoma survival and progression and provide novel biological targets for aggressive lymphomas.
    Oncotarget 11/2012; · 6.63 Impact Factor
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    ABSTRACT: We investigated the transcriptional and epigenetic repression of miR-29 by MYC, HDAC3, and EZH2 in mantle cell lymphoma and other MYC-associated lymphomas. We demonstrate that miR-29 is repressed by MYC through a corepressor complex with HDAC3 and EZH2. MYC contributes to EZH2 upregulation via repression of the EZH2 targeting miR-26a, and EZH2 induces MYC via inhibition of the MYC targeting miR-494 to create positive feedback. Combined inhibition of HDAC3 and EZH2 cooperatively disrupted the MYC-EZH2-miR-29 axis, resulting in restoration of miR-29 expression, downregulation of miR-29-targeted genes, and lymphoma growth suppression in vitro and in vivo. These findings define a MYC-mediated miRNA repression mechanism, shed light on MYC lymphomagenesis mechanisms, and reveal promising therapeutic targets for aggressive B-cell malignancies.
    Cancer cell 10/2012; 22(4):506-23. · 25.29 Impact Factor
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    ABSTRACT: PURPOSE: A deregulated epigenome contributes to the transformed phenotype of Mantle Cell Lymphoma (MCL). This involves activity of the polycomb repressive complex (PRC)2, containing three core proteins EZH2, SUZ12 and EED, in which the SET domain of EZH2 mediates the histone methyltransferase activity. We determined the effects of 3-Deazaneplanocin A (DZNep), an S-adenosylhomocysteine hydrolase inhibitor and/or pan-histone deacetylase inhibitor, panobinostat (PS) on cultured and primary MCL cells. EXPERIMENTAL DESIGN: Following treatment with DZNep and/or panobinostat, apoptosis, and the levels and activity of EZH2 and PRC2 proteins in cultured and primary MCL cells were determined. RESULTS: Treatment with DZNep depleted EZH2, SUZ12 and 3MeK27H3 in the cultured human MCL cells. DZNep also increased expression of p21, p27 and FBXO32, while depleting Cyclin D1 and Cyclin E1 levels in MCL cells. In addition, DZNep treatment induced cell cycle arrest and apoptosis in cultured and primary MCL cells. Further, as compared to treatment with each agent alone, co-treatment with DZNep and PS caused greater depletion of EZH2, SUZ12, 3MeK27H3 and Cyclin D1 levels, but induced greater expression of FBXO32, p16, p21 and p27. Combined treatment with DZNep and PS synergistically induced apoptosis of cultured and primary MCL cells but relatively spared normal CD34+ cells. Co-treatment with DZNep and PS also caused significantly greater inhibition of tumor growth of JeKo-1 xenografts in NOD/SCID mice. CONCLUSIONS: These preclinical in vitro and in vivo findings demonstrate that co-treatment with DZNep and PS is an active combined epigenetic therapy worthy of further in vivo testing against MCL.
    Clinical Cancer Research 08/2012; · 8.19 Impact Factor
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    ABSTRACT: Mantle cell lymphoma (MCL) is an aggressive and incurable subtype of B-cell non-Hodgkin lymphomas. Although patients often respond initially to first-line treatment with chemotherapy plus monoclonal antibodies, relapse and decreased response to further lines of treatment eventually occurs. Harnessing the immune system to elicit its exquisite specificity and long-lasting protection might provide sustained MCL immunity that could potentially eradicate residual malignant cells responsible for disease relapse. Here, we show that genetic or pharmacologic disruption of Stat3 in malignant B cells augments their immunogenicity leading to better activation of antigen-specific CD4(+) T cells and restoration of responsiveness of tolerized T cells. In addition, treatment of MCL-bearing mice with a specific Stat3 inhibitor resulted in decreased Stat3 phosphorylation in malignant B cells and anti-lymphoma immunity in vivo. Our findings therefore indicate that Stat3 inhibition may represent a therapeutic strategy to overcome tolerance to tumor antigens and elicit a strong immunity against MCL and other B-cell malignancies.
    Cancer Research 06/2012; 72(17):4440-8. · 9.28 Impact Factor
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    ABSTRACT: The role of HDACs in cell biology, initially limited to their effects upon histones, encompasses now more complex regulatory functions that are dependent on their tissue expression, cellular compartment distribution and the stage of cellular differentiation. Not surprisingly, HDACs have been shown to play important roles in normal B-cell biology and, aberrant expression of these proteins has been found in some B-cell malignancies1. However, the role of specific HDACs in regulation of pro-survival and cell-cycling genes in MCL and CLL still remains poorly understood. We therefore evaluated by RT-PCR the mRNA expression of specific HDACs in MCL and CLL cell lines and in primary cells from patients with these B-cell malignancies. Our analysis revealed a unique and opposing expression of HDAC10 and HDAC11 in these malignant B-cells. While HDAC11 over-expression was frequently found in MCL and CLL cells, in particular in patients with aggressive disease, an almost complete abrogation of HDAC10 was observed in malignant B-cells as compared to normal B-cell controls. These findings led us to explore the biological consequences of manipulating HDAC11 and HDAC10 in MCL and CLL cells. First, knocking-down HDAC11 (HDAC11KD) using lentiviral shRNA resulted in downregulation of cyclin D1, Cdkn1a (p21) and bcl-2. Furthermore, HDAC11KD MCL or CLL cells displayed a slower cell proliferation relative to non-target shRNA control cells. Cell cycle analysis revealed that HDAC11KD clones are arrested in G1. Conversely, over-expression of HDAC11 in the MCL cell line Z138c or in the CLL cell line MEC1 resulted in enhanced cell survival and increased proliferative capacity. Mechanistically, we have recently found that HDAC11 over-expression is associated with increased phosphorylation of STAT3, a known survival pathway in malignant B-cells. Second, HDAC10 belongs to the class II HDAC family and its biological functions remain largely unknown. Similar to our results in aggressive MCL and CLL, a decreased HDAC10 expression has been reported in patients with aggressive solid tumors2, suggesting that loss of HDAC10 expression might confer a survival advantage to malignant cells. Indeed, over-expression of HDAC10 in Z138c and MEC1 cells resulted in a rapid induction of cell death in vitro with only 5% of cells being alive at 48 hours. Our results highlight the need for a better understanding of the expression/function of specific HDACs in MCL and CLL biology. The findings of opposing roles for HDAC11 and HDAC10 in influencing cell survival and proliferation might explain the limited efficacy of pan-HDAC inhibitors (with their indiscriminate inhibition of multiple HDACs) in these B-cell malignancies, and provide support for the development of isotype-selective inhibitors targeting HDAC11.
    American Society of Hematology, 2011 Annual Meeting; 11/2011
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    ABSTRACT: Our recent study demonstrated miR-15a/16-1 downregulation in mantle cell lymphoma (MCL). Here, we investigated mechanisms of miR-15a/16-1 transcriptional repression and its epigenetic regulation by c-Myc and histone deacetylase (HDAC) in MCL. c-Myc expression was detected in MCL cell lines and in the primary MCL samples, and pri-miR-15a/16-1 mRNAs were significantly upregulated in Mino and Jeko-1 cells with c-Myc knockdown by small interfering RNAs (siRNAs). Our co-immunoprecipitation analysis showed that c-Myc interacted with HDAC3. Moreover, using chromatin immunoprecipitation, we demonstrated that both c-Myc and HDAC3 co-localized to the two promoters of the miR-15a/16-1 cluster gene, DLEU2, and inhibition of HDAC3 increased histone acetylation of the DLEU2 promoters. Luciferase reporter assay confirmed the dependence of Myc-mediated DLEU2 transcriptional repression on HDAC3. Treatment with the pan-HDAC inhibitor, suberoylanilide hydroxamic acid and HDAC3 siRNA resulted in increased miR-15a/16-1 expression. The regulatory mechanism of miR-15a/16-1 was further demonstrated in Burkitt lymphoma and Myc overexpressing cell lines. These findings highlight the role of HDAC3 in Myc-induced miR-15a/16-1 changes and reveal novel mechanisms for c-Myc-driven microRNA suppression and malignant transformation in aggressive B-cell malignancies.
    Oncogene 10/2011; 31(24):3002-8. · 8.56 Impact Factor
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    ABSTRACT: The past several years have witnessed a significant advancement in the elucidation of the molecular pathogenesis of tumors derived from B-lymphocytes. This progress has been the result of better understanding of the molecular basis of normal B-cell development from a progenitor B-cell to memory B-cell or plasma cell and how aberrations at these particular stages lead to a specific subtype of B-cell lymphoma displaying enhanced cell growth and proliferation, apoptosis inhibition and/or impaired differentiation. Here, we review the molecular principles of B-cell lymphomagenesis and how this knowledge is paving the way for the development of novel molecularly based therapeutic approaches for B-cell malignancies.
    Advances in Malignant Hematology, 03/2011: pages 266 - 273; , ISBN: 9781444394016
  • BLOOD; 01/2011
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    ABSTRACT: Mounting evidence now suggests that dynamic interactions between the cancer cell and its local and systemic microenvironment play a critical role in tumor development and that all of the clinical properties of a tumor, including response to therapy, depend heavily on the tumor stroma. We have much less understanding of the biology and genetics of stroma-tumor interactions than we do of tumor cells. Despite recent advances in the treatment of cancer, cancer still remains incurable, largely because of the emergence of drug-resistant tumor cells. Hematologic malignancies arise from defects in normal hematopoiesis and are often associated with aberrant expression of growth and survival factors, such as TGF-□, VEGF, bFGF, IL-6, and BAFF. These growth factors have also been shown to be involved in dysregulated apoptosis. Once a hematopoietic cell becomes malignant, these growth factors can be produced by both the tumor cell as well as by cells surrounding the tumor. These surrounding cells, such as bone marrow stromal cells, together with the extracellular matrix, cytokines and growth factors, and blood vessels, comprise the tumor microenvironment. This microenvironment provides a safe haven for the tumor cells to grow, and, following chemotherapeutic treatment, contributes the emergence of minimal residual disease (MRD), where a small number of drug resistant tumor cells survive cytotoxic stress. These drug resistant tumor cells, which often exhibit upregulation of anti-apoptotic pathways, are typically the cause of relapse of hematologic diseases. Thus, targeting these tumor cells along with the tumor microenvironment in which the tumor cells reside is vital in overcoming the devastating effects associated with hematologic malignancies. KeywordsDrug resistance-Leukemia-Lymphoma-Multiple myeloma-Tumor microenvironment
    12/2010: pages 215-233;
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    ABSTRACT: Follicular dendritic cells (FDCs), an essential component of the lymph node microenvironment, regulate and support B-lymphocyte differentiation, survival, and lymphoma progression. Here, we demonstrate that adhesion of mantle cell lymphoma and other non-Hodgkin lymphoma cells to FDCs reduces cell apoptosis and is associated with decreased levels of the proapoptotic protein, Bim. Bim down-regulation is posttranscriptionally regulated via up-regulation of microRNA-181a (miR-181a). miR-181a overexpression decreases, whereas miR-181a inhibition increases Bim levels by directly targeting Bim. Furthermore, we found that cell adhesion-up-regulated miR-181a contributes to FDC-mediated cell survival through Bim down-regulation, implicating miR-181a as an upstream effector of the Bim-apoptosis signaling pathway. miR-181a inhibition and Bim upregulation significantly suppressed FDC-mediated protection against apoptosis in lymphoma cell lines and primary lymphoma cells. Thus, FDCs protect B-cell lymphoma cells against apoptosis, in part through activation of a miR-181a-dependent mechanism involving down-regulation of Bim expression. We demonstrate, for the first time, that cell-cell contact controls tumor cell survival and apoptosis via microRNA in mantle cell and other non-Hodgkin lymphomas. Regulation of microRNAs by B-cell-FDC interaction may support B-cell survival, representing a novel molecular mechanism for cell adhesion-mediated drug resistance and a potential therapeutic target in B-cell lymphomas.
    Blood 12/2010; 116(24):5228-36. · 9.78 Impact Factor
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    ABSTRACT: B-cell lymphoma 6 (BCL6) and PR domain containing 1 (PRDM1) are considered as master regulators for germinal center (GC) formation and terminal B-cell differentiation. Dysregulation of BCL6 and PRDM1 has been associated with lymphomagenesis. Here, we show for the first time that direct cell-cell contact between follicular dendritic cells (FDC) and B-lymphocytes, by influencing the expression of a set of microRNAs (miRNAs), regulates the expression of BCL6 and PRDM1. We identify that, on cell adhesion to FDC, FDC induces upregulation of PRDM1 expression through downregulation of miR-9 and let-7 families and induces downregulation of BCL-6 through upregulation of miR-30 family in B-lymphocytes and lymphoma cells. We further demonstrate that the miR-30 family directly controls BCL-6 expression and miR-9-1 and let-7a directly control PRDM-1 expression through targeting their 3'UTR, mediating the FDC effect. Our studies define a novel regulatory mechanism in which the FDC, through induction of miRNAs in B-lymphocytes, orchestrates the regulation of transcription factors, promotes germinal center B-cell survival and differentiation. Dysregulation of miRNAs may interfere with B-cell survival and maturation, thus representing a novel molecular mechanism, as well as a potential therapeutic target in B-cell lymphomas.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2010; 25(1):145-52. · 10.16 Impact Factor
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    ABSTRACT: Bortezomib induces unfolded protein response (UPR) and endoplasmic reticulum stress, as well as exhibits clinical activity in patients with relapsed and refractory mantle cell lymphoma (MCL). Here, we determined the molecular basis of the improved in vitro and in vivo activity of the combination of the pan-histone deacetylase inhibitor panobinostat and bortezomib against human, cultured, and primary MCL cells. Immunoblot analyses, reverse transcription-PCR, and immunofluorescent and electron microscopy were used to determine the effects of panobinostat on bortezomib-induced aggresome formation and endoplasmic reticulum stress in MCL cells. Treatment with panobinostat induced heat shock protein 90 acetylation; depleted the levels of heat shock protein 90 client proteins, cyclin-dependent kinase 4, c-RAF, and AKT; and abrogated bortezomib-induced aggresome formation in MCL cells. Panobinostat also induced lethal UPR, associated with induction of CAAT/enhancer binding protein homologous protein (CHOP). Conversely, knockdown of CHOP attenuated panobinostat-induced cell death of MCL cells. Compared with each agent alone, cotreatment with panobinostat increased bortezomib-induced expression of CHOP and NOXA, as well as increased bortezomib-induced UPR and apoptosis of cultured and primary MCL cells. Cotreatment with panobinostat also increased bortezomib-mediated in vivo tumor growth inhibition and improved survival of mice bearing human Z138C MCL cell xenograft. These findings suggest that increased UPR and induction of CHOP are involved in enhanced anti-MCL activity of the combination of panobinostat and bortezomib.
    Clinical Cancer Research 10/2010; 16(19):4742-54. · 8.19 Impact Factor
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    ABSTRACT: Mantle cell lymphoma (MCL) is an aggressive form of B-cell lymphoma with a poor disease-free survival rate. The proteasome inhibitor bortezomib is approved for the treatment of relapsed and refractory MCL and has efficacy in about 30% of patients. However, the precise mechanism of action of bortezomib is not well understood. This report establishes a requirement for the transcription repressor PR domain zinc finger protein 1 (PRDM1, Blimp1) in the response to bortezomib. Bortezomib rapidly induces transcription of PRDM1 as part of the apoptotic response in both cell lines and primary MCL tumor cells. Knockdown of PRDM1 blocks activation of NOXA and inhibits apoptosis, whereas ectopic expression of PRDM1 alone leads to apoptosis in MCL. Two novel direct targets of PRDM1 were identified in MCL cells: MKI67 (Ki67) and proliferating cell nuclear antigen (PCNA). Both MKI67 and PCNA are required for proliferation and survival. Chromatin immunoprecipitation and knockdown studies reveal that specific repression of MKI67 and PCNA is mediated by PRDM1 in response to bortezomib. Furthermore, promoter studies and mutation/deletion analysis show that PRDM1 functions through specific sites in the PCNA proximal promoter and an MKI67 distal upstream repression domain. Together, these findings establish PRDM1 as a key mediator of bortezomib activity in MCL.
    Molecular Cancer Research 06/2010; 8(6):907-18. · 4.35 Impact Factor

Publication Stats

934 Citations
252.68 Total Impact Points

Institutions

  • 2009–2014
    • Moffitt Cancer Center
      • Department of Immunology
      Tampa, Florida, United States
  • 2007–2013
    • University of South Florida
      • Department of Oncologic Sciences
      Tampa, Florida, United States
  • 2012
    • University of Kansas
      Lawrence, Kansas, United States
    • Tianjin Medical University Cancer Institute and Hospital
      T’ien-ching-shih, Tianjin Shi, China
  • 2010
    • Georgia Health Sciences University
      Augusta, Georgia, United States
  • 2002
    • University of Pennsylvania
      Philadelphia, Pennsylvania, United States