Publications by authors named "Lan V Pham"

42 Publications

CS2164 and Venetoclax Show Synergistic Antitumoral Activities in High Grade B-Cell Lymphomas With and Rearrangements.

Front Oncol 2021 10;11:618908. Epub 2021 Mar 10.

Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, China.

High-grade B-cell lymphoma with concurrent and rearrangements (HGBL-DHL) is a rare, aggressive mature B-cell malignancy with a high likelihood of treatment failure following front-line immunochemotherapies. Patients with HGBL-DHL who develop a relapsed or refractory disease have little effective therapeutic strategies and show very poor clinical outcomes, thus calling for development of novel therapies for this specific patient population. In this study, we investigated the preclinical anti-lymphoma efficacies and potential mechanism of action of a novel treatment approach, combining the BCL2 inhibitor venetoclax with CS2164, a new orally active multitarget inhibitor, in HGBL-DHL models. This combination therapy exhibited a robust synergistic cytotoxicity against HGBL-DHL cells, evidenced by cooperatively inducing loss of cell viability and promoting cell apoptosis. Moreover, coadministration of CS2164 and venetoclax resulted in significant superior suppression of HGBL-DHL cell growth and remarkably abrogated tumor burden in a HGBL-DHL-xenografted mouse model. The synergistic lethality of CS2164 and venetoclax in HGBL-DHL cells was associated with induction of DNA damage and impairment of DNA repair ability. Of importance, the combined treatment almost abolished the expression of both BCL2 and MYC, two hallmark proteins of HGBL-DHL, and substantially blunted the activity of PI3K/AKT/mTOR signaling cascade. In addition, MCL1 and BCL-XL, two well-characterized contributors for venetoclax resistance, were significantly lessened in the presence of CS2164 and venetoclax, thus leading to the accumulation of proapoptotic proteins BAX and PUMA and then initiating the intrinsic apoptosis pathway. Taken together, these findings suggest that the regimen of CS2164 and venetoclax is highly effective to eliminate HGBL-DHL cells in the preclinical setting, warranting further clinical investigations of this regimen for the treatment of unfavorable HGBL-DHL patients.
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http://dx.doi.org/10.3389/fonc.2021.618908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988232PMC
March 2021

Aggressive B-cell Lymphoma with MYC/TP53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents.

Mol Cancer Res 2021 02 5;19(2):249-260. Epub 2020 Nov 5.

Duke University Medical Center, Division of Hematopathology and Department of Pathology, Durham, North Carolina.

Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with / double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether mutation synergizes with MYC abnormalities ( rearrangement and/or Myc protein overexpression) contributing to HGBCL-like biology and prognosis is not well investigated. In this study, patients with DLBCL with MYC/TP53 abnormalities demonstrated poor clinical outcome, high-grade morphology, and distinct gene expression signatures. To identify more effective therapies for this distinctive DLBCL subset, novel MYC/TP53/BCL-2-targeted agents were investigated in DLBCL cells with MYC/TP53 dual alterations or HGBCL-/-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of // status. Combining INCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced the cytotoxic effects in HGBCL-DH without mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent mutation. Reverse-phase protein arrays revealed the synergistic molecular actions by INCB057643, DS3032b and venetoclax to induce cell-cycle arrest and apoptosis and to inhibit AKT/MEK/ERK/mTOR pathways, as well as potential drug resistance mechanisms mediated by upregulation of Mcl-1 and RAS/RAF/MEK/ERK pathways. In summary, these findings support subclassification of DLBCL/HGBCL with dual MYC/TP53 alterations, which demonstrates distinct pathobiologic features and dismal survival with standard therapy, therefore requiring additional targeted therapies. IMPLICATIONS: The clinical and pharmacologic studies suggest recognizing DLBCL with concomitant mutation and MYC abnormalities as a distinctive entity necessary for precision oncology practice. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/2/249/F1.large.jpg.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092941PMC
February 2021

XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53.

J Hematol Oncol 2020 11 4;13(1):148. Epub 2020 Nov 4.

Division of Hematopathology, Department of Pathology, Duke University Medical Center, Durham, NC, 27710, USA.

The XPO1 inhibitor selinexor was recently approved in relapsed/refractory DLBCL patients but only demonstrated modest anti-DLBCL efficacy, prompting us to investigate the prognostic effect of XPO1 in DLBCL patients and the rational combination therapies in high-risk DLBCL. High XPO1 expression (XPO1) showed significant adverse prognostic impact in 544 studied DLBCL patients, especially in those with BCL2 overexpression. Therapeutic study in 30 DLBCL cell lines with various molecular and genetic background found robust cytotoxicity of selinexor, especially in cells with BCL2-rearranged (BCL2-R) DLBCL or high-grade B-cell lymphoma with MYC/BCL2 double-hit (HGBCL-DH). However, expression of mutant (Mut) p53 significantly reduced the cytotoxicity of selinexor in overall cell lines and the BCL2-R and HGBCL-DH subsets, consistent with the favorable impact of XPO1 observed in Mut-p53-expressing patients. The therapeutic effect of selinexor in HGBCL-DH cells was significantly enhanced when combined with a BET inhibitor INCB057643, overcoming the drug resistance in Mut-p53-expressing cells. Collectively, these data suggest that XPO1 worsens the survival of DLBCL patients with unfavorable prognostic factors such as BCL2 overexpression and double-hit, in line with the higher efficacy of selinexor demonstrated in BCL2-R DLBCL and HGBCL-DH cell lines. Expression of Mut-p53 confers resistance to selinexor treatment, which can be overcome by combined INCB057643 treatment in HGBCL-DH cells. This study provides insight into the XPO1 significance and selinexor efficacy in DLBCL, important for developing combination therapy for relapsed/refractory DLBCL and HGBCL-DH.
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http://dx.doi.org/10.1186/s13045-020-00982-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641823PMC
November 2020

Rational targeted therapeutics for double-hit lymphoma.

Int J Hematol Oncol 2019 Aug 21;8(3):IJH19. Epub 2019 Aug 21.

Center for Immunotherapy Research, Houston Methodist Research Institute, Houston, TX 77030, USA.

"Double-hit lymphomas with MYC and BCL2 translocations can be effectively treated by combined targeting of the driver oncogenes".
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http://dx.doi.org/10.2217/ijh-2019-0009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912852PMC
August 2019

Simultaneous targeting of XPO1 and BCL2 as an effective treatment strategy for double-hit lymphoma.

J Hematol Oncol 2019 11 21;12(1):119. Epub 2019 Nov 21.

Center for Immunotherapy Research, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, TX, 77030, USA.

Double-hit lymphoma (DHL) is among the most aggressive and chemoresistant lymphoma subtypes. DHLs carry genomic abnormalities in MYC, BCL2, and/or BCL6 oncogenes. Due to the simultaneous overexpression of these driver oncogenes, DHLs are highly resistant to frontline therapies. Most DHLs overexpress both MYC and BCL2 driver oncogenes concurrently. We reasoned that simultaneous suppression of the two driver oncogenes would be more effective in eradicating DHLs than inactivation of single oncogene. XPO1 is a receptor for nuclear cytoplasmic transport of protein and RNA species. Recently, XPO1 inhibition was shown to downregulate MYC expression in several cancer cell lines. We therefore examined the role of XPO1 as a therapeutic target in suppressing MYC function and the potential synergistic effects of simultaneous suppression of XPO1 and BCL2 in the treatment of DHL. Here, we demonstrate that XPO1 inhibition abrogates MYC protein expression and induces massive tumor cell apoptosis. Combined use of XPO1 and BCL2 inhibitors is highly effective in eradicating DHL cells in cell culture. Notably, in a mouse model of DHL bearing primary tumor cells derived from lymphoma patients, combined treatment with XPO1 and BCL2 inhibitors blocks tumor progression, prevents brain metastasis, and extends host survival. Thus, our study confirms the simultaneous targeting of MYC and BCL2 driver oncogenes through the combined use of XPO1 and BCL2 inhibitors as a unique approach for the treatment of DHLs.
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http://dx.doi.org/10.1186/s13045-019-0803-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868798PMC
November 2019

Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma.

Sci Transl Med 2019 05;11(491)

Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Metabolic reprogramming is linked to cancer cell growth and proliferation, metastasis, and therapeutic resistance in a multitude of cancers. Targeting dysregulated metabolic pathways to overcome resistance, an urgent clinical need in all relapsed/refractory cancers, remains difficult. Through genomic analyses of clinical specimens, we show that metabolic reprogramming toward oxidative phosphorylation (OXPHOS) and glutaminolysis is associated with therapeutic resistance to the Bruton's tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma (MCL), a B cell lymphoma subtype with poor clinical outcomes. Inhibition of OXPHOS with a clinically applicable small molecule, IACS-010759, which targets complex I of the mitochondrial electron transport chain, results in marked growth inhibition in vitro and in vivo in ibrutinib-resistant patient-derived cancer models. This work suggests that targeting metabolic pathways to subvert therapeutic resistance is a clinically viable approach to treat highly refractory malignancies.
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http://dx.doi.org/10.1126/scitranslmed.aau1167DOI Listing
May 2019

Interleukin-1 receptor associated kinase (IRAK)-M -mediated type 2 microglia polarization ameliorates the severity of experimental autoimmune encephalomyelitis (EAE).

J Autoimmun 2019 08 26;102:77-88. Epub 2019 Apr 26.

Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address:

Toll-like receptor 4 (TLR4) play a key role in activating the innate immune system during pathogen recognition. In the pathogenesis of multiple sclerosis (MS), activated TLR4 together with myeloid differentiation primary response gene 88 (MyD88) produce an inflammatory microenvironment that promotes the differentiation of microglia into the M1 phenotype, who plays a key role in the pathogenesis of MS. Interleukin-1 receptor-associated kinase (IRAK)-M is specifically expressed in microglia in central nervous system (CNS) and act as a negative regulator of TLR4-MyD88 signaling pathway. Moreover, previous studies have shown that IRAK-M promotes the differentiation of type 2 microglia; however, its role in MS has not been explored. In the present study, we demonstrated that IRAK-M expression is elevated during EAE, and IRAK-M mice significantly accelerated course and increased severity of disease, accompanied by a visible increase of the M1 microglia infiltrated. In conclusion, these data indicates that IRAK-M significantly improves EAE onset through down-regulation of the TLR4-MyD88 signaling pathway, which finally leads to differentiation of M2 phenotype in the microglia. Our study suggests that IRAK-M may be a potential therapeutic target for the treatment of MS.
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http://dx.doi.org/10.1016/j.jaut.2019.04.020DOI Listing
August 2019

Immune Profiling and Quantitative Analysis Decipher the Clinical Role of Immune-Checkpoint Expression in the Tumor Immune Microenvironment of DLBCL.

Cancer Immunol Res 2019 04 11;7(4):644-657. Epub 2019 Feb 11.

Department of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.

PD-1/L1 and CTLA-4 blockade immunotherapies have been approved for 13 types of cancers and are being studied in diffuse large B-cell lymphoma (DLBCL), the most common aggressive B-cell lymphoma. However, whether both PD-1 and CTLA-4 checkpoints are active and clinically significant in DLBCL is unknown. Whether PD-1 ligands expressed by tumor cells or by the microenvironment of DLBCL are critical for the PD-1 immune checkpoint is unclear. We performed immunophenotypic profiling for 405 patients with DLBCL using a MultiOmyx immunofluorescence platform and simultaneously quantitated expression/coexpression of 13 immune markers to identify prognostic determinants. In both training and validation cohorts, results demonstrated a central role of the tumor immune microenvironment, and when its functionality was impaired by deficiency in tumor-infiltrating T cells and/or natural killer cells, high PD-1 expression (but not CTLA-4) on CD8 T cells, or PD-L1 expression on T cells and macrophages, patients had significantly poorer survival after rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy. In contrast, tumor-cell PD-L2 expression was associated with superior survival, as well as PD-L1CD20 cells proximal (indicates interaction) to PD-1 CD8 T cells in patients with low PD-1 percentage of CD8 T cells. Gene-expression profiling results suggested the reversibility of T-cell exhaustion in PD-1/PD-L1 patients with unfavorable prognosis and implication of /, and upregulation in the microenvironment dysfunction with PD-L1 expression. This study comprehensively characterized the DLBCL immune landscape, deciphered the differential roles of various checkpoint components in rituximab-CHOP resistance in DLBCL patients, and suggests targets for PD-1/PD-L1 blockade and combination immunotherapies.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0439DOI Listing
April 2019

Regulation of SOX11 expression through CCND1 and STAT3 in mantle cell lymphoma.

Blood 2019 01 10;133(4):306-318. Epub 2018 Dec 10.

Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA.

The neural transcription factor SOX11 is usually highly expressed in typical mantle cell lymphoma (MCL), but it is absent in the more indolent form of MCL. Despite being an important diagnostic marker for this hard-to-treat malignancy, the mechanisms of aberrant SOX11 expression are largely unknown. Herein, we describe 2 modes of SOX11 regulation by the cell-cycle regulator cyclin D1 (CCND1) and the signal transducer and activator of transcription 3 (STAT3). We found that ectopic expression of CCND1 in multiple human MCL cell lines resulted in increased SOX11 transcription, which correlated with increased acetylated histones H3K9 and H3K14 (H3K9/14Ac). Increased H3K9/14Ac and SOX11 expression was also observed after histone deacetylase 1 (HDAC1) or HDAC2 was depleted by RNA interference or inhibited by the HDAC inhibitor vorinostat. Mechanistically, we showed that CCND1 interacted with and sequestered HDAC1 and HDAC2 from the locus, leading to SOX11 upregulation. Interestingly, our data revealed a potential inverse relationship between phosphorylated Y705 STAT3 and SOX11 expression in MCL cell lines, primary tumors, and patient-derived xenografts. Functionally, inactivation of STAT3 by inhibiting the upstream Janus kinase (JAK) 1 or JAK2 or by STAT3 knockdown was found to increase SOX11 expression, whereas interleukin-21 (IL-21)-induced STAT3 activation or overexpression of the constitutively active form of STAT3 decreased SOX11 expression. In addition, targeting SOX11 directly by RNA interference or indirectly by IL-21 treatment induced toxicity in SOX11 MCL cells. Collectively, we demonstrate the involvement of CCND1 and STAT3 in the regulation of SOX11 expression, providing new insights and therapeutic implications in MCL.
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http://dx.doi.org/10.1182/blood-2018-05-851667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347093PMC
January 2019

PLK1 stabilizes a MYC-dependent kinase network in aggressive B cell lymphomas.

J Clin Invest 2018 12 5;128(12):5517-5530. Epub 2018 Nov 5.

Department of Laboratory Medicine and Hematopathology, Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.

Concordant activation of MYC and BCL-2 oncoproteins in double-hit lymphoma (DHL) results in aggressive disease that is refractory to treatment. By integrating activity-based proteomic profiling and drug screens, polo-like kinase-1 (PLK1) was identified as an essential regulator of the MYC-dependent kinome in DHL. Notably, PLK1 was expressed at high levels in DHL, correlated with MYC expression, and connoted poor outcome. Further, PLK1 signaling augmented MYC protein stability, and in turn, MYC directly induced PLK1 transcription, establishing a feed-forward MYC-PLK1 circuit in DHL. Finally, inhibition of PLK1 triggered degradation of MYC and of the antiapoptotic protein MCL-1, and PLK1 inhibitors showed synergy with BCL-2 antagonists in blocking DHL cell growth, survival, and tumorigenicity, supporting clinical targeting of PLK1 in DHL.
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http://dx.doi.org/10.1172/JCI122533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6264635PMC
December 2018

B-cell receptor-mediated NFATc1 activation induces IL-10/STAT3/PD-L1 signaling in diffuse large B-cell lymphoma.

Blood 2018 10 12;132(17):1805-1817. Epub 2018 Sep 12.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Knowledge of programmed death ligand 1 (PD-L1) expression and its regulation in B-cell lymphoma cells is limited. Investigating mechanisms that control PD-L1 expression in B-cell lymphoma cells might identify biomarkers that predict the efficacy of immunotherapy with anti-programmed death-1/PD-L1 antibodies. In addition, identification of mechanisms that regulate PD-L1 may identify molecules that can be targeted to improve the clinical efficacy of immune checkpoint inhibitors. In this study, we used proteomic approaches and patient-derived B-cell lymphoma cell lines to investigate mechanisms that regulate PD-L1 expression. We found that PD-L1 expression, particularly in nongerminal center B cell-derived diffuse large B-cell lymphoma (DLBCL), is controlled and regulated by several interactive signaling pathways, including the B-cell receptor (BCR) and JAK2/STAT3 signaling pathways. We found that that BCR-mediated NFATc1 activation upregulates IL-10 chemokine expression in PD-L1 B-cell lymphoma cells. Released IL-10 activates the JAK2/STAT3 pathway, leading to STAT3-induced PD-L1 expression. IL-10 antagonist antibody abrogates IL-10/STAT3 signaling and PD-L1 protein expression. We also found that BCR pathway inhibition by BTK inhibitors (ibrutinib, acalabrutinib, and BGB-3111) blocks NFATc1 and STAT3 activation, thereby inhibiting IL-10 and PD-L1 expression. Finally, we validated the PD-L1 signaling network in 2 primary DLBCL cohorts consisting of 428 and 350 cases and showed significant correlations among IL-10, STAT3, and PD-L1. Thus, our findings reveal a complex signaling network regulating PD-L1 expression in B-cell lymphoma cells and suggest that PD-L1 expression can be modulated by small molecule inhibitors to potentiate immunotherapies.
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http://dx.doi.org/10.1182/blood-2018-03-841015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634963PMC
October 2018

The Role of Macrophage/B-Cell Interactions in the Pathophysiology of B-Cell Lymphomas.

Front Oncol 2018 8;8:147. Epub 2018 May 8.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Macrophages (MPs) are heterogeneous, multifunctional, myeloid-derived leukocytes that are part of the innate immune system, playing wide-ranging critical roles in basic biological activities, including maintenance of tissue homeostasis involving clearance of microbial pathogens. Tumor-associated MPs (TAMs) are MPs with defined specific M2 phenotypes now known to play central roles in the pathophysiology of a wide spectrum of malignant neoplasms. Also, TAMs are often intrinsic cellular components of the essential tumor microenvironment (TME). In concert with lymphoid-lineage B and T cells at various developmental stages, TAMs can mediate enhanced tumor progression, often leading to poor clinical prognosis, at least partly through secretion of chemokines, cytokines, and various active proteases shown to stimulate tumor growth, angiogenesis, metastasis, and immunosuppression. Researchers recently showed that TAMs express certain key checkpoint-associated proteins [e.g., programmed cell death protein 1 (PD-1), programmed cell death-ligand 1 (PD-L1)] that appear to be involved in T-cell activation and that these proteins are targets of other specific checkpoint-blocking immunotherapies (anti-PD-1/PD-L1) currently part of new therapeutic paradigms for chemotherapy-resistant neoplasms. Although much is known about the wide spectrum and flexibility of MPs under many normal and neoplastic conditions, relatively little is known about the increasingly important interactions between MPs and B-lymphoid cells, particularly in the TME in patients with aggressive B-cell non-Hodgkin lymphoma (NHL-B). Normal and neoplastic lymphoid and myeloid cell/MP lineages appear to share many primitive cellular characteristics as well as transcriptional factor interactions in human and animal ontogenic studies. Such cells are capable of ectopic transcription factor-induced lineage reprogramming or transdifferentiation from early myeloid/monocytic lineages to later induce B-cell lymphomagenesis in experimental murine systems. Close cellular interactions between endogenous clonal neoplastic B cells and related aberrant myeloid precursor cells/MPs appear to be important interactive components of aggressive NHL-B that we discuss herein in the larger context of the putative role of B-cell/MP cellular lineage interactions involved in NHL-B pathophysiology during ensuing lymphoma development.
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http://dx.doi.org/10.3389/fonc.2018.00147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951963PMC
May 2018

Strategic Therapeutic Targeting to Overcome Venetoclax Resistance in Aggressive B-cell Lymphomas.

Clin Cancer Res 2018 08 17;24(16):3967-3980. Epub 2018 Apr 17.

Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.

B-cell lymphoma-2 (BCL-2), an antiapoptotic protein often dysregulated in B-cell lymphomas, promotes cell survival and provides protection from stress. A recent phase I first-in-human study of the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma showed an overall response rate of 44%. These promising clinical results prompted our examination of the biological effects and mechanism of action underlying venetoclax activity in aggressive B-cell lymphoma, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). MCL and DLBCL cell lines, primary patient samples, and patient-derived xenograft (PDX) models were utilized to examine venetoclax efficacy. Furthermore, the mechanisms underlying venetoclax response and the development of venetoclax resistance were evaluated using proteomics analysis and Western blotting. Potential biomarkers linked to venetoclax activity and targeted combination therapies that can augment venetoclax response were identified. We demonstrate that DLBCL and MCL cell lines, primary patient samples, and PDX mouse models expressing high BCL-2 levels are extremely sensitive to venetoclax treatment. Proteomics studies showed that venetoclax substantially alters the expression levels and phosphorylation status of key proteins involved in cellular processes, including the DNA damage response, cell metabolism, cell growth/survival, and apoptosis. Short- and long-term exposure to venetoclax inhibited PTEN expression, leading to enhanced AKT pathway activation and concomitant susceptibility to PI3K/AKT inhibition. Intrinsic venetoclax-resistant cells possess high AKT activation and are highly sensitive to PI3K/AKT inhibition. These findings demonstrate the on-target effect of venetoclax and offer potential mechanisms to overcome acquired and intrinsic venetoclax resistance through PI3K/AKT inhibition. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3004DOI Listing
August 2018

Preclinical efficacy and biological effects of the oral proteasome inhibitor ixazomib in diffuse large B-cell lymphoma.

Oncotarget 2018 Jan 21;9(1):346-360. Epub 2017 Aug 21.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Despite advances in deciphering the molecular pathogenesis of diffuse large B-cell lymphoma (DLBCL), patients with relapsed/refractory disease, particularly those with adverse genetic features (e.g., mutated p53 or double hit lymphoma (DHL)) have very poor prognoses, and effective therapies are lacking. In this study we examined the preclinical efficacy and associated biological effects of the first oral proteasome inhibitor, ixazomib, in DLBCL and models. We demonstrated that ixazomib exhibited anti-tumor activities in 28 representative DLBCL cell lines, 10 primary DLBCL samples, and a DHL xenotransplant mouse model, at clinically achievable drug concentrations. Ixazomib sensitivity in DLBCL cells is correlated with immunoproteasomal activity; stimulating lymphoma cells with interferon gamma induced immunoproteasome activity and sensitized these cells to ixazomib. In addition, we showed that ixazomib induces apoptosis and the DNA damage response pathway, through activation of the checkpoint kinase 2 (CHK2). Hence, pharmacological inhibition of CHK2 enhances the anti-tumor activity of ixazomib in DLBCL cells. Our results indicate that ixazomib is an effective proteasome inhibitor active in DLBCL, including DHL, and its combination with a CHK2 inhibitor offers a potentially more robust therapeutic regimen for treatment-resistant DLBCL.
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http://dx.doi.org/10.18632/oncotarget.20378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787470PMC
January 2018

AKT Hyperactivation and the Potential of AKT-Targeted Therapy in Diffuse Large B-Cell Lymphoma.

Am J Pathol 2017 Aug 13;187(8):1700-1716. Epub 2017 Jun 13.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; University of Texas School of Medicine, Graduate School of Biomedical Sciences, Houston, Texas. Electronic address:

AKT signaling is important for proliferation and survival of tumor cells. The clinical significance of AKT activation in diffuse large B-cell lymphoma (DLBCL) is not well analyzed. Here, we assessed expression of phosphorylated AKT (p-AKT) in 522 DLBCL patients. We found that high levels of p-AKT nuclear expression, observed in 24.3% of the study cohort, were associated with significantly worse progression-free survival and Myc and Bcl-2 overexpression. However, multivariate analysis indicated that AKT hyperactivation was not an independent factor. miRNA profiling analysis demonstrated that 63 miRNAs directly or indirectly related to the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway were differentially expressed between DLBCLs with high and low p-AKT nuclear expression. We further targeted AKT signaling using a highly selective AKT inhibitor MK-2206 in 26 representative DLBCL cell lines and delineated signaling alterations using a reverse-phase protein array. MK-2206 treatment inhibited lymphoma cell viability, and MK-2206 sensitivity correlated with AKT activation status in DLBCL cells. On MK-2206 treatment, p-AKT levels and downstream targets of AKT signaling were significantly decreased, likely because of the decreased feedback repression; Rictor and phosphatidylinositol 3-kinase expression and other compensatory pathways were also induced. This study demonstrates the clinical and therapeutic implications of AKT hyperactivation in DLBCL and suggests that AKT inhibitors need to be combined with other targeted agents for DLBCL to achieve optimal clinical efficacy.
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http://dx.doi.org/10.1016/j.ajpath.2017.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530910PMC
August 2017

RelA NF-κB subunit activation as a therapeutic target in diffuse large B-cell lymphoma.

Aging (Albany NY) 2016 12;8(12):3321-3340

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

It has been well established that nuclear factor kappa-B (NF-κB) activation is important for tumor cell growth and survival. RelA/p65 and p50 are the most common NF-kB subunits and involved in the classical NF-kB pathway. However, the prognostic and biological significance of RelA/p65 is equivocal in the field. In this study, we assessed RelA/p65 nuclear expression by immunohistochemistry in 487 patients with diffuse large B-cell lymphoma (DLBCL), and studied the effects of molecular and pharmacological inhibition of NF-kB on cell viability. We found RelA/p65 nuclear expression, without associations with other apparent genetic or phenotypic abnormalities, had unfavorable prognostic impact in patients with stage I/II DLBCL. Gene expression profiling analysis suggested immune dysregulation and antiapoptosis may be relevant for the poorer prognosis associated with p65 hyperactivation in germinal center B-cell-like (GCB) DLBCL and in activated B-cell-like (ABC) DLBCL, respectively. We knocked down individual NF-κB subunits in representative DLBCL cells in vitro, and found targeting p65 was more effective than targeting other NF-κB subunits in inhibiting cell growth and survival. In summary, RelA/p65 nuclear overexpression correlates with significant poor survival in early-stage DLBCL patients, and therapeutic targeting RelA/p65 is effective in inhibiting proliferation and survival of DLBCL with NF-κB hyperactivation.
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http://dx.doi.org/10.18632/aging.101121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5270671PMC
December 2016

Mantle Cell Lymphoma With MYC Rearrangement: A Report of 17 Patients.

Am J Surg Pathol 2017 Feb;41(2):216-224

Departments of *Hematopathology †Pathology, University of Texas Southwestern Medical Center, Dallas, TX.

MYC rearrangement in mantle cell lymphoma (MCL) is rare, and its clinicopathologic significance is not well defined. We report 17 cases of MCL with 8q24/MYC rearrangement, detected at the time of initial diagnosis of MCL in 10 patients and subsequently during the clinical course in 7 patients. There were 12 men and 5 women with a median age of 61 years (range, 49 to 81 y). Fourteen patients had lymphadenopathy (Ann Arbor stage III/IV), and 3 patients presented with a leukemic pattern without lymphadenopathy. Thirteen of 14 patients with available karyotyping data had a complex karyotype. In 8 cases the partner chromosome locus was an IG locus: t(8;14) (n=7) and t(8;22) (n=1). When MYC rearrangement was detected, most patients had a high-risk MCL international prognostic index, and the lymphoma cells had histologically aggressive features. Immunophenotypic analysis showed that the lymphoma cells were positive for cyclin D1 (n=16/16), Myc (9/11), and P53 (n=9/9). The Ki-67 proliferation rate was high (≥60%) in 10/11 cases. All patients received chemotherapy. The median follow-up time was 23 months. Clinical follow-up was available for 14 patients and treatment response in 13 patients. Eleven of 13 patients had refractory or relapsed disease, and 11 patients died. In conclusion, MCL with MYC rearrangement is characterized by advanced-stage disease, aggressive morphologic features, a high proliferation rate, p53 expression, a complex karyotype, and a poor prognosis. We believe these neoplasms fit within the overall concept of double-hit lymphoma, and the designation double-hit MCL may be helpful. We also believe that MYC rearrangement in MCL conveys important prognostic information that should be incorporated into the pathology report.
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http://dx.doi.org/10.1097/PAS.0000000000000758DOI Listing
February 2017

Targeting the hexosamine biosynthetic pathway and O-linked N-acetylglucosamine cycling for therapeutic and imaging capabilities in diffuse large B-cell lymphoma.

Oncotarget 2016 Dec;7(49):80599-80611

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The hexosamine biosynthetic pathway (HBP) requires two key nutrients glucose and glutamine for O-linked N-acetylglucosamine (O-GlcNAc) cycling, a post-translational protein modification that adds GlcNAc to nuclear and cytoplasmic proteins. Increased GlcNAc has been linked to regulatory factors involved in cancer cell growth and survival. However, the biological significance of GlcNAc in diffuse large B-cell lymphoma (DLBCL) is not well defined. This study is the first to show that both the substrate and the endpoint O-GlcNAc transferase (OGT) enzyme of the HBP were highly expressed in DLBCL cell lines and in patient tumors compared with normal B-lymphocytes. Notably, high OGT mRNA levels were associated with poor survival of DLBCL patients. Targeting OGT via small interference RNA in DLBCL cells inhibited activation of GlcNAc, nuclear factor kappa B (NF-κB), and nuclear factor of activated T-cells 1 (NFATc1), as well as cell growth. Depleting both glucose and glutamine in DLBCL cells or treating them with an HBP inhibitor (azaserine) diminished O-GlcNAc protein substrate, inhibited constitutive NF-κB and NFATc1 activation, and induced G0/G1 cell-cycle arrest and apoptosis. Replenishing glucose-and glutamine-deprived DLBCL cells with a synthetic glucose analog (ethylenedicysteine-N-acetylglucosamine [ECG]) reversed these phenotypes. Finally, we showed in both in vitro and in vivo murine models that DLBCL cells easily take up radiolabeled technetium-99m-ECG conjugate. These findings suggest that targeting the HBP has therapeutic relevance for DLBCL and underscores the imaging potential of the glucosamine analog ECG in DLBCL.
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http://dx.doi.org/10.18632/oncotarget.12413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348344PMC
December 2016

CCND1 mutations increase protein stability and promote ibrutinib resistance in mantle cell lymphoma.

Oncotarget 2016 Nov;7(45):73558-73572

Division of Hematopoietic Stem Cell and Leukemia Research, Gehr Leukemia Center, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.

Mantle cell lymphoma (MCL) is characterized by the t(11;14) translocation, which leads to deregulated expression of the cell cycle regulatory protein cyclin D1 (CCND1). Genomic studies of MCL have also identified recurrent mutations in the coding region of CCND1. However, the functional consequence of these mutations is not known. Here, we showed that, compared to wild type (WT), single E36K, Y44D or C47S CCND1 mutations increased CCND1 protein levels in MCL cell lines. Mechanistically, these mutations stabilized CCND1 protein through attenuation of threonine-286 phosphorylation, which is important for proteolysis through the ubiquitin-proteasome pathway. In addition, the mutant proteins preferentially localized to the nucleus. Interestingly, forced expression of WT or mutant CCND1 increased resistance of MCL cell lines to ibrutinib, an FDA-approved Bruton tyrosine kinase inhibitor for MCL treatment. The Y44D mutant sustained the resistance to ibrutinib even at supraphysiologic concentrations (5-10 μM). Furthermore, primary MCL tumors with CCND1 mutations also expressed stable CCND1 protein and were resistant to ibrutinib. These findings uncover a new mechanism that is critical for the regulation of CCND1 protein levels, and is directly relevant to primary ibrutinib resistance in MCL.
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http://dx.doi.org/10.18632/oncotarget.12434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341999PMC
November 2016

Establishment and characterization of a novel MYC/BCL2 "double-hit" diffuse large B cell lymphoma cell line, RC.

J Hematol Oncol 2015 Oct 29;8:121. Epub 2015 Oct 29.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd. Unit 54, Houston, TX, 77030, USA.

Background: Diffuse large B cell lymphoma (DLBCL) is the most common type of lymphoid malignancy worldwide. Approximately 5 % of cases of DLBCL are so-called double-hit lymphomas (DHL), defined by a chromosomal translocation or rearrangement involving MYC/8q24.2 in combination with another recurrent breakpoint, usually BCL2/18q21.3. Patients with MYC/BCL2 DHL are resistant to standard front-line therapy, and currently, there is no consensus for a therapeutic strategy to treat these patients. Lack of clinically relevant or validated human experimental DHL models of any type that would improve our understanding of the biologic basis of MYC/BCL2 DHL pathophysiology continues to hamper identification of valid therapeutic targets. We describe a unique MYC/BCL2 DHL cell line with morphologic features of DLBCL that we have established, designated as RC.

Methods: We used tissue culture techniques to establish the RC cell line from primary DLBCL cells. We also utilized molecular and cellular biological techniques including flow cytometry, polymerase chain reaction (PCR), DNA fingerprinting, reverse-phase protein array, conventional cytogenetics, and fluorescence in situ hybridization (FISH) analysis to characterize the RC cell line. NSG-severe combined immunodeficiency (SCID) mice were utilized as a model for xeno-transplantation of RC cells.

Results: RC cells had the following immunophenotype: positive for CD10, CD19, CD20, CD22, CD38, CD43, CD44, and CD79b and negative for CD3, CD4, CD5, CD8, CD11c, CD14, CD30, CD56, and CD200, which was identical to the primary tumor cells. Conventional cytogenetic analysis showed a t(2;8)(p12;q24.2) and t(14;18)(q32;q21.3), corresponding to MYC and BCL2 gene rearrangements, respectively. DNA fingerprinting authenticated the RC cell line to be of the same clone as the primary tumor cells. In addition, RC cells were established in SCID mice as an in vivo model for translational therapeutics studies. Proteomic analysis showed activation of the mTOR signaling pathway in RC cells that can be targeted with an mTOR inhibitor.

Conclusion: The data presented confirm the validity of the RC cell line as a representative model of MYC/BCL2 DHL that will be useful for both in vitro and in vivo studies of DHL pathogenesis and therapeutics.
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http://dx.doi.org/10.1186/s13045-015-0218-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627381PMC
October 2015

Prognostic impact of c-Rel nuclear expression and REL amplification and crosstalk between c-Rel and the p53 pathway in diffuse large B-cell lymphoma.

Oncotarget 2015 Sep;6(27):23157-80

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Dysregulated NF-κB signaling is critical for lymphomagenesis. The regulation, function, and clinical relevance of c-Rel/NF-κB activation in diffuse large B-cell lymphoma (DLBCL) have not been well studied. In this study we analyzed the prognostic significance and gene-expression signature of c-Rel nuclear expression as surrogate of c-Rel activation in 460 patients with de novo DLBCL. Nuclear c-Rel expression, observed in 137 (26.3%) DLBCL patients frequently associated with extranoal origin, did not show significantly prognostic impact in the overall- or germinal center B-like-DLBCL cohort, likely due to decreased pAKT and Myc levels, up-regulation of FOXP3, FOXO3, MEG3 and other tumor suppressors coincided with c-Rel nuclear expression, as well as the complicated relationships between NF-κB members and their overlapping function. However, c-Rel nuclear expression correlated with significantly poorer survival in p63+ and BCL-2- activated B-cell-like-DLBCL, and in DLBCL patients with TP53 mutations. Multivariate analysis indicated that after adjusting clinical parameters, c-Rel positivity was a significantly adverse prognostic factor in DLBCL patients with wild type TP53. Gene expression profiling suggested dysregulations of cell cycle, metabolism, adhesion, and migration associated with c-Rel activation. In contrast, REL amplification did not correlate with c-Rel nuclear expression and patient survival, likely due to co-amplification of genes that negatively regulate NF-κB activation. These insights into the expression, prognostic impact, regulation and function of c-Rel as well as its crosstalk with the p53 pathway underscore the importance of c-Rel and have significant therapeutic implications.
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http://dx.doi.org/10.18632/oncotarget.4319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695110PMC
September 2015

Involvement of tumor-associated macrophage activation in vitro during development of a novel mantle cell lymphoma cell line, PF-1, derived from a typical patient with relapsed disease.

Leuk Lymphoma 2015 Jan 29;56(1):186-93. Epub 2014 Apr 29.

Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center , Houston, TX , USA.

Human mantle cell lymphoma (MCL) cell lines are scarce and have been only sporadically described and validated, and only a few have been thoroughly molecularly or genetically characterized. We describe here the successful establishment of a new MCL line, PF-1, with typical MCL characteristics. Culturing primary MCL cells in vitro initially gave rise to an essential generative microenvironment "niche" involving macrophages required for MCL growth, and eventually produced the PF-1 MCL cell line. Our analysis revealed that PF-1 is morphologically and genotypically nearly identical to the original tumor cells. The PF-1 MCL cell line that we have developed will be useful for in vitro and in vivo studies of MCL pathogenesis and therapeutics.
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http://dx.doi.org/10.3109/10428194.2014.901511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5779854PMC
January 2015

In vitro and in vivo therapeutic efficacy of carfilzomib in mantle cell lymphoma: targeting the immunoproteasome.

Mol Cancer Ther 2013 Nov 29;12(11):2494-504. Epub 2013 Aug 29.

Corresponding Authors: Liang Zhang, Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0903, Houston, TX 77030.

Mantle cell lymphoma (MCL) remains incurable due to its inevitable pattern of relapse after treatment with current existing therapies. However, the promise of a cure for MCL lies in the burgeoning area of novel agents. In this study, we elucidated the therapeutic effect and mechanism of carfilzomib, a novel long-acting second-generation proteasome inhibitor, in MCL cells. We found that carfilzomib induced growth inhibition and apoptosis in both established MCL cell lines and freshly isolated primary MCL cells in a dose-dependent manner. In contrast, carfilzomib was less toxic to normal peripheral blood mononuclear cells from healthy individuals. The carfilzomib-induced apoptosis of MCL cells was mediated by the activation of JNK, Bcl-2, and mitochondria-related pathways. In addition, carfilzomib inhibited the growth and survival signaling pathways NF-κB and STAT3. Interestingly, we discovered that expression of immunoproteasome (i-proteasome) subunits is required for the anti-MCL activity of carfilzomib in MCL cells. In MCL-bearing SCID mice/primary MCL-bearing SCID-hu mice, intravenous administration of 5 mg/kg carfilzomib on days 1 and 2 for 5 weeks slowed/abrogated tumor growth and significantly prolonged survival. Our preclinical data show that carfilzomib is a promising, potentially less toxic treatment for MCL. Furthermore, an intact i-proteasome, especially LMP2, appears to be necessary for its anti-MCL activity, suggesting that i-proteasome could serve as a biomarker for identifying patients who will benefit from carfilzomib.
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http://dx.doi.org/10.1158/1535-7163.MCT-13-0156DOI Listing
November 2013

Novel selective inhibitors of nuclear export CRM1 antagonists for therapy in mantle cell lymphoma.

Exp Hematol 2013 Jan 14;41(1):67-78.e4. Epub 2012 Sep 14.

Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Overexpression of the cellular nuclear exportin 1, more commonly called chromosomal region maintenance 1 (CRM1), has been associated with malignant progression and mortality. Therefore, activation of nuclear export can play a significant etiologic role in some forms of human neoplasia and serve as a novel target for the treatment of these cancers. Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma that remains incurable. The objective of this study was to investigate the functional significance of CRM1 in MCL by evaluating the therapeutic efficacy of CRM1 inhibition in MCL in vitro and in vivo. Our results showed that CRM1 is highly expressed in MCL cells and is involved in regulating growth and survival mechanisms through the critical nuclear factor-κB survival pathway, which is independent of p53 status. Inhibition of CRM1 by two novel selective inhibitors of nuclear export (SINE), KPT-185 and KPT-276, in MCL cells resulted in significant growth inhibition and apoptosis induction. KPT-185 also induced CRM1 accumulation in the nucleus, resulting in CRM1 degradation by the proteasome. Oral administration of KPT-276 significantly suppressed tumor growth in an MCL-bearing severe combined immunodeficient mouse model, without severe toxicity. Our data suggest that SINE CRM1 antagonists are a potential novel therapy for patients with MCL, particular in relapsed/refractory disease.
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http://dx.doi.org/10.1016/j.exphem.2012.09.002DOI Listing
January 2013

The therapeutic effects of rGel/BLyS fusion toxin in in vitro and in vivo models of mantle cell lymphoma.

Biochem Pharmacol 2012 Aug 9;84(4):451-8. Epub 2012 Jun 9.

Immunopharmacology and Targeted Therapy Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA.

Mantle cell lymphoma (MCL) is an incurable, aggressive histo-type of B-cell non-Hodgkin lymphoma associated with both high relapsed rates and relatively short survival. Because MCL over-expresses receptors for B lymphocyte stimulator (BLyS) and displays constitutively active NF-κB, agents targeting these pathways may be of therapeutic relevance in this disease. To investigate the potential clinical use of the rGel/BLyS fusion toxin in combination with bortezomib, we evaluated this fusion toxin for its ability to inhibit MCL growth in severe combined immunodeficiency (SCID) xenograft model. Compared with PBS-treated mice, mice treated with this fusion toxin prolonged both median (84 days vs. 125 days) and overall survival (0% vs. 40%) (p=0.0027). Compared with bortezomib alone-treated mice, mice treated with rGel/BLyS plus bortezomib showed significantly increased median (91 days vs. 158 days) and overall survival (0% vs. 20%) (p=0.0127). Histopathologic analysis of peritoneal intestinal mesentery from MCL-SCID mice showed no demonstrable microscopic lymphomatous involvement at 225 days after treatment with rGel/BLyS. Combination treatment resulted in a synergistic growth inhibition, down-regulation of NF-κB DNA-binding activity, inhibition of cyclin D1, Bcl-x(L), p-Akt, Akt, p-mTOR, and p-Bad, up-regulation of Bax, and induction of cellular apoptosis. Our findings demonstrate that rGel/BLyS is an effective therapeutic agent for both primary and salvage treatment of aggressive MCL expressing constitutively active NF-κB and BLyS receptors and may be an excellent candidate for clinical development.
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http://dx.doi.org/10.1016/j.bcp.2012.05.019DOI Listing
August 2012

Over-expression of Thioredoxin-1 mediates growth, survival, and chemoresistance and is a druggable target in diffuse large B-cell lymphoma.

Oncotarget 2012 Mar;3(3):314-26

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Diffuse Large B cell lymphomas (DLBCL) are the most prevalent of the non-Hodgkin lymphomas and are currently initially treated fairly successfully, but frequently relapse as refractory disease, resulting in poor salvage therapy options and short survival. The greatest challenge in improving survival of DLBCL patients is overcoming chemo-resistance, whose basis is poorly understood. Among the potential mediators of DLBCL chemo-resistance is the thioredxoin (Trx) family, primarily because Trx family members play critical roles in the regulation of cellular redox homeostasis, and recent studies have indicated that dysregulated redox homeostasis also plays a key role in chemoresistance. In this study, we showed that most of the DLBCL-derived cell lines and primary DLBCL cells express higher basal levels of Trx-1 than normal B cells and that Trx-1 expression level is associated with decreased patients survival. Our functional studies showed that inhibition of Trx-1 by small interfering RNA or a Trx-1 inhibitor (PX-12) inhibited DLBCL cell growth, clonogenicity, and also sensitized DLBCL cells to doxorubicin-induced cell growth inhibition in vitro. These results indicate that Trx-1 plays a key role in cell growth and survival, as well as chemoresistance, and is a potential target to overcome drug resistance in relapsed/refractory DLBCL.
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http://dx.doi.org/10.18632/oncotarget.463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3359887PMC
March 2012

The role of BAFF-R dysregulation in B-lymphoid lineage malignancies.

Cell Cycle 2011 Jan 15;10(2):189-90. Epub 2011 Jan 15.

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January 2011

Constitutive BR3 receptor signaling in diffuse, large B-cell lymphomas stabilizes nuclear factor-κB-inducing kinase while activating both canonical and alternative nuclear factor-κB pathways.

Blood 2011 Jan 1;117(1):200-10. Epub 2010 Oct 1.

Department of Hematopathology, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.

Aberrant nuclear factor κB (NF-κB) signaling has been found to be of particular importance in diffuse, large B-cell lymphoma (DLBCL) cell survival and proliferation. Although the canonical NF-κB signaling pathway has been studied in some detail, activation of the alternative NF-κB pathway in DLBCL is not well characterized. Important insights into the regulation of the alternative NF-κB pathway in B lymphocytes has recently revealed the regulatory importance of the survival kinase NIK (NF-κB-inducing kinase) in genetically engineered murine models. Our studies demonstrate that both the canonical and alternative NF-κB pathways are constitutively activated in DLBCL. We also demonstrate that NIK kinase aberrantly accumulates in DLBCL cells due to constitutive activation of B-cell activation factor (BAFF)-R (BR3) through interaction with autochthonous B-lymphocyte stimulator (BLyS) ligand in DLBCL cells. Activation of BR3 in DLBCL induces recruitment and degradation of tumor necrosis factor receptor-associated factor 3, which results in NIK kinase accumulation, IκBα phosphorylation, and NF-κB p100 processing, thereby resulting in continuous activation of both NF-κB pathways in DLBCL cells, leading to autonomous lymphoma cell growth and survival. These results further elucidate mechanisms involved in abnormal NF-κB activation in DLBCL, and should contribute to better future therapeutic approaches for patients with DLBCL.
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http://dx.doi.org/10.1182/blood-2010-06-290437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037744PMC
January 2011

An epigenetic chromatin remodeling role for NFATc1 in transcriptional regulation of growth and survival genes in diffuse large B-cell lymphomas.

Blood 2010 Nov 27;116(19):3899-906. Epub 2010 Jul 27.

Department of Hematopathology, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.

The nuclear factor of activated T cells (NFAT) family of transcription factors functions as integrators of multiple signaling pathways by binding to chromatin in combination with other transcription factors and coactivators to regulate genes central for cell growth and survival in hematopoietic cells. Recent experimental evidence has implicated the calcineurin/NFAT signaling pathway in the pathogenesis of various malignancies, including diffuse large B-cell lymphoma (DLBCL). However, the molecular mechanism(s) underlying NFATc1 regulation of genes controlling lymphoma cell growth and survival is still unclear. In this study, we demonstrate that the transcription factor NFATc1 regulates gene expression in DLBCL cells through a chromatin remodeling mechanism that involves recruitment of the SWItch/Sucrose NonFermentable chromatin remodeling complex ATPase enzyme SMARCA4 (also known as Brahma-related gene 1) to NFATc1 targeted gene promoters. The NFATc1/Brahma-related gene 1 complex induces promoter DNase I hypersensitive sites and recruits other transcription factors to the active chromatin site to regulate gene transcription. Targeting NFATc1 with specific small hairpin RNA inhibits DNase I hypersensitive site formation and down-regulates target gene expression. Our data support a novel epigenetic control mechanism for the transcriptional regulation of growth and survival genes by NFATc1 in the pathophysiology of DLBCL and suggests that targeting NFATc1 could potentially have therapeutic value.
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http://dx.doi.org/10.1182/blood-2009-12-257378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981542PMC
November 2010

Degrasyn potentiates the antitumor effects of bortezomib in mantle cell lymphoma cells in vitro and in vivo: therapeutic implications.

Mol Cancer Ther 2010 Jul 6;9(7):2026-36. Epub 2010 Jul 6.

Department of Hematopathology, Unit 54, The University of Texas of M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

Mantle cell lymphoma (MCL) is an aggressive histotype of B-cell non-Hodgkin lymphoma that has increased in incidence over the past few decades and is incurable, usually poorly responsive to standard chemotherapy combinations, and associated with poor prognoses. Discovering new therapeutic agents with low toxicity that produce better outcomes in patients with MCL is an ongoing challenge. Recent studies showed that degrasyn, a novel small-molecule inhibitor of the Janus kinase/signal transducer and activation of transcription (JAK/STAT) pathway, exerts antitumor activity in lymphoid tumors by inhibiting key growth and survival signaling (JAK/STAT) pathways. In the present study, we found that treatment of both typical and blastoid-variant MCL cells with degrasyn in combination with bortezomib resulted in synergistic growth inhibition and apoptosis induction in vitro. The apoptosis in these cells was correlated with the downregulation of constitutive NF-kappaB and phosphorylated STAT3 activation, leading to the inhibition of c-Myc, cyclin D1, and bcl-2 protein expression and the upregulation of bax protein expression. In vivo, degrasyn and bortezomib interacted to synergistically prevent tumor development and prolong survival durations in a xenotransplant severe combined immunodeficient mouse model of MCL. These findings suggest that agents such as degrasyn that can pharmacologically target constitutively expressed NF-kappaB and STAT3 in MCL cells may be useful therapeutic agents for MCL when administered together with bortezomib.
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http://dx.doi.org/10.1158/1535-7163.MCT-10-0238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5483974PMC
July 2010
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