Bortezomib modulates surface CD20 in B-cell malignancies and affects rituximab-mediated complement-dependent cytotoxicity

Winiarska, Magdalena; Bil, Jacek; Nowis, Dominika; Gołąb, Jakub

doi:10.1182/blood-2009-09-244129

Cited by 42 publications

(38 citation statements)

References 43 publications

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“…47 Treatment of Raji cells with 1-10M PZ-218 or PZ-210 alone for 24 hours did not significantly increase the percentage of apoptotic cells (annexin V ϩ /PI ϩ /annexin V ϩ PI ϩ ; Figure 5A-B). However, when Raji cells were treated with rituximab in combination with 3 and 10M PZ-218 or PZ-210, the pepducins enhanced rituximab-mediated cytotoxicity in a dosedependent manner, with 1.5-to 2-fold increases in the percentage of apoptotic cells compared with rituximab alone ( Figure 5B).…”

Section: Cxcr4 Pepducins Significantly Enhance Rituximab-mediated Cytmentioning

confidence: 89%

Targeting CXCR4 with cell-penetrating pepducins in lymphoma and lymphocytic leukemia

O’Callaghan

Lee

Nguyen

et al. 2012

Blood

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The chemokine receptor CXCR4, which normally regulates stromal stem cell interactions in the bone marrow, is highly expressed on a variety of malignant hematologic cells, including lymphoma and lymphocytic leukemias. A new treatment concept has arisen wherein CXCR4 may be an effective therapeutic target as an adjunct to treatment of hematologic neoplasms with chemo-and immunotherapy. In the present study, we developed pepducins, cell-penetrating lipopeptide antagonists of CXCR4, to interdict CXCL12-CXCR4 transmembrane signaling to intracellular G-proteins. We demonstrate that pepducins targeting the first (i1) or third (i3) intracellular loops of CXCR4 completely abrogate CXCL12-mediated cell migration of lymphocytic leukemias and lymphomas. Stromal-cell coculture protects lymphoma cells from apoptosis in response to treatment with the CD20-targeted Ab rituximab. However, combination treatment with CXCR4 pepducins and rituximab significantly increases the apoptotic effect of rituximab. Furthermore, treatment of mice bearing disseminated lymphoma xenografts with pepducins alone or in combination with rituximab significantly increased their survival. These data demonstrate that CXCL12-CXCR4 signaling can be effectively inhibited by cell-penetrating pepducins, which represents a potential new treatment strategy for lymphoid malignancies. (Blood. 2012;119(7):1717-1725) IntroductionHematologic malignancies account for almost 10% of new cancer cases in the United States each year. 1 The last decade has seen the introduction of rituximab, a humanized mAb directed against the CD20 Ag, as a treatment option for B-cell leukemia and lymphomas, and combination chemotherapy with rituximab is now standard treatment for aggressive non-Hodgkin lymphoma (NHL). 2 However, because approximately 60% of patients with aggressive NHL are not cured, new biologic therapies and targets are urgently needed to further improve overall survival.The chemokine G-protein-coupled receptor (GPCR) CXCR4 and its ligand, CXCL12 (also called stromal cell-derived factor-1␣ [SDF-1]), regulate a diverse array of cellular processes, including leukocyte trafficking, B-cell lymphopoiesis, and bone marrow myelopoiesis 3 ; survival and proliferation of hematopoietic stem cells (HSCs) 4 ; and homing of HSCs to the BM. Under normal physiologic conditions, HSCs and hematopoietic progenitor cells (HPCs) are predominantly present in the BM, where they give rise to the mature cells of the hematopoietic system that are released into the blood circulation. 5 CXCL12 is constitutively secreted at high levels by BM stromal cells, 6 and it is this chemokine gradient that retains HSCs and HPCs in the BM and regulates homing of CXCR4-expressing cells. 7 The small-molecule antagonist plerixafor (AMD3100), which targets the CXCR4/CXCL12-SDF1 signaling axis, is an effective clinical tool with which to enhance mobilization of HSCs to the peripheral blood for subsequent autologous transplantation, 8,9 and has recently been approved for use in combination with G-CSF as a stem c...

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Section: Cxcr4 Pepducins Significantly Enhance Rituximab-mediated Cytmentioning

confidence: 89%

Targeting CXCR4 with cell-penetrating pepducins in lymphoma and lymphocytic leukemia

O’Callaghan

Lee

Nguyen

et al. 2012

Blood

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“…We show here that bortezomib preferentially induced apoptosis in control cells over AML cells, making it less likely to be used to treat AML. Other studies have also shown unexpected results when using bortezomib, for instance Bil and colleagues showed bortezomib preferentially induced CD20 in normal B cells compared with a decrease in malignant B cells, and this differential CD20 expression led to a significant increase in rituximab-mediated complement-dependent cytotoxicity in normal B cells (33). With increasing interest in inhibiting the ubiquitin-proteosome system, better targeted proteasome inhibitors are being clinically developed.…”

Section: Discussionmentioning

confidence: 99%

High Basal Nuclear Levels of Nrf2 in Acute Myeloid Leukemia Reduces Sensitivity to Proteasome Inhibitors

2011

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Proteasome inhibitors such as bortezomib exhibit clinical efficacy in multiple myeloma, but studies in acute myeloid leukemia (AML) have been disappointing to date. The apparent failure in AML likely reflects a lack of biological understanding that might clarify applications of proteosome inhibitors in this disease. Here we show that AML cells are considerably less sensitive than control noncancerous cells to bortezomib-induced cytotoxicity, permitting most bortezomib-treated AML cells to survive treatment. We traced reduced bortezomib sensitivity to increased basal levels of nuclear Nrf2, a transcription factor that stimulates protective antioxidant enzymes. Bortezomib stimulates cytotoxicity through accumulation of reactive oxygen species (ROS) but elevated basal levels of nuclear Nrf2 present in AML cells reduced ROS levels, permitting AML cells to survive drug treatment. We further found that the Nrf2 transcriptional repressor Bach1 is rapidly inactivated by bortezomib, allowing rapid induction of Nrf2-regulated cytoprotective and detoxification genes that protect AML cells from bortezomib-induced apoptosis. By contrast, nonmalignant control cells lacked constitutive activation of Nrf2, such that bortezomib-mediated inactivation of Bach1 led to a delay in induction of Nrf2-regulated genes, effectively preventing the manifestation of apoptotic protection that is seen in AML cells. Together, our findings argue that AML might be rendered sensitive to proteasome inhibitors by cotreatment with either an Nrf2-inhibitory or Bach1-inhibitory treatment, rationalizing a targeted therapy against AML.

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“…Thus, despite the success in immunotherapy using anti-CD20 monoclonal antibodies for lymphoma patients, knowledge about the biology of CD20 is still relatively limited. Accumulating evidence indicates that CD20 expression can be controlled at transcriptional, posttranscriptional, and posttranslational levels [47], [48]. Furthermore, few examples point out that CD20 expression can be modulated by known therapeutic agents [49]–[51].…”

Section: Discussionmentioning

confidence: 99%

B Cells and Ectopic Follicular Structures: Novel Players in Anti-Tumor Programming with Prognostic Power for Patients with Metastatic Colorectal Cancer

et al. 2014

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Remarkably limited information is available about biological mechanisms that determine the disease entity of metastatic colorectal cancer in the liver (CRCLM) with no good clinical parameters to estimate prognosis. For the last few years, understanding the relationship between tumor characteristics and local immune response has gained increasing attention. Given the multifaceted roles of B-cell-driven responses, we aimed to elucidate the immunological imprint of B lymphocytes at the metastatic site, the interrelation with macrophages, and their prognostic relevance. Here we present novel algorithm allowing to assess a link between the local patient-specific immunological capacity and clinical outcome. The microscopy-based imaging platform was used for automated scanning of large-scale tissue sections and subsequent qualitative and quantitative analyses of immune cell subtypes using lineage markers and single-cell recognition strategy. Results indicate massive infiltration of CD45-positive leukocytes confined to the metastatic border. We report for the first time the accumulation of CD20-positive B lymphocytes at the tumor – liver interface comprising the major population within the large CD45-positive aggregates. Strikingly, functionally active, activation-induced cytidine deaminase (AID)-positive ectopic lymphoid structures were found to be assembled within the metastatic margin. Furthermore, the CD20-based data set revealed a strong prognostic power: patients with high CD20 content and/or ectopic follicles had significantly lower risk for disease recurrence as revealed by univariate analysis (p<0.001 for both) and in models adjusted for clinicopathological variables (p<0.001 and p = 0.01, respectively), and showed prolonged overall survival. In contrast, CD68 staining-derived data set did not show an association with clinical outcome. Taken together, we nominate the magnitude of B lymphocytes, including those organized in ectopic follicles, as novel prognostic marker which is superior to clinicopathological parameters. Findings emphasize anti-tumoral role of B cell-driven mechanism(s) and thus indicate a new way of thinking about potential treatment strategies for CRCLM patients.

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Bortezomib modulates surface CD20 in B-cell malignancies and affects rituximab-mediated complement-dependent cytotoxicity

Cited by 42 publications

References 43 publications

Targeting CXCR4 with cell-penetrating pepducins in lymphoma and lymphocytic leukemia

Targeting CXCR4 with cell-penetrating pepducins in lymphoma and lymphocytic leukemia

High Basal Nuclear Levels of Nrf2 in Acute Myeloid Leukemia Reduces Sensitivity to Proteasome Inhibitors

B Cells and Ectopic Follicular Structures: Novel Players in Anti-Tumor Programming with Prognostic Power for Patients with Metastatic Colorectal Cancer

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