Antitumoral activity of acadesine and rituximab in MCL
ABSTRACT: Acadesine is a nucleoside analogue with known antileukemic effects in different neoplasms. We investigated the activity of acadesine ne exerts a cytotoxic effect in MCL and synergizes with rituximab supporting clinical examination of this strategy for MCL patients We used microarrays to detail the gene expression changes in acadesine-, rituximab- and combination-treated tumors. Global RNA expression in tumors treated with acadesine, rituximab and the combination in a xenograft model of MCL (Jeko-1). Tumors were collected 18 days after the initiation of the treatments.
Project description:Rituximab alone or in combination with chemotherapeutics is the first-line therapy for variety of lymphoproliferative disorders including low- and high grade non-Hodgkin’s lymphomas (NHL). Although the complete response rate is quite impressive, vast majority of patient presents recurrent disease. The association between CD20 expression and clinical outcome in patients strongly suggests that reduced CD20 expression leads to inferior response to RCHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone). In order to understand how loss of CD20 leads to development of RCHOP resistance, we developed rituximab resistant DOHH2 model in vivo by chronic exposure to rituximab. Characterization of several resistant in vivo xenografts revealed one model that maintained resistance to an acute dose of rituximab and demonstrated loss of CD20. Further characterization of the model demonstrated a loss of CD20 is associated with over expression of BCL2 and BIM. In vivo efficacy studies showed resistant line is insensitive to acute dose of RCHOP and treatment with an inhibitor of BCL2 (ABT199) in combination with chemotherapy resulted in better efficacy than RCHOP alone. We have identified an in vivo model of DLBCL where loss of CD20 and over expression of anti-apoptotic protein BCL2 leads to RCHOP resistance. These data suggest the addition of BCL2 inhibitor to chemotherapy might be effective in treating CD20 negative lymphomas. mRNA profiles of parental and rituximab resistant DOHH2 xenograft were generated by deep sequencing using Illumina HiSeq
Project description:Rituximab, a monoclonal antibody against CD20, has achieved great success in the treatment of B cell lymphoma, but many patients have shown resistance to it and led to disease progression eventually. At present, the mechanism of resistance is still not clear, but we consider that it may involve the multiple genes and multiple signaling pathways. Therefore, our study aimed at searching differentially expressed genes of rituximab resistant cell lines (RRCL) by cDNA microarray, and exploring the resistant mechanism of RRCL by using the subsequent bioinformatics methods. In this study, we successfully identified seventy up-regulated genes and forty-two down-regulated genes in both two RRCL. We also isolated the MAPK signaling pathway, which was the significantly enriched pathway in resistant mechanism, through KEGG pathway analysis. Moreover, we discovered the biological behaviors of RRCL that mainly inhibit apoptosis, promote cellular proliferation, transcription and angiogenesis through Gene Ontology (GO) terms analysis. In conclusion, our results suggested that the most closely related pathway to rituximab resistance was MAPK signaling pathway, which may partly be related to its inhibiting the apoptosis of cells and promoting the proliferation of cells and vascular development. We utilized human mantle cell lymphoma cell line Jeko-1 and human Burkitt lymphoma cell line Raji to establish rituximab resistant Jeko-1/R and Raji/R cell lines. And then, in order to explore rituximab resistant mechanism, we looked for the different gene expression profile of rituximab resistant cell lines compared with the parental cell lines by cDNA microarray and carried out subsequent KEGG pathway and GO terms analysis.
Project description:The neural transcription factor SOX11 is overexpressed in aggressive lymphoid neoplasms mainly in mantle cell lymphoma (MCL). We have recently demonstrated SOX11 tumorigenic potential in vivo by showing a significant reduction on tumor growth of SOX11-knockdown MCL cells in xenograft experiments, confirming the clinical observations that SOX11 may play an important role in the aggressive behavior of MCL (Vegliante et al., 2013). However, the specific mechanisms regulated by SOX11 that promote the oncogenic and rapid tumor growth of aggressive MCL still remain to be elucidated. To further characterize the potential oncogenic mechanisms regulated by SOX11 in MCL, we have analyzed the GEP derived from the xenograft SOX11-positive and knockdown xenograft derived tumors. Differential gene expression between SOX11-positive Z138 and SOX11-negative Z138 MCL cell lines xenotransplanted in SCID mices derived tumors. To determine the transcriptional programs regulated by SOX11 we first generated a MCL cellular model with reduced SOX11 protein levels by infecting MCL cell lines with lentiviral particles carrying shRNA plasmids specifically targeting SOX11 (shSOX11.1 and shSOX11.3). Next, CB17-severe combined immunodeficient (CB17-SCID) mice (Charles River Laboratory, Wilmington, MA) were subcutaneously inoculated into their lower dorsum with Z138 shSOX11.1, shSOX11.3, shControl in Matrigel basement membrane matrix and compared the GEP of SOX11-positive and SOX11-negative MCL xenotransplant derived tumors using the Affymetrix U133+2.0 microarrays.
Project description:Endogenous or iatrogenic antitumor immune responses can improve the course of follicular lymphoma (FL), but may be diminished by immunoregulatory mechanisms in the tumor microenvironment. These may include effects of programmed death (PD)-1, a coinhibitory receptor that impairs T-cell function and is highly expressed on intratumoral T cells. In a Phase II trial, we tested the efficacy of pidilizumab, a humanized anti-PD-1 monoclonal antibody, with rituximab in patients with rituximab-sensitive FL relapsed after 1-4 prior therapies. Pidilizumab was administered at 3 mg/kg every 4 weeks for 4 infusions, plus 8 optional infusions every 4 weeks for patients with stable disease or better. Starting 2 weeks after the first infusion of pidilizumab, rituximab was given at 375 mg/m2 weekly for 4 weeks. Peripheral blood and tumor biopsies were studied to assess immunological effects of pidilizumab. The combination was well-tolerated, with no grade 3/4 toxicities. Overall (66%) and complete (52%) response rates in 29 evaluable patients were high, with tumor regression in 86% of patients. Median progression-free survival was 18.8 months, and was not reached for the 19 responders. Peripheral blood immunophenotyping showed increased memory CD4+ T cells and activation of NK cells after pidilizumab therapy. Tumor response and progression-free survival were associated with T-cell activation gene signatures in tumor gene expression profiling data, both at baseline and in changes induced by pidilizumab. The efficacy of pidilizumab with rituximab compared favorably to historical retreatment with rituximab monotherapy in patients with relapsed FL. Pidilizumab may benefit patients with pre-existing endogenous antitumor immune responses. This set contains 26 samples in total. 8 pairs of pre- and post-treatment samples, and 10 additional pre-treatment samples.
Project description:Peripheral blood was collected into PAXgene tubes from 7 patients with follicular lymphoma, in a phase 2 clinical trial of lenalidomide plus rituximab as initial therapy for advanced-stage indolent non-Hodgkin's lymphoma. Blood was collected at baseline and on Day 15 of the second 28-day cycle, for determination of the gene expression profile after globin mRNA reduction. The effect of treatment on gene expression profiles was largely based on the paired t test, using the Significance Analysis of Microarrays method.
Project description:HF-1, Granta-519, SUDHL4,Oci-Ly10 and Oci-Ly3 cell lines, representing different B cell lymphoma subtypes, were induced with rituximab (R) for three hours and analyzed for differentially expressed genes compared to untreated control.
Project description:This SuperSeries is composed of the following subset Series: GSE3646: Follicular lymphoma and normal lymphoid tissue comparisons GSE3647: Follicular lymphoma lymph node Abstract: Analysis of the patterns of gene expression in follicular lymphomas from 24 patients suggested that two groups of tumors might be distinguished. All patients, whose biopsies were obtained before any treatment, were treated with rituximab, a monoclonal antibody directed against the B cell antigen, CD20. Gene expression patterns in the tumors that subsequently failed to respond to rituximab appeared more similar to those of normal lymphoid tissues than to gene expression patterns of tumors from rituximab responders. These findings suggest the possibility that the response of follicular lymphoma to rituximab treatment may be predicted from the gene expression pattern of tumors. Refer to individual Series
Project description:We investigated the differential regulation patterns of type I anti-CD20 monoclonal antibody (mAb) rituximab and type II obinutuzumab on a transcriptional level. Using a panel of MCL cell lines, we determined the effects of obinutuzumab and rituximab as monotherapies as well as in combination on cell viability and proliferation. Obinutuzumab induced a higher reduction in cell proliferation in each mantle cell lymphoma cell line than rituximab did. Results indicate a common pattern of expression changes after binding of anti-CD20 mAbs, but also reveal a significant difference between type I and type II treatment. Combination treatment resulted in a rituximab-like expression pattern. Many deregulated genes were associated with stress signalling, cell death, immune response and other functional clusters. Our analyses identified different and antibody-specific downstream expression patterns of obinutuzumab and rituximab, which may represent the molecular basis of the superior effect of obinutuzumab in comparison to rituximab. Overall design: 25 samples with 3 replicates each
Project description:The RNA-seq data presented in this study include libraries from Mantle Cell Lymphoma (MCL) tumor cells of 4 patients, Peripheral Blood B Cells from 3 healthy volunteers and JEKO-1 MCL cell lines Overall design: RNA-Seq on MCL patient samples
Project description:We studied 498 de-novo adult DLBCL cases, which had been diagnosed between January 2002 and October 2009, as part of the International DLBCL Rituximab-CHOP Consortium Program Study We perform global gene expression profiling from formalin fixed paraffin embedded 498 DLBCL tissues RNA by SPIA mediated microarray detection and identified the distinct subgroups of the disease within DLBCL, known as germinal-center-B-cell-like (GCB), activated B-cell-like (ABC), and unclassified DLBCL (UC). RNA of 498 FFPET DLBCL patient samples were extracted, amplified using a novel RNA amplicfication method, Single Primer Isothermal Amplification (SPIA, NuGen Inc.), and hybridized to Affymetrix HG-U133 Plus 2.0 GeneChips. This dataset is the collaboration between The University of Texas at MD Anderson Cancer Center and Roche Molecular Systems, Inc.