Lisa M Rimsza

The University of Arizona, Tucson, Arizona, United States

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Publications (127)1337.86 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We studied the global miRNA expression in diffuse large B-cell lymphoma (DLBCL; n=79), Burkitt lymphoma (BL; n= 36), primary mediastinal B-cell lymphoma (PMBL; n=12), B-cell lines (n=11), and normal subsets of naïve B-cells (N), centroblasts (CB), and peripheral blood B-cells along with their corresponding gene expression profiles (GEP). The normal B-cell subsets have well-defined miRNA signatures. The CB miRNA signature was significantly associated with germinal center B-cell (GCB)-DLBCL compared to ABC-DLBCL (p=0.002). We identified a 27-miRNA signature that included MYC targets and enabled the differentiation of BL from DLBCL, a distinction comparable with the "gold standard" GEP-defined diagnosis. Distinct miRNA signatures were identified for DLBCL subgroups, including GCB-DLBCL, activated B-cell (ABC)-DLBCL and PMBL. Interestingly, most of the unclassifiable-DLBCL by GEP showed a strong similarity to the ABC-DLBCL by miRNA expression profiling. Consistent results for BL and DLBCL subgroup classification were observed in formalin-fixed, paraffin-embedded tissue, making such tests practical for clinical use. We also identified predictive miRNA biomarker signatures in DLBCL, including high expression of miR-155 which significantly associated with R-CHOP response failure. This finding was further supported by the observation that high expression of miR-155 sensitizes cells to AKT inhibitors in vitro, suggesting a novel treatment option for resistant DLBCL. Copyright © 2014 American Society of Hematology.
    Blood 12/2014; · 9.78 Impact Factor
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    ABSTRACT: Effective treatment of diffuse large B cell lymphoma (DLBCL) is plagued by heterogeneous responses to standard therapy, and molecular mechanisms underlying unfavorable outcomes in lymphoma patients remain elusive. Here, we profiled 148 genomes with 91 matching transcriptomes in an R-CHOP-treated DLBCL cohort to uncover molecular subgroups linked to treatment failure. Systematic integration of high-resolution genotyping arrays and RNA-seq data revealed novel deletions in RCOR1 to be associated with unfavorable progression free survival (P = 0.001). Integration of expression data from the clinical samples with data from RCOR1 knockdowns in the lymphoma cell lines KM-H2 and Raji yielded an RCOR1 loss-associated gene signature comprising of 233 genes. This signature identified a subgroup of patients with unfavorable overall survival (OS) (P = 0.023). The prognostic significance of the 233-gene signature for OS was reproduced in an independent cohort comprising 195 R-CHOP treated patients (P = 0.039). Additionally, we discovered that within the IPI low risk group, the gene signature provides additional prognostic value that was independent of the cell-of-origin phenotype. Taken together, we present a novel and reproducible molecular subgroup of DLBCL, impacting risk-stratification of R-CHOP treated DLBCL patients and revealing a possible new avenue for therapeutic intervention strategies.
    Blood 11/2014; · 9.78 Impact Factor
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    ABSTRACT: Patients with aggressive, BCL2 protein-positive (+) diffuse large B-cell lymphoma (DLBCL) often experience rapid disease progression that is refractory to standard therapy. However, there is potential for false-negative staining of BCL2 using the standard monoclonal mouse 124 antibody that hinders the identification of these high-risk DLBCL patients. Herein, we compare two alternative rabbit monoclonal antibodies (E17 and SP66) to the 124 clone in staining for BCL2 in formalin-fixed, paraffin-embedded DLBCL tissues. Overall, in two independent DLBCL cohorts E17 and SP66 detected BCL2 expression more frequently than 124. In the context of MYC expression, cases identified as BCL2 (+) with SP66 demonstrated the strongest correlation with worse OS. The 124 clone failed to detect BCL2 expression in the majority of translocation (+), amplification (+), and activated B-cell DLBCL cases in which high levels of BCL2 protein are expected. Using dual in-situ hybridization (Dual ISH) as a new tool to detect BCL2 translocation and amplification, we observed similar results as previously reported for fluorescence ISH for translocation but a higher amplification frequency, indicating that BCL2 amplification may be under-reported in DLBCL. Among the discrepant cases, phosphorylation of BCL2 at T69 and/or S70 was more common than in the concordant cases and may contribute to the 124 false-negatives, in addition to previously associated mutations within the epitope region. The accurate detection of BCL2 expression is important in the prognosis and treatment of DLBCL particularly with new anti-BCL2 therapies.
    Human pathology 10/2014; · 2.81 Impact Factor
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    ABSTRACT: Detection of B cell clonality is useful for assisting in the diagnosis of B cell lymphomas. Clonality assessment can be accomplished through evaluation of KAPPA and LAMBDA light chain expression. Currently, only slide based methods are available for the majority of patient biopsies and do not detect light chain protein or mRNA in many B-cell lymphomas. Herein we evaluated a new method, known as colorimetric in situ hybridization (CISH), with improved sensitivity and multiplexing capacity, for its usefulness in clonality detection in mature B cell malignancies.
    Diagnostic Pathology 07/2014; 9(1):144. · 2.41 Impact Factor
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    ABSTRACT: Lymphoma cells are subject to higher levels of oxidative stress as compared to their normal counterparts and may be vulnerable to manipulations of the cellular redox balance. We therefore designed a phase II study of imexon (Amplimexon/NSC-714597), a pro-oxidant molecule, in patients with relapsed / refractory B-cell non-Hodgkin lymphomas (NHL). Imexon was administered at 1000 mg/m2 intravenously daily for 5 days in 21-day cycles. Gene expression analysis performed on pre-treatment tumor specimens included 13 transcripts used to generate a redox signature score, previously demonstrated to correlate with lymphoma prognosis. Twenty-two patients were enrolled having follicular (n=9), diffuse large B-cell (DLBCL) (n=5), mantle cell (n=3), transformed follicular (n=2), small lymphocytic (n=2) and Burkitt (n=1) lymphoma. The most common grade 3/4 adverse events were anemia (14%) and neutropenia (9%). The overall response rate was 30%: including responses in follicular lymphoma (4/9) and DLBCL (2/5). Gene expression analyses revealed CD68 and the redox related genes, GPX1 and SOD2, as well as a higher redox score to correlate with clinical responses. To our knowledge, this is the first demonstration of clinical activity with a pro-oxidant molecule in lymphoma. Pre-treatment markers of oxidative stress may identify patients likely to respond to this therapeutic approach. This study was registered at as #NCT01314014.
    Blood 07/2014; · 9.78 Impact Factor
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    ABSTRACT: The clinicopathologic findings in Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) may show significant overlap, and MYC abnormalities, found in all BLs, also occur in a subset of DLBCL. The 2008 World Health Organization classification introduced the category of "B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL" (BCLU) in recognition of this overlap, but the clinical significance of BCLU (ie, "high-grade") morphology and the relationship between BCLU morphology and MYC abnormalities remains unclear. In this study, we identified 260 cases of non-Burkitt, diffuse aggressive B-cell lymphomas from SWOG S9704, a phase 3 randomized study of standard immunochemotherapy versus autologous stem cell transplantation. Of these, 31 cases (12%) showed BCLU morphology, and 229 (88%) showed typical DLBCL morphology. Of 198, 27 (14%) were positive for MYC by immunohistochemistry. BCLU morphology was associated with an increased incidence of MYC expression but otherwise was not associated with distinct clinicopathologic features or significantly decreased survival. MYC-positive cases were morphologically and phenotypically heterogenous and were associated with poor progression-free and overall survival in multivariate analysis. These findings confirm that BCLU does not represent a distinct clinicopathologic entity and demonstrate that BCLU morphology alone does not significantly impact survival compared with typical DLBCL. In contrast, MYC protein expression is a poor prognostic factor that may be associated with either BCLU or DLBCL morphology, and MYC immunohistochemistry is suggested for routine prognostic evaluation ( identifier: NCT00004031).
    The American journal of surgical pathology 04/2014; 38(4):494-501. · 4.59 Impact Factor
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    ABSTRACT: Peripheral T-cell lymphoma (PTCL) encompasses a heterogeneous group of neoplasms with generally poor clinical-outcome. Currently 50% of PTCLs are not-classifiable (PTCL-NOS).Gene-expression profiles on 372 PTCLs were analyzed and findings were validated by immunohistochemistry and mutation analysis. Robust molecular classifiers and oncogenic pathways that reflect the pathobiology of tumor cells and their microenvironment were identified for major PTCL-entities, including angioimmunoblastic T-cell lymphoma (AITL; n=114), anaplastic lymphoma kinase (ALK)-positive (n=31) and ALK-negative anaplastic large cell lymphoma (n=48), adult T-cell leukemia/lymphoma (n=14) and extranodal NK/T-cell lymphoma (ENKTL). ENKTL were further separated into NK-cell (n=23) and γδT-cell lymphomas (n=21). We re-classified 37% of morphologically-diagnosed PTCL-NOS cases into other specific subtypes by molecular signatures. Pathologic re-examination, immunohistochemistry and IDH2 mutation analysis supported the validity of re-classification. The remaining PTCL-NOS cases (n=121) were classified into two major molecular subgroups, characterized by high expression of either GATA3 (33%;40/121) or TBX21 (49%;59/121) and corresponding target genes. GATA3-subgroup was significantly associated with poor overall-survival (p=0.01), and also revealed distinct enriched oncogenic pathways. However, high expression of cytotoxic gene-signature within TBX21-subgroup showed poor clinical-outcome (p=0.05). In AITL, high expression of pan B-cell signatures correlated with favorable-outcome (p=0.01), whereas high monocytic-signature was associated with inferior-survival (p=0.017). Combined prognostic score was predictive of AITL survival in independent cohort (p=0.004), suggesting role of tumor microenvironment.
    Blood 03/2014; · 9.78 Impact Factor
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    ABSTRACT: Variable survival outcomes are seen following treatment for aggressive non-Hodgkin lymphoma (NHL). This study examined whether outcomes for aggressive B-cell NHL are associated with single nucleotide polymorphisms (SNPs) in oxidative stress-related genes, which can alter drug metabolism and immune responses. Genotypes for 53 SNPs in 29 genes were determined for 337 patients given anthracycline-based therapies. Their associations with progression-free survival (PFS) and overall survival (OS) were estimated by Cox proportional hazard regression; associations with hematologic toxicity were estimated by logistic regression. To validate the findings, the top 3 SNPs were tested in an independent cohort of 572 DLBCL patients. The top SNPs associated with PFS in the discovery cohort were the rare homozygotes for MPO rs2243828 (hazard ratio [HR]=1.87, 95% confidence interval [CI]=1.14-3.06, P = 0.013), AKR1C3 rs10508293 (HR=2.09, 95% CI=1.28-3.41, P=0.0032) and NCF4 rs1883112 (HR=0.66, 95% CI=0.43-1.02, P=0.06). The association of the NCF4 SNP with PFS was replicated in the validation dataset (HR=0.66, 95% CI=0.44-1.01, P=0.05) and the meta-analysis was significant (HR=0.66, 95% CI=0.49-0.89, P<0.01). The association of the MPO SNP was attenuated in the validation dataset, while the meta-analysis remained significant (HR=1.64, 95% CI=1.12-2.41). These two SNPs showed similar trends with OS in the meta-analysis (for NCF4, HR=0.72, 95% CI 0.51-1.02, P=0.07 and for MPO, HR=2.06, 95% CI 1.36-3.12, P<0.01). In addition, patients with the rare homozygote of the NCF4 SNP had an increased risk of hematologic toxicity. We concluded that genetic variations in NCF4 may contribute to treatment outcomes for patients with aggressive NHL.
    American Journal of Hematology 03/2014; · 3.48 Impact Factor
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    ABSTRACT: Classical Hodgkin lymphoma and primary mediastinal B cell lymphoma (PMBCL) are related lymphomas sharing pathological, molecular and clinical characteristics. Here we discovered by whole-genome and whole-transcriptome sequencing recurrent somatic coding-sequence mutations in the PTPN1 gene. Mutations were found in 6 of 30 (20%) Hodgkin lymphoma cases, in 6 of 9 (67%) Hodgkin lymphoma-derived cell lines, in 17 of 77 (22%) PMBCL cases and in 1 of 3 (33%) PMBCL-derived cell lines, consisting of nonsense, missense and frameshift mutations. We demonstrate that PTPN1 mutations lead to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members. Moreover, silencing of PTPN1 by RNA interference in Hodgkin lymphoma cell line KM-H2 resulted in hyperphosphorylation and overexpression of downstream oncogenic targets. Our data establish PTPN1 mutations as new drivers in lymphomagenesis.
    Nature Genetics 02/2014; · 29.65 Impact Factor
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    ABSTRACT: Constitutive activation of NF-κB is a hallmark of the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), owing to upstream signals from the B cell receptor (BCR) and MyD88 pathways. The linear polyubiquitin chain assembly complex (LUBAC) attaches linear polyubiquitin chains to IκB kinase γ, a necessary event in some pathways that engage NF-κB. Two germ line polymorphisms affecting the LUBAC subunit RNF31 are rare among healthy individuals (~1%) but enriched in ABC DLBCL (7.8%). These polymorphisms alter RNF31 α helices that mediate binding to the LUBAC subunit RBCK1, thereby increasing RNF31-RBCK1 association, LUBAC enzymatic activity, and NF-κB engagement. In the BCR pathway, LUBAC associates with the CARD11/MALT1/BCL10 adapter complex and is required for ABC DLBCL viability. A stapled RNF31 α-helical peptide based on the ABC DLBCL-associated Q622L polymorphism inhibited RFN31-RBCK1 binding, decreased NF-κB and killed ABC DLBCL cells, credentialing this protein-protein interface as a therapeutic target.
    Cancer Discovery 02/2014; · 15.93 Impact Factor
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    ABSTRACT: The assignment of diffuse large B-cell lymphoma into cell-of-origin (COO) groups is becoming increasingly important with the emergence of novel therapies that have selective biological activity in germinal center B-cell-like (GCB) or activated B-cell-like (ABC) groups. The LLMPP's Lymph2Cx assay is a parsimonious digital gene-expression (NanoString) based test for COO assignment in formalin-fixed paraffin-embedded tissue (FFPET) routinely produced in standard diagnostic processes. The 20-gene assay was trained using 51 FFPET biopsies; the locked assay was then validated using an independent cohort of 68 FFPET biopsies. Comparisons were made with COO assignment using the original COO model on matched frozen tissue. In the validation cohort the assay was accurate, with only one case with definitive COO being incorrectly assigned, and robust, with >95% concordance of COO assignment between 2 independent laboratories. These qualities, along with the rapid turn-around-time, make Lymph2Cx attractive for implementation in clinical trials and, ultimately, patient management.
    Blood 01/2014; · 9.78 Impact Factor
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    ABSTRACT: We previously reported that constitutive STAT3 activation is a prominent feature of the activated B-cell subtype of diffuse large B-cell lymphomas (ABC-DLBCL). In this study, we investigated whether STAT3 activation can risk stratify patients with DLBCL. By an immunohistochemical method, we investigated phosphotyrosine STAT3 (PY-STAT3) expression from 185 patients with DLBCL treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). Cell line-based siRNA experiments were also performed to generate an 11-gene, PY-STAT3 activation signature, which was used to study a previously published cohort of 222 patients with DLBCL. The STAT3 activation status determined by these two methods and by STAT3 mRNA levels were then correlated with survival. PY-STAT3 was detected in 37% of DLBCL and enriched in ABC-DLBCL cases (P = .03). PY-STAT3 positivity significantly correlated with poor overall survival (OS; P = .01) and event-free survival (EFS; P = .006). Similar observations were made for high levels of STAT3 mRNA. In multivariable analysis, PY-STAT3 status (P = .02), International Prognostic Index (P = .02), and BCL2 expression (P = .046) were independent prognosticators of OS in this cohort. Among the cell-of-origin subgroups, PY-STAT3 was associated with poor EFS among non-germinal center B-cell DLBCL cases only (P = .027). Similarly, the 11-gene STAT3 activation signature correlated with poor survival in the entire DLBCL cohort (OS, P < .001; EFS, P < .001) as well as the ABC-DLBCL subgroup (OS, P = .029; EFS, P = .025). STAT3 activation correlated with poor survival in patients with DLBCL treated with R-CHOP, especially those with tumors of the ABC-DLBCL subtype.
    Journal of Clinical Oncology 11/2013; · 17.88 Impact Factor
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    ABSTRACT: The efficacy of autologous stem-cell transplantation during the first remission in patients with diffuse, aggressive non-Hodgkin's lymphoma classified as high-intermediate risk or high risk on the International Prognostic Index remains controversial and is untested in the rituximab era. We treated 397 patients who had disease with an age-adjusted classification of high risk or high-intermediate risk with five cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP plus rituximab. Patients with a response were randomly assigned to receive three additional cycles of induction chemotherapy (control group) or one additional cycle of induction chemotherapy followed by autologous stem-cell transplantation (transplantation group). The primary efficacy end points were 2-year progression-free survival and overall survival. Of 370 induction-eligible patients, 253 were randomly assigned to the transplantation group (125) or the control group (128). Forty-six patients in the transplantation group and 68 in the control group had disease progression or died, with 2-year progression-free survival rates of 69 and 55%, respectively (hazard ratio in the control group vs. the transplantation group, 1.72; 95% confidence interval [CI], 1.18 to 2.51; P=0.005). Thirty-seven patients in the transplantation group and 47 in the control group died, with 2-year overall survival rates of 74 and 71%, respectively (hazard ratio, 1.26; 95% CI, 0.82 to 1.94; P=0.30). Exploratory analyses showed a differential treatment effect according to risk level for both progression-free survival (P=0.04 for interaction) and overall survival (P=0.01 for interaction). Among high-risk patients, the 2-year overall survival rate was 82% in the transplantation group and 64% in the control group. Early autologous stem-cell transplantation improved progression-free survival among patients with high-intermediate-risk or high-risk disease who had a response to induction therapy. Overall survival after transplantation was not improved, probably because of the effectiveness of salvage transplantation. (Funded by the National Cancer Institute, Department of Health and Human Services, and others; SWOG-9704 number, NCT00004031.).
    New England Journal of Medicine 10/2013; 369(18):1681-90. · 54.42 Impact Factor
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    ABSTRACT: There is currently no consensus on optimal front-line therapy for patients with follicular lymphomas (FL). We analyzed a Phase III randomized intergroup trial comparing 6 cycles of CHOP-R with six cycles of CHOP followed by iodine I-131 tositumomab radioimmunotherapy (RIT) to assess whether any subsets benefitted more from one treatment or the other, and to compare three prognostic models. We conducted univariate and multivariate Cox regression analyses of 532 patients enrolled on this trial and compared the prognostic value of the FLIPI, FLIPI2, and LDH + β2M models. Outcomes were excellent, but not statistically different between the two study arms (5 year PFS of 60% with CHOP-R and 66% with CHOP-RIT [p =0.11]; 5-yr OS of 92% with CHOP-R and 86% with CHOP-RIT [p=0.08]; overall response rate of 84% for both arms). The only factor found to potentially predict the impact of treatment was serum β2 microglobulin (β2M); among patients with normal β2M, CHOP-RIT patients had better PFS compared to CHOP-R patients, whereas among patients with high serum β2M, PFS by arm was similar (interaction p-value=.02). Conclusions All three prognostic models (FLIPI, FLIPI2, LDH + β2M) predicted both PFS and OS well, though the LDH + β2M model is easiest to apply and identified an especially poor risk subset. In an exploratory analysis using the latter model, there was a statistically significant trend suggesting that low risk patients had superior observed PFS if treated with CHOP-RIT, whereas high risk patients had a better PFS with CHOP-R.
    Clinical Cancer Research 10/2013; · 8.19 Impact Factor
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    ABSTRACT: The rapid emergence of molecularly based techniques to detect changes in the genetic landscape of diffuse large B cell lymphoma (DLBCL), including gene expression, DNA and RNA sequencing, and epigenetic profiling, has significantly influenced the understanding and therapeutic targeting of DLBCL. In this review, we briefly discuss the new methods used in the study of DLBCL. We describe the influence of the generated data on DLBCL classification and the identification of new entities and altered cell survival strategies, with a focus on the renewed interest in some classic oncogenic pathways that are currently targeted for new therapy. Finally, we examine the molecular genomic studies that revealed the importance of the tumor microenvironment in the pathogenesis of DLBCL.
    Cancer Genetics 09/2013; · 2.42 Impact Factor
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    ABSTRACT: Gain of function mutations in the H3K27 methyltransferase EZH2 represent a promising therapeutic target in germinal center lymphomas. In this study, we assessed the frequency and distribution of EZH2 mutations in a large cohort of patients with follicular lymphoma (FL) (n=366) and performed a longitudinal analysis of mutation during the disease progression from FL to transformed FL (tFL) (n=33). Mutations were detected at 3 recurrent mutation hot-spots (Y646, A682 and A692) in 27% of FL cases with variant allele frequencies (VAF) ranging from 2-61%. By comparing VAF of EZH2 with other mutation targets (CREBBP, MLL2, TNFRSF14 and MEF2B) we were able to distinguish patients harboring clonal EZH2 mutation from rarer cases with subclonal mutations. Overall, the high incidence of EZH2 mutations in FL and their stability during disease progression makes FL an appropriate disease to evaluate EZH2 targeted therapy.
    Blood 09/2013; · 9.78 Impact Factor
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    ABSTRACT: Follicular lymphoma (FL), the second most common type of non-Hodgkin lymphoma in the western world, is characterized by the t(14;18) translocation, which is present in up to 90% of cases. We studied 277 lymphoma samples [198 FL and 79 transformed FL (tFL)] using a single nucleotide polymorphism (SNP) array to identify the secondary chromosomal abnormalities that drive the development of FL and its transformation to diffuse large B-cell lymphoma (DLBCL). Common recurrent chromosomal abnormalities in FL included gains of 2, 5, 7, 6p, 8, 12, 17q, 18, 21, and X and losses on 6q and 17p. We also observed many frequent small abnormalities, including losses of 1p36.33-p36.31, 6q23.3-q24.1, and 10q23.1-q25.1 and gains of 2p16.1-p15, 8q24.13-q24.3, and 12q12-q13.13, and identified candidate genes that may be driving this selection. Recurrent abnormalities more frequent in tFL samples included gains of 3q27.3-q28 and chromosome 11 and losses of 9p21.3 and 15q. Four abnormalities, gain of X or Xp and losses of 6q23.2-24.1 or 6q13-15, predicted overall survival. Abnormalities associated with transformation of the disease likely impair immune surveillance, activate the NF-κB pathway, and deregulate p53 and B-cell transcription factors.
    Blood 09/2013; · 9.78 Impact Factor
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    ABSTRACT: Diffuse large B cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma. While the initial treatment strategy is highly effective, relapse occurs in 40% of cases. Histone deacetylase inhibitors (HDACi) are a promising class of anti-cancer drugs but their single agent efficacy against relapsed DLBCL has been variable, ranging from few complete/partial responses to some stable disease. However, most patients showed no response to HDACi monotherapy for unknown reasons. Here we show that sensitivity and resistance to the hydroxamate HDACi, PXD101, can be modeled in DLBCL cell lines. Sensitivity is characterized by G 2/M arrest and apoptosis and resistance by reversible G 1 growth arrest. These responses to PXD101 are independent of several negative prognostic indicators such as DLBCL subtype, BCL2 and MYC co-expression, and p53 mutation, suggesting that HDACi might be used effectively against highly aggressive DLBCL tumors if they are combined with other therapeutics that overcome HDACi resistance. Our investigation of mechanisms underlying HDACi resistance showed that cyclin-dependent kinase inhibitors (CKIs), p21 and p27, are upregulated by PXD101 in a sustained fashion in resistant cell lines concomitant with decreased activity of the cyclin E/cdk2 complex and decreased Rb phosphorylation. PXD101 treatment results in increased association of CKI with the cyclin E/cdk2 complex in resistant cell lines but not in a sensitive line, indicating that the CKIs play a key role in G 1 arrest. The results suggest several treatment strategies that might increase the efficacy of HDACi against aggressive DLBCL.
    Cancer biology & therapy 08/2013; 14(10). · 3.29 Impact Factor
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    ABSTRACT: Diffuse large B cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma (NHL) diagnosed in the United States, consists of at least two distinct subtypes: germinal center B (GCB) and activated B cell (ABC). Decreased major histocompatibility class II (MHCII) expression on the tumors in both DLBCL subtypes directly correlates with significant decreases in patient survival. One common mechanism accounting for MHCII downregulation in DLBCL is reduced expression of the MHC class II transactivator (CIITA), the master regulator of MHCII transcription. Furthermore, reduced CIITA expression in ABC DLBCL correlates with the presence of the transcriptional repressor positive regulatory domain-I-binding factor-1 (PRDI-BF1). However, the mechanisms underlying downregulation of CIITA in GCB DLBCL are currently unclear. In this study, we demonstrate that neither PRDI-BF1 nor CpG hypermethylation at the CIITA promoters are responsible for decreased CIITA in GCB DLBCL. In contrast, histone modifications associated with an open chromatin conformation and active transcription were significantly lower at the CIITA promoters in CIITA(-) GCB cells compared to CIITA(+) B cells, which suggests that epigenetic mechanisms contribute to repression of CIITA transcription. Treatment of CIITA(-) or CIITA(low) GCB cells with several different histone deacetylase inhibitors (HDACi) activated modest CIITA and MHCII expression. However, CIITA and MHCII levels were significantly higher in these cells after exposure to the HDAC-1-specific inhibitor MS-275. These results suggest that CIITA transcription is repressed in GCB DLBCL cells through epigenetic mechanisms involving HDACs, and that HDACi treatment can alleviate repression. These observations may have important implications for patient therapy. This article is protected by copyright. All rights reserved.
    Immunology 06/2013; · 3.74 Impact Factor
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    ABSTRACT: Mantle cell lymphoma (MCL) is a B-cell neoplasm with an aggressive clinical behaviour characterized by the t(11;14)(q13;q32) and cyclin D1 overexpression. To clarify the potential contribution of altered DNA methylation in the development and/or progression of MCL we performed genome-wide methylation profiling of a large cohort of primary MCL tumors (n=132), MCL cell lines (n=6), and normal lymphoid tissue samples (n=31), using the Infinium HumanMethylation27 BeadChip. DNA methylation was compared to gene expression, chromosomal alterations, and clinicopathological parameters. Primary MCL displayed a heterogeneous methylation pattern dominated by DNA hypomethylation when compared to normal lymphoid samples. A total of 454 hypermethylated and 875 hypomethylated genes were identified as differentially methylated in at least 10% of primary MCL. Annotation analysis of hypermethylated genes recognized WNT pathway inhibitors and several tumor suppressor genes as frequently methylated, and a substantial fraction of these genes (22%) showed a significant downregulation of their transcriptional levels. Furthermore, we identified a subset of tumors with extensive CpG methylation that had an increased proliferation signature, higher number of chromosomal alterations, and poor prognosis. Our results suggest that a subset of MCL displays a dysregulation of DNA methylation characterized by the accumulation of CpG hypermethylation highly associated with increased proliferation that may influence the clinical behavior of the tumors. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 06/2013; · 6.20 Impact Factor

Publication Stats

6k Citations
1,337.86 Total Impact Points

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  • 1996–2014
    • The University of Arizona
      • Department of Pathology
      Tucson, Arizona, United States
  • 2013
    • The Rockefeller University
      • Laboratory of Developmental Genetics
      New York City, NY, United States
    • Barts Cancer Institute
      Londinium, England, United Kingdom
  • 2012
    • BC Cancer Research Centre
      Vancouver, British Columbia, Canada
    • University of British Columbia - Vancouver
      Vancouver, British Columbia, Canada
    • Yale University
      • Yale Cancer Center
      New Haven, CT, United States
  • 2006–2012
    • University of Nebraska at Omaha
      • • Department of Pathology and Microbiology
      • • Department of Biostatistics
      Omaha, NE, United States
  • 2004–2012
    • National Cancer Institute (USA)
      • Metabolism Branch
      Maryland, United States
  • 2011
    • Oslo University Hospital
      Kristiania (historical), Oslo County, Norway
    • City of Hope National Medical Center
      Duarte, California, United States
  • 2008–2011
    • University of Wuerzburg
      • Institute for Pathology
      Würzburg, Bavaria, Germany
    • BC Cancer Agency
      Vancouver, British Columbia, Canada
  • 2006–2011
    • National Institutes of Health
      • Branch of Metabolism
      Bethesda, MD, United States
  • 2005–2011
    • Arizona Research Center
      Phoenix, Arizona, United States
  • 2010
    • Roche
      Bâle, Basel-City, Switzerland
  • 1999–2010
    • University of Florida
      • • Department of Pediatrics
      • • Department of Plant Pathology
      Gainesville, FL, United States
  • 2009
    • Roswell Park Cancer Institute
      • Department of Immunology
      Buffalo, NY, United States
    • Hospital Clínic de Barcelona
      Barcino, Catalonia, Spain
  • 2008–2009
    • Cancer Research UK
      Londinium, England, United Kingdom