Erlend Bremertun Smeland

• Bai, Baoyan; Wise, Jillian Frances; Vodak, Daniel; Nakken, Sigve; Sharma, Ankush & Blaker, Yngvild Nuvin [Show all 23 contributors for this article] (2024). Multi-omics profiling of longitudinal samples reveals early genomic changes in follicular lymphoma. Blood Cancer Journal. 14:147(1), p. 1–12. doi: 10.1038/s41408-024-01124-5. Full text in Research Archive Show summary

  Follicular lymphoma (FL) is the most common indolent type of B-cell non-Hodgkin lymphoma. Advances in treatment have improved overall survival, but early relapse or transformation to aggressive disease is associated with inferior outcome. To identify early genetic events and track tumor clonal evolution, we performed multi-omics analysis of 94 longitudinal biopsies from 44 FL patients; 22 with transformation (tFL) and 22 with relapse without transformation (nFL). Deep whole-exome sequencing confirmed recurrent mutations in genes encoding epigenetic regulators (CREBBP, KMT2D, EZH2, EP300), with similar mutational landscape in nFL and tFL patients. Calculation of genomic distances between longitudinal samples revealed complex evolutionary patterns in both subgroups. CREBBP and KMT2D mutations were identified as genetic events that occur early in the disease course, and cases with CREBBP KAT domain mutations had low risk of transformation. Gains in chromosomes 12 and 18 (TCF4), and loss in 6q were identified as early and stable copy number alterations. Identification of such early and stable genetic events may provide opportunities for early disease detection and disease monitoring. Integrative analysis revealed that tumors with EZH2 mutations exhibited reduced gene expression of numerous histone genes, including histone linker genes. This might contribute to the epigenetic dysregulation in FL.

• Casey, Nicholas Paul; Klee, Clara Helena; Bøthun, Anne Fåne; Caulier, Benjamin William; Graczyk-Jarzynka, Agnieszka & Krawczyk, Marta [Show all 17 contributors for this article] (2023). Efficient chimeric antigen receptor targeting of a central epitope of CD22. Journal of Biological Chemistry. ISSN 0021-9258. 299(7). doi: 10.1016/j.jbc.2023.104883. Full text in Research Archive Show summary

  Chimeric antigen receptor (CAR) T-cell therapy has had considerable success in the treatment of B-cell malignancies. Targeting the B-lineage marker CD19 has brought great advances to the treatment of acute lymphoblastic leukemia and B-cell lymphomas. However, relapse remains an issue in many cases. Such relapse can result from downregulation or loss of CD19 from the malignant cell population or expression of alternate isoforms. Consequently, there remains a need to target alternative B-cell antigens and diversify the spectrum of epitopes targeted within the same antigen. CD22 has been identified as a substitute target in cases of CD19-negative relapse. One anti-CD22 antibody—clone m971—targets a membrane-proximal epitope of CD22 and has been widely validated and used in the clinic. Here, we have compared m971-CAR with a novel CAR derived from IS7, an antibody that targets a central epitope on CD22. The IS7-CAR has superior avidity and is active and specific against CD22-positive targets, including B-acute lymphoblastic leukemia patient-derived xenograft samples. Side-by-side comparisons indicated that while IS7-CAR killed less rapidly than m971-CAR in vitro, it remains efficient in controlling lymphoma xenograft models in vivo. Thus, IS7-CAR presents a potential alternative candidate for the treatment of refractory B-cell malignancies.

• Isaksen, Kathrine Thuestad; Galleberg, Renate Berget; Mastroianni, Maria Adele; Rinde, Marit; Rusten, Leiv Sindre & Barzenje, Dlawer Abdulla [Show all 15 contributors for this article] (2023). The Geriatric Prognostic Index: a clinical prediction model for survival of older diffuse large B-cell lymphoma patients treated with standard immunochemotherapy. Haematologica. ISSN 0390-6078. 108(9), p. 2454–2466. doi: 10.3324/haematol.2022.282289. Full text in Research Archive Show summary

  The International prognostic Index (IPI) is the most widely used clinical prediction model for diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), but may be suboptimal in older patients. We aimed to develop and externally validate a clinical prediction model for older, RCHOP- treated DLBCL patients by examining geriatric assessment and lymphoma-related parameters in real-world cohorts. A population-based training set of 365 R-CHOP-treated DLBCL patients ≥70 years was identified through the Cancer Registry of Norway. The external test set consisted of a population-based cohort of 193 patients. Data on candidate predictors were retrieved from the Cancer Registry and through review of clinical records. Cox regression models for 2-year overall survival were used for model selection. Activities of daily living, the Charlson Comorbidity Index, age, sex, albumin, stage, Eastern Cooperative Oncology Group performance status and lactate dehydrogenase level were identified as independent predictors and combined into a Geriatric Prognostic Index (GPI). The GPI demonstrated good discrimination (optimismcorrected C-index 0.752), and identified low-, intermediate- and high-risk groups with significantly different survivals (2- year overall survival, 94%, 65%, and 25%, respectively). At external validation, the continuous and grouped GPI demonstrated good discrimination (C-index 0.727 and 0.710, respectively) and the GPI groups had significantly different survivals (2-year overall survival 95%, 65%, and 44%, respectively). Both the continuous and grouped GPI showed better discrimination than the IPI, revised-IPI and National Comprehensive Cancer Network (NCCN)-IPI (C-index 0.621, 0.583, and 0.670, respectively). In conclusion, we have developed and externally validated a GPI for older DLBCL patients treated with R-CHOP that outperformed the IPI, revised-IPI and NCCN-IPI. A web-based calculator is available at https://wide.shinyapps. io/GPIcalculator/.

• Spasevska, Ivana; Sharma, Ankush; Steen, Chloe Beate; Josefsson, Sarah Elisabet; Blaker, Yngvild Nuvin & Kolstad, Arne [Show all 26 contributors for this article] (2023). Diversity of intratumoral regulatory T cells in B-cell non-Hodgkin lymphoma. Blood Advances. ISSN 2473-9529. 7(23), p. 7216–7230. doi: 10.1182/bloodadvances.2023010158. Full text in Research Archive Show summary

  Abstract Tumor-infiltrating regulatory T cells (Tregs) contribute to an immunosuppressive tumor microenvironment. Despite extensive studies, the prognostic impact of tumor-infiltrating Tregs in B-cell non-Hodgkin lymphomas (B-NHLs) remains unclear. Emerging studies suggest substantial heterogeneity in the phenotypes and suppressive capacities of Tregs, emphasizing the importance of understanding Treg diversity and the need for additional markers to identify highly suppressive Tregs. Here, we applied single-cell RNA sequencing and T-cell receptor sequencing combined with high-dimensional cytometry to decipher the heterogeneity of intratumoral Tregs in diffuse large B-cell lymphoma and follicular lymphoma (FL), compared with that in nonmalignant tonsillar tissue. We identified 3 distinct transcriptional states of Tregs: resting, activated, and unconventional LAG3+FOXP3− Tregs. Activated Tregs were enriched in B-NHL tumors, coexpressed several checkpoint receptors, and had stronger immunosuppressive activity compared with resting Tregs. In FL, activated Tregs were found in closer proximity to CD4+ and CD8+ T cells than other cell types. Furthermore, we used a computational approach to develop unique gene signature matrices, which were used to enumerate each Treg subset in cohorts with bulk gene expression data. In 2 independent FL cohorts, activated Tregs was the major subset, and high abundance was associated with adverse outcome. This study demonstrates that Tregs infiltrating B-NHL tumors are transcriptionally and functionally diverse. Highly immunosuppressive activated Tregs were enriched in tumor tissue but absent in the peripheral blood. Our data suggest that a deeper understanding of Treg heterogeneity in B-NHL could open new paths for rational drug design, facilitating selective targeting to improve antitumor immunity.

• Huse, Kanutte; Bai, Baoyan; Hilden, Vera Irene; Bollum, Lise Kristin; Våtsveen, Thea Kristin & Munthe, Ludvig Andre [Show all 10 contributors for this article] (2022). Mechanism of CD79A and CD79B support for IgM+ B cell fitness through B cell receptor surface expression. Journal of Immunology. ISSN 0022-1767. 209(10), p. 2042–2053. doi: 10.4049/jimmunol.2200144. Full text in Research Archive Show summary

  he BCR consists of surface-bound Ig and a heterodimeric signaling unit comprised of CD79A and CD79B. Upon cognate Ag recognition, the receptor initiates important signals for B cell development and function. The receptor also conveys Ag-independent survival signals termed tonic signaling. Although the requirement of a CD79A/CD79B heterodimer for BCR complex assembly and surface expression is well established based on mice models, few studies have investigated this in human mature B cells. In this study, we found that human tonsillar B cells with high surface expression of IgM or IgG had potentiated BCR signaling compared with BCRlow cells, and high IgM expression in germinal center B cells was associated with reduced apoptosis. We explored the mechanism for IgM surface expression by CRISPR/Cas9-induced deletion of CD79A or CD79B in four B lymphoma cell lines. Deletion of either CD79 protein caused loss of surface IgM in all cell lines and reduced fitness in three. From two cell lines, we generated stable CD79A or CD79B knockout clones and demonstrated that loss of CD79A or CD79B caused a block in N-glycan maturation and accumulation of immature proteins, compatible with retention of BCR components in the endoplasmic reticulum. Rescue experiments with CD79B wild-type restored surface expression of CD79A and IgM with mature glycosylation, whereas a naturally occurring CD79B G137S mutant disrupting CD79A/CD79B heterodimerization did not. Our study highlights that CD79A and CD79B are required for surface IgM expression in human B cells and illuminates the importance of the IgM expression level for signaling and fitness.

• Isaksen, Kathrine Thuestad; Mastroianni, Maria Adele; Rinde, Marit; Rusten, Leiv Sindre; Barzenje, Dlawer Abdulla & Ramslien, Lloyd Frode [Show all 13 contributors for this article] (2021). A simplified frailty score predicts survival and can aid treatment-intensity decisions in older patients with DLBCL. Blood Advances. ISSN 2473-9529. 5(22), p. 4771–4782. doi: 10.1182/bloodadvances.2021004777. Full text in Research Archive Show summary

  Diffuse large B-cell lymphoma (DLBCL) patients have a median age of 70 years. Yet, empirical knowledge on treatment for older patients is limited as they are frequently excluded from clinical trials. We aimed to construct a simplified frailty score and examine survival and treatment-related mortality (TRM) according to frailty status and treatment intensity in an older, real-world DLBCL population. All patients ≥70 years diagnosed with DLBCL 2006-2016 in south-eastern Norway (n=784) were included retrospectively, and divided into a training (n=522) and validation cohort (n=262). We constructed and validated a frailty score based on geriatric assessment variables, and examined survival and TRM according to frailty status and treatment. The frailty score identified three frailty groups with distinct survival and TRM, independent of established prognostic factors (2-year overall survival (OS) fit 82%, unfit 47%, frail 14%, P80%) was associated with better survival than attenuated R-CHOP (2-year OS 86% vs 70%, P=0.012), also in adjusted analysis. For unfit and frail patients, full-dose R-CHOP was not superior to attenuated R-CHOP, while an anthracycline-free regimen was associated with poorer survival in adjusted analyses. A simplified frailty score identified unfit and frail patients with higher risk of death and TRM, which can aid treatment intensity decisions in older DLBCL patients. In this study, fit patients benefit from full-dose R-CHOP, while unfit and frail patients have no benefit of full-dose R-CHOP over R-miniCHOP. An online calculator for assessment of the frailty score is available at https://wide.shinyapps.io/app-frailty/

• Ramis-Zaldivar, Joan Enric; Gonzalez-Farre, Blanca; Nicolae, Alina; Pack, Svetlana; Clot, Guillem & Nadeu, Ferran [Show all 26 contributors for this article] (2021). MAPK and JAK-STAT pathways dysregulation in plasmablastic lymphoma. Haematologica. ISSN 0390-6078. 106(10), p. 2682–2693. doi: 10.3324/haematol.2020.271957. Full text in Research Archive Show summary

  Plasmablastic lymphoma (PBL) is an aggressive B-cell lymphoma with an immunoblastic/large-cell morphology and terminal B-cell differentiation. The differential diagnosis from Burkitt lymphoma, plasma cell myeloma and some variants of diffuse large B-cell lymphoma may be challenging because of the overlapping morphological, genetic and immunophenotypic features. Furthermore, the genomic landscape in PBL is not well known. To characterize the genetic and molecular heterogeneity of these tumors, we investigated 34 cases of PBL using an integrated approach, including fluorescence in situ hybridization, targeted sequencing of 94 B-cell lymphoma-related genes, and copy-number arrays. PBL were characterized by high genetic complexity including MYC translocations (87%), gains of 1q21.1-q44, trisomy 7, 8q23.2- q24.21, 11p13-p11.2, 11q14.2-q25, 12p and 19p13.3-p13.13, losses of 1p33, 1p31.1-p22.3, 13q and 17p13.3-p11.2, and recurrent mutations of STAT3 (37%), NRAS and TP53 (33%), MYC and EP300 (19%) and CARD11, SOCS1 and TET2 (11%). Pathway enrichment analysis suggested a cooperative action between MYC alterations and MAPK (49%) and JAK-STAT (40%) signaling pathways. Of note, Epstein-Barr virus (EBV)-negative PBL cases had higher mutational and copy-number load and more frequent TP53, CARD11 and MYC mutations, whereas EBVpositive PBL tended to have more mutations affecting the JAK-STAT pathway. In conclusion, these findings further unravel the distinctive molecular heterogeneity of PBL identifying novel molecular targets and the different genetic profile of these tumors in relation to EBV infection.

• Oksvold, Morten Pedersen; Berglund, Ulrika Warpman; Gad, Helge; Bai, Baoyan; Stokke, Trond & Rein, Idun Dale [Show all 14 contributors for this article] (2021). Karonudib has potent anti-tumor effects in preclinical models of B-cell lymphoma. Scientific Reports. 11(1). doi: 10.1038/s41598-021-85613-8. Full text in Research Archive Show summary

  Abstract Chemo-immunotherapy has improved survival in B-cell lymphoma patients, but refractory/relapsed diseases still represent a major challenge, urging for development of new therapeutics. Karonudib (TH1579) was developed to inhibit MTH1, an enzyme preventing oxidized dNTP-incorporation in DNA. MTH1 is highly upregulated in tumor biopsies from patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, hence confirming a rationale for targeting MTH1. Here, we tested the efficacy of karonudib in vitro and in preclinical B-cell lymphoma models. Using a range of B-cell lymphoma cell lines, karonudib strongly reduced viability at concentrations well tolerated by activated normal B cells. In B-cell lymphoma cells, karonudib increased incorporation of 8-oxo-dGTP into DNA, and prominently induced prometaphase arrest and apoptosis due to failure in spindle assembly. MTH1 knockout cell lines were less sensitive to karonudib-induced apoptosis, but were displaying cell cycle arrest phenotype similar to the wild type cells, indicating a dual inhibitory role of the drug. Karonudib was highly potent as single agent in two different lymphoma xenograft models, including an ABC DLBCL patient derived xenograft, leading to prolonged survival and fully controlled tumor growth. Together, our preclinical findings provide a rationale for further clinical testing of karonudib in B-cell lymphoma.

• Köksal, Hakan; Dillard, Pierre; Juzeniene, Asta; Kvalheim, Gunnar; Smeland, Erlend B. & Myklebust, June Helen [Show all 8 contributors for this article] (2021). Combinatorial CAR design improves target restriction. Journal of Biological Chemistry. ISSN 0021-9258. 296:100116, p. 1–13. doi: 10.1074/jbc.RA120.016234. Full text in Research Archive Show summary

  CAR T cells targeting the B lymphocyte antigen CD19 have led to remarkable clinical results in B cell leukemia and lymphoma but eliminate all B lineage cells, leading to increased susceptibility to severe infections. As malignant B cells will express either immunoglobulin (Ig) light chain κ or λ, we designed a second-generation CAR targeting Igκ, IGK CAR. This construct demonstrated high target specificity but displayed reduced efficacy in the presence of serum IgG. Since CD19 CAR is insensitive to serum IgG, we designed various combinatorial CAR constructs in order to maintain the CD19 CAR T cell efficacy, but with IGK CAR target selectivity. The Kz-19BB design, combining CD19 CAR containing a 4-1BB costimulatory domain with an IGK CAR containing a CD3zeta stimulatory domain, maintained the target specificity of IgK CAR and was resistant to the presence of soluble IgG. Our results demonstrate that a combinatorial CAR approach can improve target selectivity and efficacy.

• Wise, Jillian; Nakken, Sigve; Steen, Chloe Beate; Vodak, Daniel; Trøen, Gunhild & Johannessen, Bjarne [Show all 24 contributors for this article] (2020). Mutational dynamics and immune evasion in diffuse large B-cell lymphoma explored in a relapse-enriched patient series. Blood Advances. ISSN 2473-9529. 4(9), p. 1859–1866. doi: 10.1182/bloodadvances.2019001325. Full text in Research Archive Show summary

  • Diagnostic and relapse diffuse large B-cell lymphoma (DLBCL) biopsies reveal increased mutational burden/loss of heterozygosity in HLA-A. • Serially sampled tumor biopsies provide insight into therapeutic targets and evolutionary divergence in relapsed/refractory DLBCL.

• Steen, Chloe Beate; Leich, Ellen; Myklebust, June Helen; Lockmer, Sandra; Wise, Jillian & Wahlin, Björn Engelbrekt [Show all 14 contributors for this article] (2019). A clinico-molecular predictor identifies follicular lymphoma patients at risk of early transformation after first-line immunotherapy. Haematologica. ISSN 0390-6078. 104(10), p. 460–464. doi: 10.3324/haematol.2018.209080. Full text in Research Archive
• Josefsson, Sarah Elisabet; Beiske, Klaus; Blaker, Yngvild Nuvin; Førsund, Mette S; Holte, Harald & Østenstad, Bjørn [Show all 15 contributors for this article] (2019). TIGIT and PD-1 mark intratumoral T cells with reduced effector function in B-cell non-Hodgkin lymphoma. Cancer immunology research. ISSN 2326-6066. 7(3), p. 355–362. doi: 10.1158/2326-6066.CIR-18-0351. Full text in Research Archive Show summary

  Checkpoint blockade can reverse T-cell exhaustion and promote antitumor responses. Although blocking the PD-1 pathway has been successful in Hodgkin lymphoma, response rates have been modest in B-cell non-Hodgkin lymphoma (NHL). Coblockade of checkpoint receptors may therefore be necessary to optimize antitumor T-cell responses. Here, characterization of coinhibitory receptor expression in intratumoral T cells from different NHL types identified TIGIT and PD-1 as frequently expressed coinhibitory receptors. Tumors from NHL patients were enriched in CD8+ and CD4+ T effector memory cells that displayed high coexpression of TIGIT and PD-1, and coexpression of these checkpoint receptors identified T cells with reduced production of IFNγ, TNFα, and IL2. The suppressed cytokine production could be improved upon in vitro culture in the absence of ligands. Whereas PD-L1 was expressed by macrophages, the TIGIT ligands CD155 and CD112 were expressed by lymphoma cells in 39% and 50% of DLBCL cases and in some mantle cell lymphoma cases, as well as by endothelium and follicular dendritic cells in all NHLs investigated. Collectively, our results show that TIGIT and PD-1 mark dysfunctional T cells and suggest that TIGIT and PD-1 coblockade should be further explored to elicit potent antitumor responses in patients with NHL.

• Huse, Kanutte; Wogsland, Cara Ellen; Polikowsky, Hannah G.; Diggins, Kirsten E.; Smeland, Erlend B & Myklebust, June [Show all 7 contributors for this article] (2019). Human Germinal Center B Cells Differ from Naive and Memory B Cells in CD40 Expression and CD40L-Induced Signaling Response. Cytometry Part A. ISSN 1552-4922. 95(4), p. 442–449. doi: 10.1002/cyto.a.23737. Full text in Research Archive
• Köksal, Hakan; Dillard, Pierre; Josefsson, Sarah Elisabet; Maggadottir, Solrun Melkorka; Pollmann, Sylvie Mireille & Fåne, Anne [Show all 16 contributors for this article] (2019). Preclinical development of CD37CAR T-cell therapy for treatment of B-cell lymphoma. Blood Advances. ISSN 2473-9529. 3(8), p. 1230–1243. doi: 10.1182/bloodadvances.2018029678. Full text in Research Archive Show summary

  T cells modified to express chimeric antigen receptor (CAR) targeting CD19 (CD19CAR) have produced remarkable clinical responses in patients with relapsed/refractory B-cell acute lymphoblastic leukemia. CD19CAR T-cell therapy has also demonstrated prominent effects in B-cell non-Hodgkin lymphoma (B-NHL) patients. However, a subset of patients who relapse after CD19CAR T-cell therapy have outgrowth of CD19− tumor cells. Hence, development of alternative CARs targeting other B-cell markers represents an unmet medical need for B-cell acute lymphoblastic leukemia and B-NHL. Here, we confirmed previous data by showing that, overall, B-NHL has high expression of CD37. A second-generation CD37CAR was designed, and its efficacy in T cells was compared with that of CD19CAR. In vitro assessment of cytotoxicity and T-cell function upon coculture of the CAR T cells with different target B-cell lymphoma cell lines demonstrated comparable efficacy between the 2 CARs. In an aggressive B-cell lymphoma xenograft model, CD37CAR T cells were as potent as CD19CAR T cells in controlling tumor growth. In a second xenograft model, using U2932 lymphoma cells containing a CD19− subpopulation, CD37CAR T cells efficiently controlled tumor growth and prolonged survival, whereas CD19CAR T cells had limited effect. We further show that, unlike CD19CAR, CD37CAR was not sensitive to antigen masking. Finally, CD37CAR reactivity was restricted to B-lineage cells. Collectively, our results demonstrated that CD37CAR T cells also can effectively eradicate B-cell lymphoma tumors when CD19 antigen expression is lost and support further clinical testing for patients with relapsed/refractory B-NHL.

• Våtsveen, Thea Kristin; Myhre, Marit Renee; Steen, Chloe Beate; Wälchli, Sébastien; Lingjærde, Ole Christian & Bai, Baoyan [Show all 14 contributors for this article] (2018). Artesunate shows potent anti-tumor activity in B-cell lymphoma. Journal of Hematology & Oncology. 11:23, p. 1–12. doi: 10.1186/s13045-018-0561-0. Full text in Research Archive Show summary

  Background Although chemo-immunotherapy has led to an improved overall survival for most B-cell lymphoma types, relapsed and refractory disease remains a challenge. The malaria drug artesunate has previously been identified as a growth suppressor in some cancer types and was tested as a new treatment option in B-cell lymphoma. Methods We included artesunate in a cancer sensitivity drug screen in B lymphoma cell lines. The preclinical properties of artesunate was tested as single agent in vitro in 18 B-cell lymphoma cell lines representing different histologies and in vivo in an aggressive B-cell lymphoma xenograft model, using NSG mice. Artesunate-treated B lymphoma cell lines were analyzed by functional assays, gene expression profiling, and protein expression to identify the mechanism of action. Results Drug screening identified artesunate as a highly potent anti-lymphoma drug.Artesunate induced potent growth suppression in most B lymphoma cells with an IC50 comparable to concentrations measured in serum from artesunate-treated malaria patients, while leaving normal B-cells unaffected. Artesunate markedly inhibited highly aggressive tumor growth in a xenograft model. Gene expression analysis identified endoplasmic reticulum (ER) stress and the unfolded protein response as the most affected pathways and artesunate-induced expression of the ER stress markers ATF-4 and DDIT3 was specifically upregulated in malignant B-cells, but not in normal B-cells. In addition, artesunate significantly suppressed the overall cell metabolism, affecting both respiration and glycolysis. Conclusions Artesunate demonstrated potent apoptosis-inducing effects across a broad range of B-cell lymphoma cell lines in vitro, and a prominent anti-lymphoma activity in vivo, suggesting it to be a relevant drug for treatment of B-cell lymphoma.

• Mottok, Anja; Wright, George; Rosenwald, Andreas; Ott, German; Ramsower, Colleen & Campo, Elias [Show all 25 contributors for this article] (2018). Molecular classification of primary mediastinal large B-cell lymphoma using routinely available tissue specimens. Blood. ISSN 0006-4971. 132(22), p. 2401–2405. doi: 10.1182/blood-2018-05-851154. Full text in Research Archive
• Holte, Harald; Beiske, Klaus; Boyle, Merrill; Trøen, Gunhild; Blaker, Yngvild Nuvin & Myklebust, June [Show all 13 contributors for this article] (2018). The MCL35 gene expression proliferation assay predicts high-risk MCL patients in a Norwegian cohort of younger patients given intensive first line therapy. British Journal of Haematology. ISSN 0007-1048. p. 1–10. doi: 10.1111/bjh.15518. Full text in Research Archive
• Josefsson, Sarah Elisabet Göthberg; Huse, Kanutte; Kolstad, Arne; Beiske, Klaus; Pende, Daniela & Steen, Chloe Beate [Show all 13 contributors for this article] (2017). T cells expressing checkpoint receptor TIGIT are enriched in follicular lymphoma tumors and characterized by reversible suppression of T-cell receptor signaling. Clinical Cancer Research. ISSN 1078-0432. 24(4), p. 870–881. doi: 10.1158/1078-0432.CCR-17-2337. Full text in Research Archive Show summary

  Purpose: T cells infiltrating follicular lymphoma (FL) tumors are considered dysfunctional, yet the optimal target for immune checkpoint blockade is unknown. Characterizing coinhibitory receptor expression patterns and signaling responses in FL T-cell subsets might reveal new therapeutic targets. Experimental Design: Surface expression of 9 coinhibitory receptors governing T-cell function was characterized in T-cell subsets from FL lymph node tumors and from healthy donor tonsils and peripheral blood samples, using high-dimensional flow cytometry. The results were integrated with T-cell receptor (TCR)-induced signaling and cytokine production. Expression of T-cell immunoglobulin and ITIM domain (TIGIT) ligands was detected by immunohistochemistry. Results: TIGIT was a frequently expressed coinhibitory receptor in FL, expressed by the majority of CD8 T effector memory cells, which commonly coexpressed exhaustion markers such as PD-1 and CD244. CD8 FL T cells demonstrated highly reduced TCR-induced phosphorylation (p) of ERK and reduced production of IFNγ, while TCR proximal signaling (p-CD3ζ, p-SLP76) was not affected. The TIGIT ligands CD112 and CD155 were expressed by follicular dendritic cells in the tumor microenvironment. Dysfunctional TCR signaling correlated with TIGIT expression in FL CD8 T cells and could be fully restored upon in vitro culture. The costimulatory receptor CD226 was downregulated in TIGIT+ compared with TIGIT− CD8 FL T cells, further skewing the balance toward immunosuppression. Conclusions: TIGIT blockade is a relevant strategy for improved immunotherapy in FL. A deeper understanding of the interplay between coinhibitory receptors and key T-cell signaling events can further assist in engineering immunotherapeutic regimens to improve clinical outcomes of cancer patients.

• Bollum, Lise Kristin; Huse, Kanutte; Oksvold, Morten Pedersen; Bai, Baoyan; Hilden, Vera Irene & Forfang, Lise [Show all 10 contributors for this article] (2017). BMP-7 induces apoptosis in human germinal center B cells and is influenced by TGF-β receptor type I ALK5. PLOS ONE. 12(5). doi: 10.1371/journal.pone.0177188. Full text in Research Archive Show summary

  Selection and maturation of B cells into plasma cells producing high-affinity antibodies occur in germinal centers (GC). GCs form transiently in secondary lymphoid organs upon antigen challenge, and the GC reaction is a highly regulated process. TGF-β is a potent negative regulator, but the influence of other family members including bone morphogenetic proteins (BMPs) is less known. Studies of human peripheral blood B lymphocytes showed that BMP-6 suppressed plasmablast differentiation, whereas BMP-7 induced apoptosis. Here, we show that human naïve and GC B cells had a strikingly different receptor expression pattern. GC B cells expressed high levels of BMP type I receptor but low levels of type II receptors, whereas naïve B cells had the opposite pattern. Furthermore, GC B cells had elevated levels of downstream signaling components SMAD1 and SMAD5, but reduced levels of the inhibitory SMAD7. Functional assays of GC B cells revealed that BMP-7 suppressed the viability-promoting effect of CD40L and IL-21, but had no effect on CD40L- and IL-21-induced differentiation into plasmablasts. BMP-7-induced apoptosis was counteracted by a selective TGF-β type I receptor (ALK4/5/7) inhibitor, but not by a selective BMP receptor type I inhibitor. Furthermore, overexpression of truncated ALK5 in a B-cell line counteracted BMP-7-induced apoptosis, whereas overexpression of truncated ALK4 had no effect. BMP-7 mRNA and protein was readily detected in tonsillar B cells, indicating a physiological relevance of the study. Altogether, we identified BMP-7 as a negative regulator of GC B-cell survival. The effect was counteracted by truncated ALK5, suggesting greater complexity in regulating BMP-7 signaling than previously believed.

• Scott, David W.; Abrisqueta, Pau; Wright, George W.; Slack, Graham W.; Mottok, Anja & Villa, Diego [Show all 31 contributors for this article] (2017). New molecular assay for the proliferation signature in mantle cell lymphoma applicable to formalin-fixed paraffin-embedded biopsies. Journal of Clinical Oncology. ISSN 0732-183X. 35(15), p. 1668–1677. doi: 10.1200/JCO.2016.70.7901. Full text in Research Archive
• Blaker, Yngvild Nuvin; Spetalen, Signe; Eide, Marianne Brodtkorb; Lingjærde, Ole Christian; Beiske, Klaus & Østenstad, Bjørn [Show all 13 contributors for this article] (2016). The tumour microenvironment influences survival and time to transformation in follicular lymphoma in the rituximab era. British Journal of Haematology. ISSN 0007-1048. 175(1), p. 102–114. doi: 10.1111/bjh.14201. Full text in Research Archive
• Fiskvik, Idun Hege; Beiske, Klaus; Delabie, Jan; Yri, Olav Erich; Spetalen, Signe & Karjalainen-Lindsberg, Marja-Liisa [Show all 10 contributors for this article] (2015). Combining MYC, BCL2 and TP53 gene and protein expression alterations improves risk stratification in diffuse large B-cell lymphoma. Leukemia and Lymphoma. ISSN 1042-8194. 56(6), p. 1742–1749. doi: 10.3109/10428194.2014.970550. Full text in Research Archive
• Oksvold, Morten Pedersen; Duyvestyn, Johanna M.; Dagger, Samantha A.; Taylor, Samuel J.; Forfang, Lise & Myklebust, June [Show all 8 contributors for this article] (2015). The targeting of human and mouse B lymphocytes by dasatinib. Experimental Hematology. ISSN 0301-472X. 43(5), p. 352–363.e4. doi: 10.1016/j.exphem.2015.01.008. Full text in Research Archive
• Wise, Jillian Frances; Nakken, Sigve; Vodak, Daniel; Trøen, Gunhild; Lingjærde, Ole Christian & Meza-Zepeda, Leonardo A [Show all 12 contributors for this article] (2015). Discovery of recurrent mutations associated with chemo-immunotherapy relapse in diffuse large B-cell lymphoma. Blood. ISSN 0006-4971. 126(23), p. 110–110. doi: 10.1182/blood.v126.23.110.110. Full text in Research Archive
• Blaker, Yngvild Nuvin; Brodtkorb, Marianne; Maddison, John; Hveem, Tarjei Sveinsgjerd; Nesheim, John Arne & Mohn, Hans Martin [Show all 13 contributors for this article] (2015). Computerized image analysis of the Ki-67 proliferation index in mantle cell lymphoma. Histopathology. ISSN 0309-0167. 67(1), p. 62–69. doi: 10.1111/his.12624. Full text in Research Archive
• Riihijärvi, Sari; Fiskvik, Idun Hege; Taskinen, Minna; Vajavaara, Heli; Tikkala, Maria & Yri, Olav Erich [Show all 11 contributors for this article] (2015). Prognostic influence of macrophages in patients with diffuse large B-Cell lymphoma: A correlative study from a nordic phase ii trial. Haematologica. ISSN 0390-6078. 100(2), p. 238–245. doi: 10.3324/haematol.2014.113472. Full text in Research Archive
• Scott, David W.; Wright, George W.; Williams, P.Mickey; Lih, Chih-Jian; Walsh, William & Jaffe, Elaine S. [Show all 24 contributors for this article] (2014). Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood. ISSN 0006-4971. 123(8), p. 1214–1217. doi: 10.1182/blood-2013-11-536433. Full text in Research Archive
• Yang, Yibin; Schmitz, Roland; Mitala, Joseph; Whiting, Amanda; Xiao, Wenming & Ceribelli, Michele [Show all 29 contributors for this article] (2014). Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms. Cancer Discovery. ISSN 2159-8274. 4(4), p. 480–493. doi: 10.1158/2159-8290.CD-13-0915. Full text in Research Archive
• Oksvold, Morten Pedersen; Kullmann, Anette; Forfang, Lise; Kierulf, Bente; Li, Mu & Brech, Andreas [Show all 10 contributors for this article] (2014). Expression of B-Cell surface antigens in subpopulations of exosomes released from B-cell lymphoma cells. Clinical Therapeutics. ISSN 0149-2918. 36(6), p. 847–862.e1. doi: 10.1016/j.clinthera.2014.05.010. Full text in Research Archive
• Muppidi, Jagan R.; Schmitz, Roland; Green, Jesse A.; Xiao, Wenming; Larsen, Adrien B. & Braun, Sterling E. [Show all 24 contributors for this article] (2014). Loss of signalling via G α 13 in germinal centre B-cell-derived lymphoma. Nature. ISSN 0028-0836. 516(7530), p. 254–258. doi: 10.1038/nature13765. Full text in Research Archive
• Wahlin, Björn Engelbrekt; Sundström, Christer; Sander, Birgitta; Christensson, Birger; Jeppsson-Ahlberg, Åsa & Hjalmarsson, Eric [Show all 11 contributors for this article] (2014). Higher World Health Organization grades of follicular lymphoma correlate with better outcome in two Nordic Lymphoma Group trials of rituximab without chemotherapy. Leukemia and Lymphoma. ISSN 1042-8194. 55(2), p. 288–295. doi: 10.3109/10428194.2013.802778. Full text in Research Archive
• Brodtkorb, Marianne; Lingjærde, Ole Christian; Huse, Kanutte; Trøen, Gunhild; Hystad, Marit Elise & Hilden, Vera Irene [Show all 12 contributors for this article] (2014). Whole-genome integrative analysis reveals expression signatures predicting transformation in follicular lymphoma. Blood. ISSN 0006-4971. 123(7), p. 1051–1054. doi: 10.1182/blood-2013-07-512392. Full text in Research Archive
• Bethge, Nicole; Honne, Hilde; Andresen, Kim; Hilden, Vera Irene; Trøen, Gunhild & Liestøl, Knut [Show all 10 contributors for this article] (2014). A gene panel, including LRP12, is frequently hypermethylated in major types of B-cell lymphoma. PLOS ONE. 9(9). doi: 10.1371/journal.pone.0104249. Full text in Research Archive
• Blaker, Yngvild Nuvin; Eide, Marianne Brodtkorb; Liestøl, Knut; Lauritzsen, Grete Fossum; Kolstad, Arne & Fosså, Alexander [Show all 8 contributors for this article] (2014). High dose chemotherapy with autologous stem cell transplant for patients with transformed B-cell non-Hodgkin lymphoma in the rituximab era. Leukemia and Lymphoma. ISSN 1042-8194. 55(10), p. 2319–2327. doi: 10.3109/10428194.2013.871632. Full text in Research Archive
• Bethge, Nicole; Lothe, Ragnhild A; Honne, Hilde; Andresen, Kim; Trøen, Gunhild & Eknæs, Mette [Show all 11 contributors for this article] (2014). Colorectal cancer DNA methylation marker panel validated with high performance in Non-Hodgkin lymphoma. Epigenetics. ISSN 1559-2294. 9(3), p. 428–436. doi: 10.4161/epi.27554. Full text in Research Archive
• Yri, Olav Erich; Ekstrøm, Per Olaf; Hilden, Vera Irene; Gaudernack, Gustav; Liestøl, Knut & Smeland, Erlend B [Show all 7 contributors for this article] (2013). Influence of polymorphisms in genes encoding immunoregulatory proteins and metabolizing enzymes on susceptibility and outcome in patients with diffuse large B-cell lymphoma treated with rituximab. Leukemia and Lymphoma. ISSN 1042-8194. 54(10), p. 2205–2214. doi: 10.3109/10428194.2013.774392. Full text in Research Archive
• Bödör, Csaba; Grossmann, Vera; Popov, Nikolay; Okosun, Jessica; O'Riain, Ciarán & Tan, King [Show all 34 contributors for this article] (2013). EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood. ISSN 0006-4971. 122(18), p. 3165–3168. doi: 10.1182/blood-2013-04-496893. Full text in Research Archive
• Bethge, Nicole; Honne, Hilde; Hilden, Vera Irene; Trøen, Gunhild; Eknæs, Mette & Liestøl, Knut [Show all 10 contributors for this article] (2013). Identification of Highly Methylated Genes across Various Types of B-Cell Non-Hodgkin Lymphoma. PLOS ONE. 8(11). doi: 10.1371/journal.pone.0079602. Full text in Research Archive
• Fiskvik, Idun Hege; Aamot, Hege Vangstein; Delabie, Jan; Smeland, Erlend B; Stokke, Trond & Heim, Sverre [Show all 7 contributors for this article] (2013). Karyotyping of diffuse large B-cell lymphomas: loss of 17p is associated with poor patient outcome. European Journal of Haematology. ISSN 0902-4441. 91(4), p. 332–338. doi: 10.1111/ejh.12171. Full text in Research Archive
• Wahlin, Björn Engelbrekt; Yri, Olav Erich; Kimby, Eva; Holte, Harald; Delabie, Jan & Smeland, Erlend B [Show all 9 contributors for this article] (2012). Clinical significance of the WHO grades of follicular lymphoma in a population-based cohort of 505 patients with long follow-up times. British Journal of Haematology. ISSN 0007-1048. 156(2), p. 225–233. doi: 10.1111/j.1365-2141.2011.08942.x. Full text in Research Archive
• Yri, Olav Erich; Ekstrøm, Per Olaf; Hilden, Vera Irene; Gaudernack, Gustav; Liestøl, Knut & Smeland, Erlend B [Show all 7 contributors for this article] (2012). Polymorphisms in genes encoding interleukin-10 and drug metabolizing enzymes GSTP1, GSTT1, GSTA1 and UGT1A1 influence risk and outcome in Hodgkin lymphoma. Leukemia and Lymphoma. ISSN 1042-8194. 53(10), p. 1934–1944. doi: 10.3109/10428194.2012.682307. Full text in Research Archive
• Schmitz, Roland; Young, Ryan M.; Ceribelli, Michele; Jhavar, Sameer; Xiao, Wenming & Zhang, Meili [Show all 42 contributors for this article] (2012). Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature. ISSN 0028-0836. 490(7418), p. 116–120. doi: 10.1038/nature11378. Full text in Research Archive
• Huse, Kanutte; Bakkebø, Maren; Waelchli, Sebastien; Oksvold, Morten Pedersen; Hilden, Vera Irene & Forfang, Lise [Show all 11 contributors for this article] (2012). Role of Smad Proteins in Resistance to BMP-Induced Growth Inhibition in B-Cell Lymphoma. PLOS ONE. 7(10). doi: 10.1371/journal.pone.0046117. Full text in Research Archive Show summary

  Bone morphogenetic protein (BMP) expression and signaling are altered in a variety of cancers, but the functional impact of these alterations is uncertain. In this study we investigated the impact of expression of multiple BMPs and their signaling pathway components in human B-cell lymphoma. BMP messages, in particular BMP7, were detected in normal and malignant B cells. Addition of exogenous BMPs inhibited DNA synthesis in most lymphoma cell lines examined, but some cell lines were resistant. Tumor specimens from three out of five lymphoma patients were also resistant to BMPs, as determined by no activation of the BMP effectors Smad1/5/8. We have previously shown that BMP-7 potently induced apoptosis in normal B cells, which was in contrast to no or little inhibitory effect of this BMP in the lymphoma cells tested. BMP-resistance mechanisms were investigated by comparing sensitive and resistant cell lines. While BMP receptors are downregulated in many cancers, we documented similar receptor levels in resistant and sensitive lymphoma cells. We found a positive correlation between activation of Smad1/5/8 and inhibition of DNA synthesis. Gene expression analysis of two independent data sets showed that the levels of inhibitory Smads varied across different B-cell lymphoma. Furthermore, stable overexpression of Smad7 in two different BMP-sensitive cell lines with low endogenous levels of SMAD7, rendered them completely resistant to BMPs. This work highlights the role of Smads in determining the sensitivity to BMPs and shows that upregulation of Smad7 in cancer cells is sufficient to escape the negative effects of BMPs.

• Oksvold, Morten Pedersen; Pedersen, Nina Marie; Forfang, Lise & Smeland, Erlend B (2012). Effect of cycloheximide on epidermal growth factor receptor trafficking and signaling. FEBS Letters. ISSN 0014-5793. 586(20), p. 3575–3581. doi: 10.1016/j.febslet.2012.08.022. Full text in Research Archive
• Bakkebø, Maren; Huse, Kanutte; Hilden, Vera Irene; Forfang, Lise; Myklebust, June & Smeland, Erlend B [Show all 7 contributors for this article] (2012). SARA is dispensable for functional TGF-beta signaling. FEBS Letters. ISSN 0014-5793. 586(19), p. 3367–3372. doi: 10.1016/j.febslet.2012.07.027. Full text in Research Archive
• Malumbres, Raquel; Fresquet, Vicente; Roman-Gomez, Jose; Bobadilla, Miriam; Robles, Eloy F. & Altobelli, Giovanna G. [Show all 14 contributors for this article] (2011). LMO2 expression reflects the different stages of blast maturation and genetic features in B-cell acute lymphoblastic leukemia and predicts clinical outcome. Haematologica. ISSN 0390-6078. 96(7), p. 980–986. doi: 10.3324/haematol.2011.040568. Full text in Research Archive
• Ngo, Vu N.; Young, Ryan M.; Schmitz, Roland; Jhavar, Sameer; Xiao, Wenming & Lim, Kian-Huat [Show all 31 contributors for this article] (2011). Oncogenically active MYD88 mutations in human lymphoma. Nature. ISSN 0028-0836. 470(7332), p. 115–U133. doi: 10.1038/nature09671. Full text in Research Archive
• Josefsen, Dag; Forfang, Lise; Dyrhaug, Marianne; Blystad, Anne Kirsti; Stokke, Trond & Smeland, Erlend B [Show all 7 contributors for this article] (2011). Side population cells in highly enriched CD34-positive cells from peripheral blood progenitor cells identify an immature subtype of hematopoietic progenitor cells but do not predict time to engraftment in patients treated with high-dose therapy. European Journal of Haematology. ISSN 0902-4441. 87(6), p. 494–502. doi: 10.1111/j.1600-0609.2011.01681.x. Full text in Research Archive
• Huse, Kanutte; Bakkebø, Maren Kolltveit; Oksvold, Morten Pedersen; Forfang, Lise; Hilden, Vera Irene & Stokke, Trond [Show all 8 contributors for this article] (2011). Bone morphogenetic proteins inhibit CD40L/IL-21-induced Ig production in human B cells: Differential effects of BMP-6 and BMP-7. European Journal of Immunology. ISSN 0014-2980. 41(11), p. 3135–3145. doi: 10.1002/eji.201141558. Full text in Research Archive
• Eide, Marianne Brodtkorb; Liestøl, Knut; Lingjærde, Ole Christian; Hystad, Marit Elise; Kresse, Stine Henrichson & Meza, Leonardo Zepeda [Show all 12 contributors for this article] (2010). Genomic alterations reveal potential for higher grade transformation in follicular lymphoma and confirm parallel evolution of tumor cell clones. Blood. ISSN 0006-4971. 116(9), p. 1489–1497. doi: 10.1182/blood-2010-03-272278. Full text in Research Archive
• Davis, RE; Ngo, VN; Lenz, Georg; Tolar, Pavel; Young, RM & Romesser, PB [Show all 37 contributors for this article] (2010). Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. ISSN 0028-0836. 463(7277), p. 88–92. doi: 10.1038/nature08638. Full text in Research Archive
• Bakkebø, Maren Kolltveit; Huse, Kanutte; Hilden, Vera Irene; Smeland, Erlend B & Oksvold, Morten Pedersen (2010). TGF-beta-induced growth inhibition in B-cell lymphoma correlates with Smad1/5 signalling and constitutively active p38 MAPK. BMC Immunology. 11. doi: 10.1186/1471-2172-11-57. Full text in Research Archive
• Rui, Lixin; Emre, N. C. Tolga; Kruhlak, Michael J.; Chung, Hye-Jung; Steidl, Christian & Slack, Graham [Show all 35 contributors for this article] (2010). Cooperative Epigenetic Modulation by Cancer Amplicon Genes. Cancer Cell. ISSN 1535-6108. 18(6), p. 590–605. doi: 10.1016/j.ccr.2010.11.013. Full text in Research Archive
• O'Riain, C; O'Shea, DM; Yang, Y; Dieu, R Le; Gribben, JG & Summers, K [Show all 27 contributors for this article] (2009). Array-based DNA methylation profiling in follicular lymphoma. Leukemia. ISSN 0887-6924. 23(10), p. 1858–1866. doi: 10.1038/leu.2009.114. Full text in Research Archive
• Holte, Harald; Kvaløy, Stein Olav; Delabie, Jan; Trøen, Gunhild & Smeland, Erlend B (2009). Molekylær diagnostikk av maligne lymfomer. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 129(22), p. 2352–2356. Full text in Research Archive
• Lenz, Georg; Davis, RE; Ngo, VN; Lam, L; George, TC & Wright, GW [Show all 22 contributors for this article] (2008). Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science. ISSN 0036-8075. 319(5870), p. 1676–1679. doi: 10.1126/science.1153629. Full text in Research Archive
• Lenz, G; Wright, G; Dave, SS; Xiao, W; Powell, J & Zhao, H [Show all 50 contributors for this article] (2008). Stromal Gene Signatures in Large-B-Cell Lymphomas. New England Journal of Medicine. ISSN 0028-4793. 359(22), p. 2313–2323. Full text in Research Archive
• O'Shea, D; O'Riain, C; Taylor, C; Waters, R; Carlotti, E & MacDougall, F [Show all 20 contributors for this article] (2008). The presence of TP53 mutation at diagnosis of follicular lymphoma identifies a high-risk group of patients with shortened time to disease progression and poorer overall survival. Blood. ISSN 0006-4971. 112, p. 3126–3129. doi: 10.1182/blood-2008-05-154013. Full text in Research Archive
• Sivertsen, Einar; Huse, K; Hystad, ME; Kersten, C; Smeland, Erlend B & Myklebust, JH (2007). Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells. European Journal of Immunology. ISSN 0014-2980. 37, p. 2937–2948. doi: 10.1002/eji.200636759. Full text in Research Archive
• Sivertsen, Einar; Huse, Kanutte; Hystad, Marit Elise; Kersten, Christian; Smeland, Erlend B & Myklebust, June (2007). Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat Tag cells. European Journal of Immunology. ISSN 0014-2980. 37(10), p. 2937–2948. Full text in Research Archive
• Hystad, ME; Myklebust, JH; Bø, Trond Hellem; Bo, TH; Sivertsen, EA & Rian, E [Show all 13 contributors for this article] (2007). Characterization of early stages of human B cell development by gene expression profiling. Journal of Immunology. ISSN 0022-1767. 179, p. 3662–3671. Full text in Research Archive
• Sivertsen, EA; Hystad, ME; Gufzkow, Kristine B.; Dosen, G; Smeland, Erlend B & Blomhoff, Heidi Kiil [Show all 7 contributors for this article] (2006). PI3K/Akt-dependent Epo-induced signalling and target genes in human early erythroid progenitor cells. British Journal of Haematology. ISSN 0007-1048. 135, p. 117–128. Full text in Research Archive
• Sivertsen, Einar Andreas; Hystad, Marit Elise; Gutzkow, Kristine B; Døsen, Guri; Smeland, Erlend B & Blomhoff, Heidi Kiil [Show all 7 contributors for this article] (2006). PI3K/Akt-dependent Epo-induced signalling and target genes in human early erythroid progenitor cells. British Journal of Haematology. ISSN 0007-1048. 135(1), p. 117–128. Full text in Research Archive
• Dave, SS; Fu, K; Wright, GW; Lam, LT; Kluin, P & Boerma, EJ [Show all 38 contributors for this article] (2006). Molecular diagnosis of Burkitt's lymphoma. New England Journal of Medicine. ISSN 0028-4793. 354, p. 2431–2442. Full text in Research Archive
• Kersten, Christian; Dosen, Guri; Myklebust, June; Sivertsen, Einar; Hystad, Marit Elise & Smeland, Erlend B [Show all 7 contributors for this article] (2006). BMP-6 inhibits human bone marrow B lymphopoiesis - Upregulation of Id1 and Id3. Experimental Hematology. ISSN 0301-472X. 34(1), p. 72–81. doi: 10.1016/j.exphem.2005.09.010. Full text in Research Archive
• Torlakovic, Emina; Malecka, Agnieszka Maria; Myklebust, June Helen; Tierens, Anne; Åsheim, Hans-Christian & Smeland, Erlend B. [Show all 8 contributors for this article] (2005). PU.1 protein expression has a positive linear association with protein expression of germinal centre B cell genes including BCL-6, CD10, CD20 and CD22: identification of PU.1 putative binding sites in the BCL-6 promotor. Journal of Pathology. ISSN 0022-3417. doi: 10.1002/path.1777. Full text in Research Archive
• Bea, Silvia; Zettl, A; Wright, George; Salaverria, I; Jahn, Philipp & Moreno, Victor [Show all 12 contributors for this article] (2005). Diffuse large B-cell lymphoma subgrups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood. ISSN 0006-4971. 106(9), p. 3183–3190. doi: 10.1182/blood-2005-04-1399. Full text in Research Archive
• Kersten, Christian; Sivertsen, Einar; Hystad, Marit Elise; Forfang, Lise; Smeland, Erlend B & Myklebust, June (2005). BMP-6 inhibits growth of mature human B cells; induction of Smad phosphorylation and upregulation of Id1. BMC Immunology. 6, p. 9–9. doi: 10.1186/1471-2172-6-9. Full text in Research Archive Show summary

  Background Bone morphogenetic proteins (BMPs) belong to the TGF-β superfamily and are secreted proteins with pleiotropic roles in many different cell types. A potential role of BMP-6 in the immune system has been implied by various studies of malignant and rheumatoid diseases. In the present study, we explored the role of BMP-6 in normal human peripheral blood B cells. Results The B cells were found to express BMP type I and type II receptors and BMP-6 rapidly induced phosphorylation of Smad1/5/8. Furthermore, Smad-phosphorylation was followed by upregulation of Id1 mRNA and Id1 protein, whereas Id2 and Id3 expression was not affected. Furthermore, we found that BMP-6 had an antiproliferative effect both in naïve (CD19+CD27-) and memory B cells (CD19+CD27+) stimulated with anti-IgM alone or the combined action of anti-IgM and CD40L. Additionally, BMP-6 induced cell death in activated memory B cells. Importantly, the antiproliferative effect of BMP-6 in B-cells was completely neutralized by the natural antagonist, noggin. Furthermore, B cells were demonstrated to upregulate BMP-6 mRNA upon stimulation with anti-IgM. Conclusion In mature human B cells, BMP-6 inhibited cell growth, and rapidly induced phosphorylation of Smad1/5/8 followed by an upregulation of Id1.

• Torlakovic, Emina; Malecka, A; Aasheim, HC; Tierens, Anne; Nesland, Jahn M & Smeland, Erlend B [Show all 9 contributors for this article] (2005). PU.1 protein expression has a positive linear association with protein expression of germinal centre B cell genes including BCL-6, CD10, CD20 and CD22: Identification of PU.1 putative binding sites in the BCL-6 promotor. Journal of Pathology. ISSN 0022-3417. 206, p. 312–319. Full text in Research Archive
• Kersten, Christian; Delabie, Jan; Gaudernack, Gustav; Smeland, Erlend B & Fosså, Alexander (2004). Analysis of the autoantibody repertoire in Burkitt's lymphoma patients: frequent response against the transcription factor ATF-2. Cancer Immunology and Immunotherapy. ISSN 0340-7004. 53(12), p. 1119–1126. doi: 10.1007/s00262-004-0558-0. Full text in Research Archive
• Dave, Sandeep S; Wright, George; Tan, Bruce; Rosenwald, Andreas; Gascoyne, Randy D & Chan, Wing C [Show all 22 contributors for this article] (2004). Survival following diagnosis of follicular lymphoma is predicted by molecular features of non-malignant tumor-infiltrating immune cells. New England Journal of Medicine. ISSN 0028-4793. 351(21), p. 2159–2169. Full text in Research Archive
• Fosså, Alexander; Alsøe, Lene; Crameri, R; Berner, Aasmund; Hernes, Eivor & Funderud, Steinar [Show all 8 contributors for this article] (2004). Serological cloning of cancer/testis antigens expressed in prostate cancer using cDNA phage surface display. Cancer Immunology and Immunotherapy. ISSN 0340-7004. 53, p. 431–438. Full text in Research Archive
• Fosså, Alexander; Berner, Aasmund; Fosså, Sophie Dorothea; Hernes, Eivor; Gaudernack, Gustav & Smeland, Erlend B (2004). NY-ESO-1 proteine expression and humoral immune responses in prostate cancer. The Prostate. ISSN 0270-4137. 59(4), p. 440–447. Full text in Research Archive
• Rosenwald, A.; Wright, Georg Henrik von; Wiestner, A; Chan, W.C.; Connors, J.M. & Campo, w [Show all 10 contributors for this article] (2003). The proliferation gene signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell. ISSN 1535-6108. 3(2), p. 185–197. Full text in Research Archive
• Rosenwald, A.; Wright, Georg Henrik von; Leroy, K; Gaulard, P; Yu, Xing-Qing & Gascoyne, R.D. [Show all 15 contributors for this article] (2003). Molecular diagnosis of primary mediastinal b cell lympho,a identifies a clinically favourable subgroup of diffuse large B cell lymphoma related to Hodgkin's lymhoma. Journal of Experimental Medicine (JEM). ISSN 0022-1007. 198(6), p. 851–862. Full text in Research Archive
• Smeland, Erlend B; Holte, Harald & Delabie, Jan (2003). Molecular diagnosis of primary mediastinal B-cell lymphoma related to Hodgin lymphoma. Journal of Experimental Medicine (JEM). ISSN 0022-1007. 198(6), p. 851–862. Full text in Research Archive
• Smeland, Erlend B; Kvaløy, Stein; Holte, Harald & Delabie, Jan (2003). The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell. ISSN 1535-6108. 3(2), p. 185–197. Full text in Research Archive
• Rosenwald, Andreas; Wright, George; Wiestner, Adrian; Chan, Wing C; Connors, Joseph M & Campo, Elias [Show all 13 contributors for this article] (2003). The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. Cancer Cell. ISSN 1535-6108. 3(2), p. 185–197. Full text in Research Archive
• Rosenwald, A.; Wright, George; Leroy, Karen; Xin, Yu; Smeland, Erlend B & Kvaløy, Stein [Show all 8 contributors for this article] (2003). Molecular diagnosis of primary mediastinal B-cell lymphoma identifies a clincally favorable subgroup of diffuse large B-cell lymphoma related to Hodgkin lymphoma. Journal of Experimental Medicine (JEM). ISSN 0022-1007. 198(6), p. 851–862. Full text in Research Archive
• Josefsen, Dag & Smeland, Erlend B (2002). Retinoic receptors and apoptosis of human CD34 positive hematopoietic progenitor cells, Modern Trends in Skin Pharmacology. Molecular and Clinicl Aspects. D. Tsambaos and H. Merck. p. 117–128. Full text in Research Archive
• Rosenwald, A.; Smeland, Erlend B; Kvaløy, Stein; Delabie, Jan; Holte, Hege Ruge & Krajci, Peter [Show all 7 contributors for this article] (2002). The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. New England Journal of Medicine. ISSN 0028-4793. 346(25), p. 1937–1947. Full text in Research Archive
• Wang, Jacob Edward; Delabie, Jan; Aasheim, Hans-Christian; Smeland, Erlend B & Myklebost, Ola (2002). Clustering of the SOM easily reveals distinct gene expression patterns: results of a reanalysis of lymphoma study. Bioinformatics. ISSN 1367-4803. 3(1), p. 36–36. Full text in Research Archive
• Wang, Junbai; Delabie, Jan; aasheim, Hans-Christian; Smeland, Erlend B & Myklebost, Ola (2002). Clustering of the SOM easily reveals distinct gene expression patterns: results of a reanalysis of lymphoma study. BMC Bioinformatics. Full text in Research Archive
• Wang, Junbai; Delabie, Jan; Åsheim, Hans-Christian; Smeland, Erlend B. & Myklebost, Ola (2002). Clustering of the SOM easily reveals distinct gene expression patterns: results of a reanalysis of lymphoma study. BMC Bioinformatics. doi: 10.1186/1471-2105-3-36. Full text in Research Archive Show summary

  Background A method to evaluate and analyze the massive data generated by series of microarray experiments is of utmost importance to reveal the hidden patterns of gene expression. Because of the complexity and the high dimensionality of microarray gene expression profiles, the dimensional reduction of raw expression data and the feature selections necessary for, for example, classification of disease samples remains a challenge. To solve the problem we propose a two-level analysis. First self-organizing map (SOM) is used. SOM is a vector quantization method that simplifies and reduces the dimensionality of original measurements and visualizes individual tumor sample in a SOM component plane. Next, hierarchical clustering and K-means clustering is used to identify patterns of gene expression useful for classification of samples. Results We tested the two-level analysis on public data from diffuse large B-cell lymphomas. The analysis easily distinguished major gene expression patterns without the need for supervision: a germinal center-related, a proliferation, an inflammatory and a plasma cell differentiation-related gene expression pattern. The first three patterns matched the patterns described in the original publication using supervised clustering analysis, whereas the fourth one was novel. Conclusions Our study shows that by using SOM as an intermediate step to analyze genome-wide gene expression data, the gene expression patterns can more easily be revealed. The "expression display" by the SOM component plane summarises the complicated data in a way that allows the clinician to evaluate the classification options rather than giving a fixed diagnosis.

• Rosenwald, A.; Wright, Georg Henrik von; Chan, W.C.; Connors, J.M.; Campo, E. & Risher, R. [Show all 10 contributors for this article] (2002). The use of molecular profiling to predict survival after chemotherapy for diffuse large B-cell lymphoma. New England Journal of Medicine. ISSN 0028-4793. 346(25), p. 1937–1947. Full text in Research Archive
• Myklebust, June Helene; Blomhoff, Heidi Kiil; Rusten, Leiv & Smeland, Erlend B (2002). Activation of phosphatidylinosol 3-kinase is important for erythropoietin-induced erythropoiesis from CD34+ hematopoietic progenitor cells. Experimental Hematology. ISSN 0301-472X. 30, p. 990–1000. Full text in Research Archive
• Myklebust, June Helene; Blomhoff, Heidi Kiil; Rusten, Leiv; Stokke, Trond & Smeland, Erlend B (2002). Activation of PI3K but not p38 or ERK is regulated for EPO-induced erythropoiesis form CD34+ hematopoietic cells. Experimental Hematology. ISSN 0301-472X. 30, p. 990–1000. Full text in Research Archive
• Smeland, Erlend B & Funderud, Steinar (2001). Anders Jahres medisinske priser 2001. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 121, p. 2751–2752. Full text in Research Archive
• Lyngstadaas, Anita & Smeland, Erlend B (2001). Genterapi - status og anbefalinger for norsk medisin. Den norske tannlegeforenings Tidende. ISSN 0029-2303. 111(4), p. 10–16. Full text in Research Archive
• Stokke, Trond; D'Angelis, Paula; Smedshammer, L.; Galteland, Eivind; Steen, Harald & Smeland, Erlend B [Show all 7 contributors for this article] (2001). Loss of chromosome 11q21-23.1 and 17p and gain of chromosome 6p are independent prognostic indicators in B-cell Non-Hodgkin's lymphoma. British Journal of Cancer. ISSN 0007-0920. 85, p. 1900–1913. Full text in Research Archive

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• Bai, Baoyan; Vodák, Daniel; Nakken, Sigve; Wise, Jillian; Blaker, Yngvild Nuvin & Lingjærde, Ole Christian [Show all 18 contributors for this article] (2019). Deep profiling of genetic aberrations and clonal evolution in follicular lymphoma. Blood. ISSN 0006-4971. 134(1), p. 20–20. doi: 10.1182/blood-2019-128403. Full text in Research Archive
• Malecka, Agnieszka Maria; Tierens, Anne; Østlie, Ingunn; Schmitz, Roland; Trøen, Gunhild & Spetalen, Signe [Show all 10 contributors for this article] (2015). Primary diffuse large B-cell lymphoma associated with clonally-related monoclonal B lymphocytosis indicates a common precursor cell. Haematologica. ISSN 0390-6078. 100(10), p. e415–e418. doi: 10.3324/haematol.2015.126656. Full text in Research Archive
• Yri, Olav Erich; Hilden, Vera Irene; Smeland, Erlend B; Gaudernack, Gustav; Liestøl, Knut & Ekstrøm, Per Olaf [Show all 7 contributors for this article] (2011). GENETIC POLYMORPHISMS INFLUENCE THE RISK OF HODGKIN'S LYMPHOMA. Annals of Oncology. ISSN 0923-7534. 22, p. 138–138. Full text in Research Archive
• Wahlin, Björn Engelbrekt; Sundström, Christer; Holte, Harald; Sander, Birgitta; Østenstad, Bjørn & Brown, Peter de Nully [Show all 10 contributors for this article] (2011). Increasing Grades of Follicular Lymphoma Correlate with Better Prognosis in Patients Treated with Rituximab. Blood. ISSN 0006-4971. 118(21), p. 713–713. Full text in Research Archive
• Huse, Kanutte; Bakkebø, Maren; Forfang, Lise; Hilden, Vera Irene; Smeland, Erlend B & Myklebust, June (2010). Bone Morphogenetic Proteins Inhibit CD40L-and IL-21-Induced Ig Production In Human B Cells: Differential Effects of BMP-6 and BMP-7. Blood. ISSN 0006-4971. 116(21), p. 729–729. Full text in Research Archive
• Smeland, Erlend B; Vartdal, Frode & Wisløff, Finn Georg B (2010). Tett samarbeid, men ikke overstyring. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 130(6), p. 590–591. Full text in Research Archive
• Smeland, Erlend B; Vartdal, Frode & Wisløff, Finn Georg B (2010). Ledelse og akademisk kompetanse. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 130(6), p. 591–591. Full text in Research Archive
• Kyte, Jon A; Gaudernack, Gustav; Smeland, Erlend B & Funderud, Steinar (2007). Immuno-gene therapy of cancer with tumor-mRNA transfected dendritic cells. Universitetet i Oslo. ISSN 9788280724182. Full text in Research Archive
• Sivertsen, Einar & Smeland, Erlend B (2007). Characterization of signaling pathways in normal and malignant hematopoietic cells by microarray technologies. Universitetet i Oslo. ISSN 9788280724267. Full text in Research Archive
• Kersten, Christian & Smeland, Erlend B (2007). Studies of tumor associated antigens and BMP-6 signalling in normal and neoplastic B cells. Universitetet i Oslo. ISSN 9788280724090. Full text in Research Archive

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