| 1. |
- Apollonio, Benedetta, et al.
(författare)
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Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma
- 2023
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Ingår i: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 133:13
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Tidskriftsartikel (refereegranskat)abstract
- Recent transcriptomic-based analysis of diffuse large B cell lymphoma (DLBCL) has highlighted the clinical relevance of LN fibroblast and tumor-infiltrating lymphocyte (TIL) signatures within the tumor microenvironment (TME). However, the immunomodulatory role of fibroblasts in lymphoma remains unclear. Here, by studying human and mouse DLBCL-LNs, we identified the presence of an aberrantly remodeled fibroblastic reticular cell (FRC) network expressing elevated fibroblast activated protein (FAP). RNA-Seq analyses revealed that exposure to DLBCL reprogrammed key immunoregulatory pathways in FRCs, including a switch from homeostatic to inflammatory chemokine expression and elevated antigen-presentation molecules. Functional assays showed that DLBCL-activated FRCs (DLBCL-FRCs) hindered optimal TIL and chimeric antigen receptor (CAR) T cell migration. Moreover, DLBCL-FRCs inhibited CD'+ TIL cytotoxicity in an antigen-specific manner. Notably, the interrogation of patient LNs with imaging mass cytometry identified distinct environments differing in their CD'+ TIL-FRC composition and spatial organization that associated with survival outcomes. We further demonstrated the potential to target inhibitory FRCs to rejuvenate interacting TILs. Cotreating organotypic cultures with FAP-targeted immunostimulatory drugs and a bispecific antibody (glofitamab) augmented antilymphoma TIL cytotoxicity. Our study reveals an immunosuppressive role of FRCs in DLBCL, with implications for immune evasion, disease pathogenesis, and optimizing immunotherapy for patients.
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| 2. |
- Benner, Axel, et al.
(författare)
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MDM2 promotor polymorphism and disease characteristics in chronic lymphocytic leukemia : results of an individual patient data-based meta-analysis
- 2014
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 99:8, s. 1285-1291
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Tidskriftsartikel (refereegranskat)abstract
- A number of single nucleotide polymorphisms have been associated with disease predisposition in chronic lymphocytic leukemia. A single nucleotide polymorphism in the MDM2 promotor region, MDM2SNP309, was shown to soothe the p53 pathway. In the current study, we aimed to clarify the effect of the MDM2SNP309 on chronic lymphocytic leukemia characteristics and outcome. We performed a meta-analysis of data from 2598 individual patients from 10 different cohorts. Patients' data and genetic analysis for MDM2SNP309 genotype, immunoglobulin heavy chain variable region mutation status and fluorescence in situ hybridization results were collected. There were no differences in overall survival based on the polymorphism (log rank test, stratified by study cohort; P=0.76; GG genotype: cohort-adjusted median overall survival of 151 months; TG: 153 months; TT: 149 months). In a multivariable Cox proportional hazards regression analysis, advanced age, male sex and unmutated immunoglobulin heavy chain variable region genes were associated with inferior survival, but not the MDM2 genotype. The MDM2SNP309 is unlikely to influence disease characteristics and prognosis in chronic lymphocytic leukemia. Studies investigating the impact of individual single nucleotide polymorphisms on prognosis are often controversial. This may be due to selection bias and small sample size. A meta-analysis based on individual patient data provides a reasonable strategy for prognostic factor analyses in the case of small individual studies. Individual patient data-based meta-analysis can, therefore, be a powerful tool to assess genetic risk factors in the absence of large studies.
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| 3. |
- Bin Kaderi, Mohamed Arifin, 1978-
(författare)
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Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The clinical course of chronic lymphocytic leukemia (CLL) is highly heterogeneous, which has prompted the search for biomarkers that can predict prognosis in this disease. The IGHV gene mutation status and certain genomic aberrations have been identified as reliable prognostic markers of clinical outcome for this disorder. However, the search for more feasible prognostic markers in CLL is still being pursued. Recently, certain single nucleotide polymorphisms (SNPs) in the GNAS1, BCL2 and MDM2 genes and the RNA expression levels of the LPL, ZAP70, TCL1, CLLU1 and MCL1 genes were suggested as novel prognostic markers in CLL. In papers I-III, we performed genotyping analyses of the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms in 268-418 CLL patients and related the genotypes with clinical data. Association studies between the polymorphisms and established prognostic markers (i.e. IGHV mutation status, genomic aberrations, CD38 expression) were also performed. Our studies did not find any significant relationship between these SNPs with either clinical outcome or other known prognostic markers in CLL. In paper IV, we measured the RNA expression levels of LPL, ZAP70, TCL1, CLLU1 and MCL1 in 252 CLL cases and correlated these levels with clinical outcome. Here, we verified that high expression of all these RNA-based markers, except MCL1, were associated with an unfavourable prognosis. We also confirmed a close relationship between IGHV mutation status and the RNA-based markers, especially for LPL and CLLU1 expression. Among the RNA-based markers, multivariate analysis revealed LPL expression as the strongest independent prognostic marker for overall survival and time to treatment. Furthermore, the RNA-based markers could add further prognostic information to established markers in subgroups of patients, with LPL expression status giving the most significant results. In summary, data from papers I-III could not verify the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms as prognostic markers in CLL. Future SNP markers must hence be confirmed in large, independent cohorts before being proposed as prognostic marker in CLL. In paper IV, we conclude that LPL expression appears to be the strongest among the RNA-based markers for CLL prognostication. Further efforts to standardize LPL quantification are required before it can be applied in the clinical laboratory to predict clinical outcome in this disease.
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| 4. |
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| 5. |
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| 6. |
- Crowther-Swanepoel, Dalemari, et al.
(författare)
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Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:2, s. 132-136
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Tidskriftsartikel (refereegranskat)abstract
- To identify new risk variants for chronic lymphocytic leukemia (CLL), we conducted a genome-wide association study of 299,983 tagging SNPs, with validation in four additional series totaling 2,503 cases and 5,789 controls. We identified four new risk loci for CLL at 2q37.3 (rs757978, FARP2; odds ratio (OR) = 1.39; P = 2.11 x 10(-9)), 8q24.21 (rs2456449; OR = 1.26; P = 7.84 x 10(-10)), 15q21.3 (rs7169431; OR = 1.36; P = 4.74 x 10(-7)) and 16q24.1 (rs305061; OR = 1.22; P = 3.60 x 10(-7)). We also found evidence for risk loci at 15q25.2 (rs783540, CPEB1; OR = 1.18; P = 3.67 x 10(-6)) and 18q21.1 (rs1036935; OR = 1.22; P = 2.28 x 10(-6)). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy.
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| 7. |
- Crowther-Swanepoel, Dalemari, et al.
(författare)
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Verification that common variation at 2q37.1, 6p25.3, 11q24.1, 15q23, and 19q13.32 influences chronic lymphocytic leukaemia risk
- 2010
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 150:4, s. 473-479
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Tidskriftsartikel (refereegranskat)abstract
- P>A recent genome wide association study of chronic lymphocytic leukaemia (CLL) provided evidence that common variation at 2q13 (rs17483466), 2q37.1 (rs13397985), 6p25.3 (rs872071), 11q24.1 (rs735665), 15q23 (rs7176508) and 19q13.32 (rs11083846) affects CLL risk. To verify and further explore the relationship between these variants and CLL risk we genotyped case-control datasets from Spain and Sweden (824 cases, 850 controls). Combined data provided statistically significant support for an association between genotypes at rs13397985, rs872071, rs735665, rs7176508 and rs11083846 and CLL risk. CLL risk increased with increasing numbers of risk alleles (P-trend = 1 center dot 40 x 10-15), consistent with a polygenic model of disease susceptibility. These data validate the relationship between common variation and risk of CLL.
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| 8. |
- Glimelius, Bengt, et al.
(författare)
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U-CAN : a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
- 2018
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Ingår i: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 57:2, s. 187-194
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Tidskriftsartikel (refereegranskat)abstract
- Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.
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| 9. |
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| 10. |
- Law, PJ, et al.
(författare)
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Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia
- 2017
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8, s. 14175-
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Tidskriftsartikel (refereegranskat)abstract
- Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10−13), 1q42.13 (rs41271473, P=1.06 × 10−10), 4q24 (rs71597109, P=1.37 × 10−10), 4q35.1 (rs57214277, P=3.69 × 10−8), 6p21.31 (rs3800461, P=1.97 × 10−8), 11q23.2 (rs61904987, P=2.64 × 10−11), 18q21.1 (rs1036935, P=3.27 × 10−8), 19p13.3 (rs7254272, P=4.67 × 10−8) and 22q13.33 (rs140522, P=2.70 × 10−9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response.
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| 11. |
- Sava, Georgina P., et al.
(författare)
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rs2072135, a low-penetrance variant for chronic lymphocytic leukaemia?
- 2013
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 162:2, s. 221-228
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Tidskriftsartikel (refereegranskat)abstract
- Recent multi-stage genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) that are robustly associated with chronic lymphocytic leukaemia (CLL) risk. Given that most of these SNPs map to non-coding regions of the genome, it suggests that the functional basis of many GWAS signals will be through differential gene expression. By referencing publically accessible expression quantitative trait loci (eQTL) data on lymphoblastoid cells lines (LCLs) we have globally demonstrated an association between GWAS P-values and eQTLs, consistent with much of the variation in CLL risk being defined by variants impacting on gene expression. To explore using eQTL data to select GWAS SNPs for replication, we genotyped rs2072135 (GWAS P-value=00024, eQTL P-value=1510(-19)) in five independent case-control series totalling 1968 cases and 3538 controls. While not attaining statistical significance (combined P-value=1x10(-4)), rs2072135 defines a promising risk locus for CLL. Incorporating eQTL information offers an attractive strategy for selecting SNPs from GWAS for validation.
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| 12. |
- Speedy, Helen E., et al.
(författare)
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A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:1, s. 56-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) of chronic lymphocytic leukemia (CLL) have shown that common genetic variation contributes to the heritable risk of CLL. To identify additional CLL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1,739 individuals with CLL (cases) and 5,199 controls with validation in an additional 1,144 cases and 3,151 controls. A combined analysis identified new susceptibility loci mapping to 3q26.2 (rs10936599, P = 1.74 x 10(-9)), 4q26 (rs6858698, P = 3.07 x 10(-9)), 6q25.2 (IPCEF1, rs2236256, P = 1.50 x 10(-10)) and 7q31.33 (POT1, rs17246404, P = 3.40 x 10(-8)). Additionally, we identified a promising association at 5p15.33 (CLPTM1L, rs31490, P = 1.72 x 10(-7)) and validated recently reported putative associations at 5p15.33 (TERT, rs10069690, P = 1.12 x 10(-10)) and 8q22.3 (rs2511714, P = 2.90 x 10(-9)). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CLL.
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| 13. |
- Went, Molly, et al.
(författare)
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Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology
- 2018
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Ingår i: Blood Cancer Journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.
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| 14. |
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| 15. |
- Agathangelidis, Andreas, et al.
(författare)
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Highly similar genomic landscapes in monoclonal B-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia with low frequency of driver mutations
- 2018
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 103:5, s. 865-873
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Tidskriftsartikel (refereegranskat)abstract
- Despite the recent discovery of recurrent driver mutations in chronic lymphocytic leukemia, the genetic factors involved in disease onset remain largely unknown. To address this issue, we per-formed whole-genome sequencing in 11 individuals with monoclonal B-cell lymphocytosis, both of the low-count and high-count subtypes, and 5 patients with ultra-stable chronic lymphocytic leukemia (>10 years without progression from initial diagnosis). All three entities were indistinguishable at the genomic level exhibiting low genomic complexity and similar types of somatic mutations. Exonic mutations were not frequently identified in putative chronic lymphocytic leukemia driver genes in all settings, including low-count monoclonal B-cell lymphocytosis. To corroborate these findings, we also performed deep sequencing in 11 known frequently mutated genes in an extended cohort of 28 monoclonal B-cell lym phocytosis/chronic lymphocytic leukemia cases. Interestingly, shared mutations were detected between clonal B cells and paired polymorphonuclear cells, strengthening the notion that at least a fraction of somatic mutations may occur before disease onset, likely at the hematopoietic stem cell level. Finally, we identified previously unreported non-coding variants targeting pathways relevant to B-cell and chronic lymphocytic leukemia development, likely associated with the acquisition of the characteristic neoplastic phenotype typical of both monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia.
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| 16. |
- Agathangelidis, Andreas, et al.
(författare)
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Immunoglobulin Gene Sequence Analysis In Chronic Lymphocytic Leukemia : From Patient Material To Sequence Interpretation
- 2018
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Ingår i: Journal of Visualized Experiments. - : JOURNAL OF VISUALIZED EXPERIMENTS. - 1940-087X. ; :141
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Tidskriftsartikel (refereegranskat)abstract
- During B cell maturation, the complex process of immunoglobulin (IG) gene V(D)J recombination coupled with somatic hypermutation (SHM) gives rise to a unique DNA sequence within each individual B cell. Since B cell malignancies result from the clonal expansion of a single cell, IG genes represent a unique molecular signature common to all the malignant cells within an individual patient; thus, IG gene rearrangements can be used as clonal markers. In addition to serving as an important clonal identifier, the IG gene sequence can act as a 'molecular timeline' since it is associated with specific developmental stages and hence reflects the history of the B cell involved in the neoplastic transformation. Moreover, for certain malignancies, in particular chronic lymphocytic leukemia (CLL), the IG gene sequence holds prognostic and potentially predictive capabilities. That said, extrapolating meaningful conclusions from IG gene sequence analysis would be impossible if robust methods and tools were not available to aid in their analysis. This article, drawing on the vast experience of the European Research Initiative on CLL (ERIC), details the technical aspects and essential requirements necessary to ensure reliable and reproducible IG gene sequence analysis in CLL, a test that is now recommended for all CLL patients prior to treatment. More specifically, the various analytical stages are described ranging from the identification of the clonotypic IG gene rearrangement and the determination of the nucleotide sequence to the accurate clinical interpretation of the IG gene sequence data.
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| 17. |
- Agathangelidis, Andreas, et al.
(författare)
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Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia : a molecular classification with implications for targeted therapies
- 2012
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 119:19, s. 4467-4475
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Tidskriftsartikel (refereegranskat)abstract
- Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped BCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as well as the identification of "CLL-biased" features in BCR Ig stereotypes. To this end, we examined 7596 Ig VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, 3 times the size of the largest published series, with an updated version of our purpose-built clustering algorithm. We document that CLL may be subdivided into 2 distinct categories: one with stereotyped and the other with nonstereotyped BCRs, at an approximate ratio of 1: 2, and provide evidence suggesting a different ontogeny for these 2 categories. We also show that subset-defining sequence patterns in CLL differ from those underlying BCR stereotypy in other B-cell malignancies. Notably, 19 major subsets contained from 20 to 213 sequences each, collectively accounting for 943 sequences or one-eighth of the cohort. Hence, this compartmentalized examination of VH sequences may pave the way toward a molecular classification of CLL with implications for targeted therapeutic interventions, applicable to a significant number of patients assigned to the same subset.
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| 18. |
- Agathangelidis, Andreas, et al.
(författare)
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Unlocking the secrets of immunoglobulin receptors in mantle cell lymphoma : Implications for the origin and selection of the malignant cells
- 2011
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Ingår i: Seminars in Cancer Biology. - : Elsevier BV. - 1044-579X .- 1096-3650. ; 21:5, s. 299-307
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Forskningsöversikt (refereegranskat)abstract
- Immunogenetic analysis of mantle cell lymphoma (MCL) has offered important evidence helping to decipher the immune pathways leading to its development and also prompting a reappraisal of the views about its ontogeny. In particular, older and more recent studies have demonstrated that MCL is characterized by a highly distinctive immunoglobulin gene repertoire with remarkable predominance of the IGHV3-21 and IGHV4-34 genes; restricted associations of IGHV,IGHD and IGHJ genes, culminating in the creation of quasi-identical ("stereotyped") heavy complementarity-determining region 3 sequences in roughly 10% of cases; and, very precisely targeted and, probably, functionally driven somatic hypermutation, ranging from minimal (in most cases) to pronounced. Furthermore, comparison to other entities, in particular CLL, revealed that several of these immunogenetic features are "MCL-biased". On these grounds, an antigen-driven origin of MCL could be envisaged, at least for subsets of cases.
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| 19. |
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| 20. |
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| 21. |
- Amini, Rose-Marie, et al.
(författare)
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A novel B-cell line (U-2932) established from a patient with a diffuse large B-cell lymphoma following Hodgkin lymphoma
- 2002
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Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 43:11, s. 2179-2189
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about mechanisms leading to secondary non-Hodgkin lymphomas (NHL) in patients treated for Hodgkin lymphoma (HL). Our aim was to characterise in detail a cell line derived from a diffuse large B-cell lymphoma (DLBCL) that had developed in a patient with relapsing HL. The cell line U-2932 was established from ascites in a patient suffering from DLBCL previously treated for HL with multiple chemotherapy regimens. Characterisation was based on morphology, immunophenotype, Epstein-Barr virus (EBV)-status, IgH gene rearrangement status, tumourigenicity, p53 sequencing, and immunohistochemical expression of p53, BCL-2 and BCL-6. The karyotype was investigated using G-banding, comparative genomic hybridisation (CGH) and spectral karyotype (SKY) analysis. This cell line shows typical morphological features of a DLBCL and grows as colonies in nude mice. It expresses a B-cell phenotype with a somatically hypermutated V(H)4-39 gene and is negative for EBV. The origin of U-2932 was confirmed by demonstrating an identical V(H)4 rearrangement in ascites from the patient. A point mutation of the tumour-suppressor gene p53 was detected in amino acid position 176 and immunohistochemical over-expression of the p53 protein was also demonstrated. U-2932 carries a complex karyotype including high-level amplifications of the chromosomal bands 18q21 and 3q27 and expresses aberrant BCL-2 and BCL-6 immunohistochemically. We were unable to investigate the clonal relationship between the original HL and U-2932. In conclusion, U-2932 is a unique B cell line established from a patient suffering from HL followed by NHL. Overexpression of BCL-2, BCL-6 and p53 may play a role in the tumourigenesis and drug resistance. This cell line may become a useful tool to better understand the mechanisms responsible for development of secondary NHL in patients treated for HL.
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| 22. |
- Andreasson, Ulrika, et al.
(författare)
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B cell lymphomas express CX(3)CR1 a non-B cell lineage adhesion molecule
- 2008
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Ingår i: Cancer Letters. - : Elsevier BV. - 0304-3835 .- 1872-7980. ; 259:2, s. 138-145
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Tidskriftsartikel (refereegranskat)abstract
- To study the differential expression of cell membrane-bound receptors and their potential role in growth and/or survival of the tumor cells, highly purified follicular lymphoma cells were analyzed, using gene expression analysis, and compared to non-malignant B cell populations. Filtering the genome for overexpressed genes coding for cell membrane-bound proteins/receptors resulted in a hit list of 27 identified genes. Among these, we have focused on the aberrant over expression of CX3CR1, in different types of B cell lymphoma, as compared to non-malignant B cells. We show that CX3CR1, which normally is not expressed on B cells, is expressed both at the mRNA and protein level in several subtypes of lymphoma. CX3CR1 has also shown to be involved in the homing to specific tissues that express the ligand, CX3CL1, in breast and prostate cancer and may thus be involved in dissemination of lymphoma.
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| 23. |
- Andreasson, Ulrika, et al.
(författare)
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Identification of molecular targets associated with transformed diffuse large B cell lymphoma using highly purified tumor cells
- 2009
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Ingår i: American Journal of Hematology. - : Wiley. - 0361-8609 .- 1096-8652. ; 84:12, s. 803-808
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Tidskriftsartikel (refereegranskat)abstract
- Follicular lymphoma (FL) frequently transforms into the more aggressive diffuse large B cell lymphoma (DLBCL-tr), but no protein biomarkers have been identified for predictive or early diagnosis. Gene expression analyses have identified genes changing on transformation but have failed to be reproducible in different studies, reflecting the heterogeneity within the tumor tissue and between tumor samples. Gene expression analyses on Affymetrix Human Genome U133 Plus 2.0 arrays were performed, using flow cytometry sorted tumor cells derived from FL and transformed DLBCL. To identify molecular targets associated with the transformation, subsequent immunohistochemistry (IHC) analyses of the corresponding proteins were performed. Using highly purified cells, this study identified 163 genes, which were significantly deregulated during the transformation in a majority of cases. Among the upregulated transcripts, 13 genes were selected for validation using IHC, based on the availability of commercial antibodies, and galectin-3 and NEK2 proteins specifically identify DLBCL-tr, when compared with FL. We demonstrate that by purifying tumor cells through cell sorting, thereby reducing the heterogeneity due to infiltrating cells, it was possible to identify distinct differences between tumor entities rather than variations due to cellular composition. Galectin-3 and NEK2 both identified a subgroup of DLBCL-tr, and the function of these protein markers also suggests a biological role in the transformation process.
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| 24. |
- Andreasson, Ulrika, et al.
(författare)
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Identification of uniquely expressed transcription factors in highly purified B-cell lymphoma samples.
- 2010
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Ingår i: American Journal of Hematology. - : Wiley. - 0361-8609 .- 1096-8652. ; 85:6, s. 418-425
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Tidskriftsartikel (refereegranskat)abstract
- Transcription factors (TFs) are critical for B-cell differentiation, affecting gene expression both by repression and transcriptional activation. Still, this information is not used for classification of B-cell lymphomas (BCLs). Traditionally, BCLs are diagnosed based on a phenotypic resemblance to normal B-cells; assessed by immunohistochemistry or flow cytometry, by using a handful of phenotypic markers. In the last decade, diagnostic and prognostic evaluation has been facilitated by global gene expression profiling (GEP), providing a new powerful means for the classification, prediction of survival, and response to treatment of lymphomas. However, most GEP studies have typically been performed on whole tissue samples, containing varying degrees of tumor cell content, which results in uncertainties in data analysis. In this study, global GEP analyses were performed on highly purified, flow-cytometry sorted tumor-cells from eight subgroups of BCLs. This enabled identification of TFs that can be uniquely associated to the tumor cells of chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), hairy cell leukemia (HCL), and mantle cell lymphoma (MCL). The identified transcription factors influence both the global and specific gene expression of the BCLs and have possible implications for diagnosis and treatment.
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| 25. |
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