Publications by authors named "Jesper Jurlander"

32 Publications

Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL.

Blood 2014 May 15;123(21):3255-62. Epub 2014 Apr 15.

Department of Hematology, Academisch Medisch Centrum, Amsterdam, The Netherlands.

The randomized Haemato Oncology Foundation for Adults in The Netherlands 68 phase 3 trial compared front-line chemotherapy with chemotherapy plus the CD52 monoclonal antibody alemtuzumab for high-risk chronic lymphocytic leukemia, defined as at least 1 of the following: unmutated immunoglobulin heavy chain genes, deletion 17p or 11q, or trisomy 12. Fit patients were randomized to receive either 6 28-day cycles of oral FC chemotherapy (days 1 through 3: fludarabine 40 mg/m(2) per day and cyclophosphamide 250 mg/m(2) per day: n = 139) or FC plus subcutaneous alemtuzumab 30 mg day 1 (FCA, n = 133). FCA prolonged the primary end point, progression-free survival (3-year progression-free survival 53 vs 37%, P = .01), but not the secondary end point, overall survival (OS). However, a post hoc analysis showed that FCA increased OS in patients younger than 65 years (3-year OS 85% vs 76%, P = .035). FCA also increased the overall response rate (88 vs 78%, P = .036), and the bone marrow minimal residual disease-negative complete remission rate (64% vs 43%, P = .016). Opportunistic infections were more frequent following FCA, but without an increase in treatment related mortality (FCA: 3.8%, FC: 4.3%). FCA improves progression-free survival in high-risk chronic lymphocytic leukemia. As anticipated, FCA is more immunosuppressive than FC, but with due vigilance, does not lead to a higher treatment-related mortality. This study was registered at www.trialregister.nl as trial no. NTR529.
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http://dx.doi.org/10.1182/blood-2014-01-547737DOI Listing
May 2014

Combination of two anti-CD5 monoclonal antibodies synergistically induces complement-dependent cytotoxicity of chronic lymphocytic leukaemia cells.

Br J Haematol 2013 Oct 8;163(2):182-93. Epub 2013 Aug 8.

Symphogen A/S, Lyngby, Denmark; Department of Haematology L4042, Rigshospitalet, Copenhagen.

The treatment of chronic lymphocytic leukaemia (CLL) has been improved by introduction of monoclonal antibodies (mAbs) that exert their effect through secondary effector mechanisms. CLL cells are characterized by expression of CD5 and CD23 along with CD19 and CD20, hence anti-CD5 Abs that engage secondary effector functions represent an attractive opportunity for CLL treatment. Here, a repertoire of mAbs against human CD5 was generated and tested for ability to induce complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) both as single mAbs and combinations of two mAbs against non-overlapping epitopes on human CD5. The results demonstrated that combinations of two mAbs significantly increased the level of CDC compared to the single mAbs, while no enhancement of ADCC was seen with anti-CD5 mAb combinations. High levels of CDC and ADCC correlated with low levels of Ab-induced CD5 internalization and degradation. Importantly, an anti-CD5 mAb combination enhanced CDC of CLL cells when combined with the anti-CD20 mAbs rituximab and ofatumumab as well as with the anti-CD52 mAb alemtuzumab. These results suggest that an anti-CD5 mAb combination inducing CDC and ADCC may be effective alone, in combination with mAbs against other targets or combined with chemotherapy for CLL and other CD5-expressing haematological or lymphoid malignancies.
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http://dx.doi.org/10.1111/bjh.12503DOI Listing
October 2013

Molecular characterization of neoplastic and normal "sister" lymphoblastoid B-cell lines from chronic lymphocytic leukemia.

Leuk Lymphoma 2013 Aug 25;54(8):1769-79. Epub 2013 Feb 25.

Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.

Chronic lymphocytic leukemia (CLL) B-cells resemble self-renewing CD5 + B-cells carrying auto/xeno-antigen-reactive B-cell receptors (BCRs) and multiple innate pattern-recognition receptors, such as Toll-like receptors and scavenger receptors. Integration of signals from BCRs with multiple surface membrane receptors determines whether the cells will be proliferating, anergic or apoptotic. To better understand the role of antigen in leukemogenesis, CLL cell lines producing monoclonal antibodies (mAbs) will facilitate structural analysis of antigens and supply DNA for genetic studies. We present here a comprehensive genotypic and phenotypic characterization of available CLL and normal B-cell-derived lymphoblastoid cell lines (LCLs) from the same individuals (n = 17). Authenticity and verification studies of CLL-patient origin were done by IGHV sequencing, fluorescence in situ hybridization (FISH) and DNA/short tandem repeat (STR) fingerprinting. Innate B-cell features, i.e. natural Ab production and CD5 receptors, were present in most CLL cell lines, but in none of the normal LCLs. This panel of immortalized CLL-derived cell lines is a valuable reference representing a renewable source of authentic Abs and DNA.
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http://dx.doi.org/10.3109/10428194.2013.764418DOI Listing
August 2013

Plasma alemtuzumab levels in patients with chronic lymphocytic leukemia treated with alemtuzumab combined with chemotherapy reflect the efficacy of the treatment: a hypothesis.

Leuk Lymphoma 2013 Apr 4;54(4):790-3. Epub 2013 Jan 4.

Department of Hematology, Rigshospitalet, Copenhagen, Denmark.

In the HOVON68 trial comparing subcutaneous low-dose alemtuzumab (LD-A) used together with fludarabine (F) and cyclophosphamide (C) with FC alone in high-risk chronic lymphocytic leukemia (CLL), LD-AFC resulted in significantly more clinical and molecular responses than FC, but also in more opportunistic infections. In a subgroup analysis of alemtuzumab trough levels during treatment by a sensitive enzyme-linked immunosorbent assay (ELISA) method, detectable levels were found in 4/6 complete and 0/3 partial responders. A relationship between alemtuzumab plasma levels, response and duration of lymphocytopenia was evident. We hypothesize that following combination therapy, the response may not be a function of the alemtuzumab levels, but the opposite, that plasma alemtuzumab levels are a function of the efficacy of the entire treatment, and the fewer leukemic target cells that are remaining, the higher are the levels of plasma alemtuzumab. This concept may well provide a guide for alemtuzumab dosage in future trials.
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http://dx.doi.org/10.3109/10428194.2012.720373DOI Listing
April 2013

Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies.

Blood 2012 May 13;119(19):4467-75. Epub 2012 Mar 13.

Institute of Agrobiotechnology, Center for Research and Technology Hellas, Thessaloniki, Greece.

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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http://dx.doi.org/10.1182/blood-2011-11-393694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392073PMC
May 2012

Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia.

Haematologica 2011 Aug 5;96(8):1161-9. Epub 2011 May 5.

Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

Background: High-resolution genomic microarrays enable simultaneous detection of copy-number aberrations such as the known recurrent aberrations in chronic lymphocytic leukemia [del(11q), del(13q), del(17p) and trisomy 12], and copy-number neutral loss of heterozygosity. Moreover, comparison of genomic profiles from sequential patients' samples allows detection of clonal evolution.

Design And Methods: We screened samples from 369 patients with newly diagnosed chronic lymphocytic leukemia from a population-based cohort using 250K single nucleotide polymorphism-arrays. Clonal evolution was evaluated in 59 follow-up samples obtained after 5-9 years.

Results: At diagnosis, copy-number aberrations were identified in 90% of patients; 70% carried known recurrent alterations, including del(13q) (55%), trisomy 12 (10.5%), del(11q) (10%), and del(17p) (4%). Additional recurrent aberrations were detected on chromosomes 2 (1.9%), 4 (1.4%), 8 (1.6%) and 14 (1.6%). Thirteen patients (3.5%) displayed recurrent copy-number neutral loss of heterozygosity on 13q, of whom 11 had concurrent homozygous del(13q). Genomic complexity and large 13q deletions correlated with inferior outcome, while the former was linked to poor-prognostic aberrations. In the follow-up study, clonal evolution developed in 8/24 (33%) patients with unmutated IGHV, and in 4/25 (16%) IGHV-mutated and treated patients. In contrast, untreated patients with mutated IGHV (n=10) did not acquire additional aberrations. The most common secondary event, del(13q), was detected in 6/12 (50%) of all patients with acquired alterations. Interestingly, aberrations on, for example, chromosome 6q, 8p, 9p and 10q developed exclusively in patients with unmutated IGHV.

Conclusions: Whole-genome screening revealed a high frequency of genomic aberrations in newly diagnosed chronic lymphocytic leukemia. Clonal evolution was associated with other markers of aggressive disease and commonly included the known recurrent aberrations.
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http://dx.doi.org/10.3324/haematol.2010.039768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148910PMC
August 2011

LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia.

Haematologica 2011 Aug 20;96(8):1153-60. Epub 2011 Apr 20.

Dept. of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

Background: The expression levels of LPL, ZAP70, TCL1A, CLLU1 and MCL1 have recently been proposed as prognostic factors in chronic lymphocytic leukemia. However, few studies have systematically compared these different RNA-based markers.

Design And Methods: Using real-time quantitative PCR, we measured the mRNA expression levels of these genes in unsorted samples from 252 newly diagnosed chronic lymphocytic leukemia patients and correlated our data with established prognostic markers (for example Binet stage, CD38, IGHV gene mutational status and genomic aberrations) and clinical outcome.

Results: High expression levels of all RNA-based markers, except MCL1, predicted shorter overall survival and time to treatment, with LPL being the most significant. In multivariate analysis including the RNA-based markers, LPL expression was the only independent prognostic marker for overall survival and time to treatment. When studying LPL expression and the established markers, LPL expression retained its independent prognostic strength for overall survival. All of the RNA-based markers, albeit with varying ability, added prognostic information to established markers, with LPL expression giving the most significant results. Notably, high LPL expression predicted a worse outcome in good-prognosis subgroups, such as patients with mutated IGHV genes, Binet stage A, CD38 negativity or favorable cytogenetics. In particular, the combination of LPL expression and CD38 could further stratify Binet stage A patients.

Conclusions: LPL expression is the strongest RNA-based prognostic marker in chronic lymphocytic leukemia that could potentially be applied to predict outcome in the clinical setting, particularly in the large group of patients with favorable prognosis.
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http://dx.doi.org/10.3324/haematol.2010.039396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148909PMC
August 2011

Quality of life in patients with diffuse large B-cell lymphoma treated with dose-dense chemotherapy is only affected temporarily.

Leuk Lymphoma 2011 Mar 21;52(3):400-8. Epub 2011 Jan 21.

Department of Hematology, Rigshospitalet, Copenhagen, Denmark.

(R)-CHOP-14 has substantially improved outcome in DLBCL, but may have increased morbidity and reduced quality of life (QoL). Our aim was to evaluate QoL during (R)-CHOP-14-based chemotherapy. Twenty-six patients participated (small single-center study). EORTC QLQ-C30 was completed pre-treatment, mid-treatment, 14 days post-treatment, and 3 months post-treatment. Scores were compared to a reference population, and analyzed separately. Pre-treatment, global health status (p = 0.004), physical functioning (p = 0.036), role functioning (p = 0.017), and emotional functioning (p = 0.040) were reduced, and fatigue (p = 0.009) and appetite loss (p = 0.007) increased compared to the reference population. During treatment, physical functioning and role functioning decreased significantly, whereas emotional functioning, fatigue, and diarrhea increased. Three months post-treatment, scores were generally equivalent to those of the reference population, and lower for nausea/vomiting (p < 0.001) and constipation (p < 0.001). Disease-related symptoms were frequent in high-risk DLBCL. Treatment-related symptoms were normalized 3 months post-treatment. In conclusion, QoL is only temporarily affected during (R)-CHOP-14-based chemotherapy, and the treatment regimen is therefore feasible.
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http://dx.doi.org/10.3109/10428194.2010.541310DOI Listing
March 2011

TP53 Mutations are infrequent in newly diagnosed chronic lymphocytic leukemia.

Leuk Res 2011 Feb 25;35(2):272-4. Epub 2010 Sep 25.

Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala SE-751 85, Sweden.

TP53 mutations in the absence of 17p-deletion correlate with rapid disease progression and poor survival in chronic lymphocytic leukemia (CLL). Herein, we determined the TP53 mutation frequency in 268 newly diagnosed CLL patients from a population-based material. Overall, we detected TP53 mutations in 3.7% of patients (n = 10), where 7/10 cases showed a concomitant 17p-deletion, confirming the high prevalence of TP53 mutation in 17p-deleted patients. Only 3 (1.1%) of the newly diagnosed patients in our cohort thereby carried TP53 mutations without 17p-deletion, a frequency that is much lower than previous reports on referral cohorts (3-6%). Our findings imply that TP53 mutations are rare at CLL onset and instead may arise during disease progression.
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http://dx.doi.org/10.1016/j.leukres.2010.08.023DOI Listing
February 2011

Distinct gene expression profiles in subsets of chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors.

Haematologica 2010 Dec 26;95(12):2072-9. Epub 2010 Aug 26.

Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.

Background: Numerous subsets of patients with chronic lymphocytic leukemia display similar immunoglobulin gene usage with almost identical complementarity determining region 3 sequences. Among IGHV4-34 cases, two such subsets with "stereotyped" B-cell receptors were recently identified, i.e. subset #4 (IGHV4-34/IGKV2-30) and subset #16 (IGHV4-34/IGKV3-20). Subset #4 patients appear to share biological and clinical features, e.g. young age at diagnosis and indolent disease, whereas little is known about subset #16 at a clinical level.

Design And Methods: We investigated the global gene expression pattern in sorted chronic lymphocytic leukemia cells from 25 subset/non-subset IGHV4-34 patients using Affymetrix gene expression arrays.

Results: Although generally few differences were found when comparing subset to non-subset 4/16 IGHV4-34 cases, distinct gene expression profiles were revealed for subset #4 versus subset #16. The differentially expressed genes, predominantly with lower expression in subset #4 patients, are involved in important cell regulatory pathways including cell-cycle control, proliferation and immune response, which may partly explain the low-proliferative disease observed in subset #4 patients.

Conclusions: Our novel data demonstrate distinct gene expression profiles among patients with stereotyped IGHV4-34 B-cell receptors, providing further evidence for biological differences in the pathogenesis of these subsets and underscoring the functional relevance of subset assignment based on B-cell receptor sequence features.
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http://dx.doi.org/10.3324/haematol.2010.028639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2995565PMC
December 2010

Verification that common variation at 2q37.1, 6p25.3, 11q24.1, 15q23, and 19q13.32 influences chronic lymphocytic leukaemia risk.

Br J Haematol 2010 Aug 10;150(4):473-9. Epub 2010 Jun 10.

Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK.

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) = 1.40 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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http://dx.doi.org/10.1111/j.1365-2141.2010.08270.xDOI Listing
August 2010

High-density screening reveals a different spectrum of genomic aberrations in chronic lymphocytic leukemia patients with 'stereotyped' IGHV3-21 and IGHV4-34 B-cell receptors.

Haematologica 2010 Sep 26;95(9):1519-25. Epub 2010 Apr 26.

Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-751-85 Uppsala, Sweden.

Background: The existence of multiple subsets of chronic lymphocytic leukemia expressing 'stereotyped' B-cell receptors implies the involvement of antigen(s) in leukemogenesis. Studies also indicate that 'stereotypy' may influence the clinical course of patients with chronic lymphocytic leukemia, for example, in subsets with stereotyped IGHV3-21 and IGHV4-34 B-cell receptors; however, little is known regarding the genomic profile of patients in these subsets.

Design And Methods: We applied 250K single nucleotide polymorphism-arrays to study copy-number aberrations and copy-number neutral loss-of-heterozygosity in patients with stereotyped IGHV3-21 (subset #2, n=29), stereotyped IGHV4-34 (subset #4, n=17; subset #16, n=8) and non-subset #2 IGHV3-21 (n=13) and non-subset #4/16 IGHV4-34 (n=34) patients.

Results: Over 90% of patients in subset #2 and non-subset #2 carried copy-number aberrations, whereas 75-76% of patients in subset #4 and subset #16 showed copy-number aberrations. Subset #2 and non-subset #2 patients also displayed a higher average number of aberrations compared to patients in subset #4. Deletion of 13q was the only known recurrent aberration detected in subset #4 (35%); this aberration was even more frequent in subset #2 (79%). del(11q) was more frequent in subset #2 and non-subset #2 (31% and 23%) patients than in subset #4 and non-subset #4/16 patients. Recurrent copy-number neutral loss-of-heterozygosity was mainly detected on chromosome 13q, independently of B-cell receptor stereotypy.

Conclusions: Genomic aberrations were more common in subset #2 and non-subset #2 than in subset #4. The particularly high frequency of del(11q) in subset #2 may be linked to the adverse outcome reported for patients in this subset. Conversely, the lower prevalence of copy-number aberrations and the absence of poor-prognostic aberrations in subset #4 may reflect an inherently low-proliferative disease, which would prevent accumulation of genomic alterations.
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http://dx.doi.org/10.3324/haematol.2009.021014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930953PMC
September 2010

Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk.

Nat Genet 2010 Feb 10;42(2):132-6. Epub 2010 Jan 10.

Institute of Cancer Research, Sutton, Surrey, UK.

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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http://dx.doi.org/10.1038/ng.510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321238PMC
February 2010

Lack of association between the MDM2 promoter polymorphism SNP309 and clinical outcome in chronic lymphocytic leukemia.

Leuk Res 2010 Mar 1;34(3):335-9. Epub 2009 Jul 1.

Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.

The 309T>G polymorphism in the promoter region of the MDM2 gene, known as SNP309, has recently been suggested as an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL) although this has been questioned. To investigate this further, we analyzed the MDM2 SNP309 genotypes in 418 CLL patients and correlated the results with established CLL prognostic factors, time to treatment and overall survival. In this Swedish cohort, no association existed between any particular MDM2 SNP309 genotype, overall survival and time to treatment. Furthermore, no correlation was shown between the MDM2 SNP309 genotypes and Binet stage, IGHV mutational status and recurrent genomic aberrations. In summary, this study argues against the use of the MDM2 SNP309 as a prognostic marker in CLL.
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http://dx.doi.org/10.1016/j.leukres.2009.06.006DOI Listing
March 2010

Propionic acid secreted from propionibacteria induces NKG2D ligand expression on human-activated T lymphocytes and cancer cells.

J Immunol 2009 Jul 24;183(2):897-906. Epub 2009 Jun 24.

Department of Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark.

We found that propionic acid secreted from propionibacteria induces expression of the NKG2D ligands MICA/B on activated T lymphocytes and different cancer cells, without affecting MICA/B expression on resting peripheral blood cells. Growth supernatant from propionibacteria or propionate alone could directly stimulate functional MICA/B surface expression and MICA promoter activity by a mechanism dependent on intracellular calcium. Deletion and point mutations further demonstrated that a GC-box motif around -110 from the MICA transcription start site is essential for propionate-mediated MICA promoter activity. Other short-chain fatty acids such as lactate, acetate, and butyrate could also induce MICA/B expression. We observed a striking difference in the molecular signaling pathways that regulate MICA/B. A functional glycolytic pathway was essential for MICA/B expression after exposure to propionate and CMV. In contrast, compounds with histone deacetylase-inhibitory activity such as butyrate and FR901228 stimulated MICA/B expression through a pathway that was not affected by inhibition of glycolysis, clearly suggesting that MICA/B is regulated through different molecular mechanisms. We propose that propionate, produced either by bacteria or during cellular metabolism, has significant immunoregulatory function and may be cancer prophylactic.
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http://dx.doi.org/10.4049/jimmunol.0803014DOI Listing
July 2009

[Multi-facetted clinical presentation of thrombotic thrombocytopenic purpura].

Ugeskr Laeger 2009 Jan;171(5):340-2

Medicinsk Haematologisk Afdeling L, Rigshospitalet, DK-2100 København Ø.

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathic disease. TTP is due to reduced activity of the von Willebrand factor which cleaves ADAMTS13. The disease is characterized by thrombocytopenia (<20 billion/l) intravascular Coombs-negative haemolysis and schistocytes in blood smears. Determination of the ADAMTS13-activity is now becoming available as a routine analysis. We present two cases that illustrate the multi-facetted clinical presentation under which TTP occurs. The importance of access to ADAMTS13 measurements is stressed.
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January 2009

Screening for copy-number alterations and loss of heterozygosity in chronic lymphocytic leukemia--a comparative study of four differently designed, high resolution microarray platforms.

Genes Chromosomes Cancer 2008 Aug;47(8):697-711

Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Hematology and Transplantation, Lund University, Lund, Sweden.

Screening for gene copy-number alterations (CNAs) has improved by applying genome-wide microarrays, where SNP arrays also allow analysis of loss of heterozygozity (LOH). We here analyzed 10 chronic lymphocytic leukemia (CLL) samples using four different high-resolution platforms: BAC arrays (32K), oligonucleotide arrays (185K, Agilent), and two SNP arrays (250K, Affymetrix and 317K, Illumina). Cross-platform comparison revealed 29 concordantly detected CNAs, including known recurrent alterations, which confirmed that all platforms are powerful tools when screening for large aberrations. However, detection of 32 additional regions present in 2-3 platforms illustrated a discrepancy in detection of small CNAs, which often involved reported copy-number variations. LOH analysis using dChip revealed concordance of mainly large regions, but showed numerous, small nonoverlapping regions and LOH escaping detection. Evaluation of baseline variation and copy-number ratio response showed the best performance for the Agilent platform and confirmed the robustness of BAC arrays. Accordingly, these platforms demonstrated a higher degree of platform-specific CNAs. The SNP arrays displayed higher technical variation, although this was compensated by high density of elements. Affymetrix detected a higher degree of CNAs compared to Illumina, while the latter showed a lower noise level and higher detection rate in the LOH analysis. Large-scale studies of genomic aberrations are now feasible, but new tools for LOH analysis are requested.
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http://dx.doi.org/10.1002/gcc.20575DOI Listing
August 2008

Long-term molecular remissions in patients with indolent lymphoma treated with rituximab as a single agent or in combination with interferon alpha-2a: a randomized phase II study from the Nordic Lymphoma Group.

Leuk Lymphoma 2008 Jan;49(1):102-12

Karolinska University Hospital, Stockholm, Sweden.

The purpose of this phase II randomized trial was to evaluate the effect and safety of interferon-alpha2a (IFN) in combination with extended dosing rituximab in patients with symptomatic, advanced indolent lymphoma responding to a standard single course of rituximab. Totally 123 patients were treated with rituximab 375 mg/m2 once weekly for 4 weeks leading to 14 complete response (CR; 11%), 56 partial response (PR; 46%), and 13 minor responses (MR; 11%). Patients achieving either PR or MR were randomized to four more infusions of rituximab alone (n = 36) or in combination with five weeks of IFN (n = 33), with an overall response rate (CR + PR) of 78% and 94%, respectively. Significantly more patients in the combination arm improved their response from PR/MR to CR (P < 0.05) and more maintained their responses for > or = 24 months (72% versus 50%), respectively. Overall, 26 out of the 52 patients who achieved CR underwent minimal residual disease (MRD) evaluation. Totally 17 of these (65%) achieved MRD negativity, 14 of whom remain in CR after 4.8 years' follow-up. The addition of IFN to rituximab was generally safe, but reversible thrombocytopenia and neutropenia were noted in one and six patients, respectively, requiring a reduction in the IFN dose. Extended rituximab is effective and well tolerated and combination with IFN seems to improve both the quality and duration of the responses, providing the opportunity to achieve long-term molecular CRs and prolonged failure-free survival without chemotherapy.
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http://dx.doi.org/10.1080/10428190701704647DOI Listing
January 2008

Feasibility, efficacy and safety of CHOP-14 in elderly patients with very high-risk diffuse large B-cell lymphoma.

Eur J Haematol 2007 Aug 28;79(2):100-6. Epub 2007 Jun 28.

Department of Hematology, Rigshospitalet, Copenhagen, Denmark.

Objectives: The dose-dense CHOP-14 regimen is efficient and safe in elderly patients with diffuse large B-cell lymphoma (DLBCL). However, no clinical data regarding very high-risk patients [age >75 yr and/or performance status (PS) >3] are available. The objective of this study was to evaluate the feasibility, efficacy and safety of CHOP-14 in these patients not eligible for clinical trials.

Methods: We analyzed 65 patients treated with CHOP-14. Patients were stratified into two cohorts; A: very high-risk (age 60-75 with PS = 4 or age >75; n = 24) and B: standard risk (age 60-75 with PS < or =3 or age <60; n = 41).

Results: Fifty eight percent in cohort A achieved complete response (CR) compared with 80% in cohort B (P = 0.054). The 3-yr event free survival (EFS) was 40% vs. 52% (ns), 3-yr overall survival (OAS) 44% vs. 68% (P = 0.017). Median schedule-erosion was 14 (0-67) (A) vs. 8 (0-44) (B) days (ns) and dose-erosion was confined to vincristine-reduction in both cohorts. Therapy-associated deaths did not differ. However, a significant increase in hospital admission was found in cohort A, where 88% required hospitalization (median 47 d) compared with 68% (median 9 d) in cohort B (P = 0.003). The patients presented with a combination of opportunistic infections, malnutrition and decreasing PS.

Conclusions: Although the 3-yr OAS in very high-risk DLBCL is encouraging, the high frequency of severe toxicity with infections and malnutrition responsible for increased morbidity during treatment, warrants for careful attention to these very high-risk patients.
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http://dx.doi.org/10.1111/j.1600-0609.2007.00877.xDOI Listing
August 2007

Kaposi sarcoma-associated herpes virus targets the lymphotactin receptor with both a broad spectrum antagonist vCCL2 and a highly selective and potent agonist vCCL3.

J Biol Chem 2007 Jun 2;282(24):17794-805. Epub 2007 Apr 2.

Laboratory for Molecular Pharmacology, Panum Institute, 18/6, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.

Large DNA viruses such as herpesvirus and poxvirus encode proteins that target and exploit the chemokine system of their host. These proteins have the potential to block or change the orchestrated recruitment of leukocytes to sites of viral infection. The genome of Kaposi sarcoma-associated herpes virus (KSHV) encodes three chemokine-like proteins named vCCL1, vCCL2, and vCCL3. In this study vCCL3 was probed in parallel with vCCL1 and vCCL2 against a panel of the 18 classified human chemokine receptors. In calcium mobilization assays vCCL1 acted as a selective CCR8 agonist, whereas vCCL2 was found to act as a broad spectrum chemokine antagonist of human chemokine receptors, including the lymphotactin receptor. In contrast vCCL3 was found to be a highly selective agonist for the human lymphotactin receptor XCR1. The potency of vCCL3 was found to be 10-fold higher than the endogenous human XCL1 chemokine in respect to phosphatidylinositol turnover and calcium mobilization as well as chemotaxis. High expression of XCR1 was found in placenta and neutrophils by real-time PCR. These data are consistent with reports of different expression profiles for vCCL2 and vCCL3 during the life cycle of KSHV, indicate a novel, sophisticated exploitation by the virus of specifically the lymphotactin receptor by both agonist and antagonist mechanisms, and suggest a unique physiological importance of this (somewhat overlooked) chemokine receptor.
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http://dx.doi.org/10.1074/jbc.M702001200DOI Listing
June 2007

CLLU1 expression analysis adds prognostic information to risk prediction in chronic lymphocytic leukemia.

Blood 2007 Jun 6;109(11):4973-9. Epub 2007 Feb 6.

The Leukemia Laboratory, Department of Hematology, Rigshospitalet and University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.

We recently identified a disease-specific gene CLLU1 in chronic lymphocytic leukemia (CLL) and also demonstrated that high CLLU1 expression levels predict poor clinical outcome. To validate this finding, we measured CLLU1 mRNA expression levels by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in 175 patients with CLL. Analyses of IgV(H) mutational status, ZAP-70 expression, CD38 expression, and chromosomal aberrations were also performed. High levels of CLLU1 expression were associated with shorter overall survival (P < .001), with a 7% increase in risk of early death by each doubling of the CLLU1 expression level. Stratification for age at diagnosis demonstrated a strong prognostic significance of CLLU1 expression in patients younger than 70 years (P < .001), but not in patients aged 70 or older (P = .61). The prognostic significance of IgV(H) mutational status and ZAP-70 expression had a similar age-dependent variation. Multivariate analysis in the younger age group showed that CLLU1 expression analysis added further prognostic information within all prognostic subgroups, with the exception of patients with unmutated IgV(H) CLL. Only CLLU1 expression and IgV(H) mutational status had independent predictive power. Thus, analysis of CLLU1 expression is highly applicable in risk prediction in CLL for patients of an age eligible for risk stratification.
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http://dx.doi.org/10.1182/blood-2006-11-054916DOI Listing
June 2007

CLLU1 expression levels predict time to initiation of therapy and overall survival in chronic lymphocytic leukemia.

Eur J Haematol 2006 Jun 9;76(6):455-64. Epub 2006 Mar 9.

Department of Hematology, The Leukemia Laboratory, Rigshospitalet, Denmark.

Objectives: Chronic lymphocytic leukemia (CLL) is an incurable disease with a highly variable clinical course. IgV(H) mutational status, chromosomal aberrations, CD38 expression and ZAP-70 expression are prognostic markers in CLL, however, they are not exclusively confined to this disease. We recently identified a novel CLL-specific gene (CLL upregulated gene1, CLLU1) that is exclusively upregulated in CLL cells. Here we describe our evaluation of the prognostic significance of CLLU1 in CLL.

Methods: A cohort of 59 previously untreated CLL patients was studied. We determined the expression levels of two CLLU1 transcripts, cDNA1 and CDS, by quantitative RT-PCR. The relation between CLLU1 expression and time to therapy, overall survival and presence or absence of ZAP-70, CD38, chromosomal aberrations or IgV(H) mutations in the 59 patients was analyzed.

Results: Analyzed as a continuous, quantitative parameter CLLU1 levels significantly predicted time from diagnosis to initiation of therapy (P < or = 0.0003) Analyzed as a categorical parameter, by segregation of the patients into groups with cDNA1 or CDS expression above or below the median, the CLLU1 levels significantly predicted time from diagnosis to initiation of therapy (P = 0.001) and predicted overall survival with borderline significance (P < or = 0.05). Patient stratification according to clinical stage, cytogenetics, IgV(H) mutational status, ZAP-70 and CD38, demonstrated significantly increased CLLU1 expression in all investigated CLL poor risk groups. CLLU1 expression levels contributed additional prognostic information to ZAP-70-positive patients.

Conclusions: CLLU1 is the first identified CLL specific gene. The CLLU1 mRNA expression level can predict time to initiation of treatment and survival in CLL patients.
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http://dx.doi.org/10.1111/j.0902-4441.2005.t01-1-EJH2530.xDOI Listing
June 2006

Identification of a gene on chromosome 12q22 uniquely overexpressed in chronic lymphocytic leukemia.

Blood 2006 Apr 8;107(7):2904-11. Epub 2005 Dec 8.

Department of Hematology, 4041, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, DK.

The pathogenesis of chronic lymphocytic leukemia (CLL) is unknown but may involve aberrant activation of signaling pathways. Somatic hypermutations in rearranged immunoglobulin heavy-chain (IgVH) genes allow a division of CLL patients into 2 categories: mutated IgVH genes are associated with an indolent disease, whereas unmutated IgVH genes define an aggressive form. Using differential display to compare gene expression in CLL cells with and without IgVH hypermutations, we identified a novel gene, CLL up-regulated gene 1 (CLLU1), that was highly up-regulated in CLL cells without IgVH hypermutations. CLLU1 mapped to chromosome 12q22, within a cluster of genes that are active in germinal center B cells. However, appreciable levels of CLLU1 were detectable only in CLL cells and not in a panel of normal tissue extracts or in any other tested hematologic malignancy. High expression of CLLU1 in CLL samples occurred irrespective of trisomy 12 or large chromosomal rearrangements. CLLU1 encodes 6 mRNAs with no sequence homology to any known gene, and most transcripts appear to be noncoding. Two transcripts, however, potentially encode a peptide with remarkable structural similarity to human interleukin 4. These data, in particular the unique and restricted expression pattern, suggest that CLLU1 is the first disease-specific gene identified in CLL.
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http://dx.doi.org/10.1182/blood-2005-07-2615DOI Listing
April 2006

[Radioimmunotherapy in non-Hodgkin's lymphoma. With focus on anti-CD20 treatment].

Ugeskr Laeger 2005 Oct;167(41):3867-9

H:S Rigshospitalet, Finsencenteret, Haematologisk Afdeling L 4042, og Universitetssjukhuset i Lund, Onkologisk Klinik, Sverige.

Radioimmunotherapy in indolent NHL is a new and promising therapy which adds a new therapeutic tool to the treatment palette. Recent advantages in RIT are described and perspectives discussed.
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October 2005

FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma.

Blood 2006 Jan 8;107(1):52-9. Epub 2005 Sep 8.

PET and Cyclotron Unit, Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital, 9, Blegdamsvej, DK-2100 Copenhagen Ø, Denmark.

Risk-adapted lymphoma treatment requires early and accurate assessment of prognosis. This investigation prospectively assessed the value of positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose (FDG-PET) after two cycles of chemotherapy for prediction of progression-free survival (PFS) and overall survival (OS) in Hodgkin lymphoma (HL). Seventy-seven consecutive, newly diagnosed patients underwent FDG-PET at staging, after two and four cycles of chemotherapy, and after completion of chemotherapy. Median follow-up was 23 months. After two cycles of chemotherapy, 61 patients had negative FDG-PET scans and 16 patients had positive scans. Eleven of 16 FDG-PET-positive patients progressed and 2 died. Three of 61 FDG-PET-negative patients progressed; all were alive at latest follow-up. Survival analyses showed strong associations between early FDG-PET after two cycles and PFS (P < .001) and OS (P < .01). For prediction of PFS, interim FDG-PET was as accurate after two cycles as later during treatment and superior to computerized tomography (CT) at all times. In regression analyses, early interim FDG-PET was stronger than established prognostic factors. Other significant prognostic factors were stage and extranodal disease. Early interim FDG-PET is a strong and independent predictor of PFS in HL. A positive early interim FDG-PET is highly predictive of progression in patients with advanced-stage or extranodal disease.
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http://dx.doi.org/10.1182/blood-2005-06-2252DOI Listing
January 2006

How myeloma cells escape bisphosphonate-mediated killing: development of specific resistance with preserved sensitivity to conventional chemotherapeutics.

Br J Haematol 2003 Jul;122(2):202-10

Department of Haematology, University of Copenhagen, Denmark.

Although amino-bisphosphonates (N-BPs) induce apoptosis of myeloma cells in vitro, most in-vivo studies fail to demonstrate a corresponding antitumour effect. This discrepancy might reflect the development of resistance to the antitumour effects of N-BP in myeloma cells when they are exposed to N-BP for a prolonged time. To test this hypothesis, two N-BP-sensitive human myeloma cell lines were continuously exposed to increasing concentrations of the N-BP alendronate for 6 weeks. During this treatment period, 10 out of 10 sublines developed reduced apoptotic and antiproliferative responses to alendronate treatment. This de novo alendronate resistance was accompanied by resistance to another N-BP (zoledronate) but not to an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase or Fas ligand. Importantly, N-BP-resistant myeloma cells also remained sensitive to conventional myeloma chemotherapeutics (melphalan, doxorubicin and vincristine). Further analysis of the N-BP-resistant cells revealed an increased activity of the N-BP-specific target enzyme farnesyl pyrophosphate synthase, without upregulation of its gene transcription. Our results suggest that continuous exposure of myeloma cells to alendronate leads to the development of N-BP resistance. This is associated with an increased activity of farnesyl pyrophosphate synthase and does not evolve from defective apoptotic pathways. Importantly, the antitumour effects of conventional myeloma chemotherapeutics are preserved in the N-BP-resistant myeloma cells.
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http://dx.doi.org/10.1046/j.1365-2141.2003.04437.xDOI Listing
July 2003

The in vivo profile of transcription factors during neutrophil differentiation in human bone marrow.

Blood 2003 Jun 30;101(11):4322-32. Epub 2003 Jan 30.

Department of Hematology, Rigshospitalet, University of Copenhagen, Denmark.

In vivo distribution of myeloid transcription factors during granulopoiesis was investigated by Northern and Western blotting in 3 neutrophil precursor populations from human bone marrow: immature (myeloblasts [MBs] and promyelocytes [PMs]); intermediate mature (myelocytes [MCs] and metamyelocytes [MMs]); and mature neutrophil cells (band cells [BCs] and segmented neutrophil cells [SCs]). Nonneutrophil cells were removed with magnetic-bead-coupled antibodies against CD2, CD3, CD14, CD19, CD56, CD61, glycophorin-A, and CD49d (BCs/SCs) before RNA and protein extraction. Polymorphonuclear neutrophils (PMNs) from peripheral blood depleted with anti-CD49d antibodies were also included. Expression of acute myeloid leukemia 1b (AML-1b), c-myb, GATA-1, and CCAAT/enhancer binding protein gamma (C/EBP-gamma) was seen primarily in MBs/PMs, and little expression was found in more mature cells. The level of C/EBP-alpha was constant in the bone marrow-derived cells and decreased in PMNs. C/EBP-epsilon was found primarily in MCs/MMs and was almost absent in more mature cells. Expression of C/EBP-beta, C/EBP-delta, and C/EBP-zeta was observed from the MC/MM stage onward, with peak levels in the most mature cells. The amount of PU.1 increased throughout maturation whereas the level of Elf-1 reached a nadir in MCs/MMs The PU.1 coactivator c-jun and c-jun's dimerization partner c-fos were both detectable in MCs/MMs and increased in amount with maturity. CCAAT displacement protein (CDP) was found at comparable levels at all stages of differentiation. This demonstrates a highly individualized expression of the transcription factors, which can form the basis for the heterogeneous expression of granule proteins during granulopoiesis and cell cycle arrest in metamyelocytes.
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http://dx.doi.org/10.1182/blood-2002-03-0835DOI Listing
June 2003