19 results on '"Juliusson, Gunnar"'
Search Results
2. High incidence of chronic graft-versus-host disease after myeloablative allogeneic stem cell transplantation for chronic lymphocytic leukemia in Sweden: graft-versus-leukemia effect protects against relapse
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Machaczka, Maciej, Johansson, Jan-Erik, Remberger, Mats, Hallböök, Helene, Lazarevic, Vladimir Lj, Wahlin, Björn Engelbrekt, Omar, Hamdy, Wahlin, Anders, Juliusson, Gunnar, Kimby, Eva, and Hägglund, Hans
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- 2013
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3. Management of Non-Hodgkin’s Lymphomas in Adults in Scandinavia, the United Kingdom and the Netherlands: Conclusions of the Fourth Intercity Meeting, 1988
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Juliusson, Gunnar, Abrahamsen, Arne F., Cavallin-Ståhl, Eva, Goldstone, Anthony H., Lister, Andrew, Nissen, Nis I., Robèrt, Karl-Hendrik, Singer, Charles R. J., Somers, Reinier, Öst, Åke, Gahrton, Gösta, Veronesi, U., editor, and Monfardini, Silvio, editor
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- 1990
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4. Cloning of two candidate tumor suppressor genes within a 10 kb region on chromosome 13q14, frequently deleted in chronic lymphocytic leukemia
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Liu, Yie, Corcoran, Martin, Rasool, Omid, Ivanova, Ganka, Ibbotson, Rachel, Grandér, Dan, Iyengar, Arati, Baranova, Anna, Kashuba, Vladimir, Merup, Mats, Wu, Xiushan, Gardiner, Anne, Mullenbach, Roman, Poltaraus, Andrew, Hultström, Anna Linda, Juliusson, Gunnar, Chapman, Robert, Tiller, Mary, Cotter, Finbarr, Gahrton, Gösta, Yankovsky, Nick, Zabarovsky, Eugene, Einhorn, Stefan, and Oscier, David
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- 1997
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5. A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia.
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Speedy, Helen E, Di Bernardo, Maria Chiara, Sava, Georgina P, Dyer, Martin J S, Holroyd, Amy, Wang, Yufei, Sunter, Nicola J, Mansouri, Larry, Juliusson, Gunnar, Smedby, Karin E, Roos, Göran, Jayne, Sandrine, Majid, Aneela, Dearden, Claire, Hall, Andrew G, Mainou-Fowler, Tryfonia, Jackson, Graham H, Summerfield, Geoffrey, Harris, Robert J, and Pettitt, Andrew R
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GENOMES ,DISEASE susceptibility ,CHRONIC lymphocytic leukemia ,HUMAN genetic variation ,META-analysis ,RISK assessment ,GENETICS - 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 × 10
−9 ), 4q26 (rs6858698, P = 3.07 × 10−9 ), 6q25.2 (IPCEF1, rs2236256, P = 1.50 × 10−10 ) and 7q31.33 (POT1, rs17246404, P = 3.40 × 10−8 ). Additionally, we identified a promising association at 5p15.33 (CLPTM1L, rs31490, P = 1.72 × 10−7 ) and validated recently reported putative associations at 5p15.33 (TERT, rs10069690, P = 1.12 × 10−10 ) and 8q22.3 (rs2511714, P = 2.90 × 10−9 ). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CLL. [ABSTRACT FROM AUTHOR]- Published
- 2014
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6. rs2072135, a low-penetrance variant for chronic lymphocytic leukaemia?
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Sava, Georgina P., Speedy, Helen E., Bernardo, Maria Chiara, Deaglio, Silvia, Karabon, Lidia, Frydecka, Irena, Woszczyk, Dariusz, Rossi, Davide, Gaidano, Gianluca, Mansouri, Larry, Smedby, Karin E., Juliusson, Gunnar, Rosenquist, Richard, Catovsky, Daniel, and Houlston, Richard S.
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CHRONIC lymphocytic leukemia ,SINGLE nucleotide polymorphisms ,GENETIC code ,GENE expression ,CANCER cells ,LOCUS (Genetics) - 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 = 0·0024, eQTL P-value = 1·510
−19 ) in five independent case-control series totalling 1968 cases and 3538 controls. While not attaining statistical significance (combined P-value = 1 × 10−4 ), rs2072135 defines a promising risk locus for CLL. Incorporating eQTL information offers an attractive strategy for selecting SNPs from GWAS for validation. [ABSTRACT FROM AUTHOR]- Published
- 2013
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7. NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients.
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Willander, Kerstin, Kumar Dutta, Ravi, Ungerbäck, Jonas, Gunnarsson, Rebeqa, Juliusson, Gunnar, Fredrikson, Mats, Linderholm, Mats, Sööderkvist, Peter, Dutta, Ravi Kumar, and Söderkvist, Peter
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GENETIC mutation ,CHRONIC lymphocytic leukemia ,LEUKEMIA ,B cells ,CONFORMATIONAL analysis ,REGRESSION analysis ,PROGNOSIS ,RESEARCH ,RESEARCH methodology ,CELL receptors ,GENETIC polymorphisms ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,KAPLAN-Meier estimator ,PROPORTIONAL hazards models - Abstract
Background: NOTCH1 PEST domain mutations in chronic lymphocytic leukemia have recently been shown to be of prognostic relevance. Both NOTCH1 and NOTCH2 are constitutively activated in B-cell CLL but not expressed in normal B cells and may be involved in survival and resistance to apoptosis in CLL. We screened for mutations in different parts of both NOTCH1 and NOTCH2 genes and related the changes to survival and other known risk factors.Methods: In a cohort of 209 CLL patients, we used single strand conformation analysis to determine which of the samples carrying the NOTCH mutations and direct dideoxy sequencing was used to determine the exact nucleotide changes. Kaplan-Meier curves and log rank test were used to determine overall survival for NOTCH1 mutated cases and Cox regression analysis was used to calculate hazardous ratios.Results: In the present study, we found NOTCH1 PEST domain mutations in 6.7% of the cases. A shorter overall survival was found in patients with NOTCH1 mutations compared to wildtype (p = 0.049). Further, we also examined the extracellular and the heterodimerisation domains of the NOTCH1 gene and the PEST domain and heterodimerisation domain of the NOTCH2 gene, but no mutations were found in these regions. NOTCH1 mutations were most commonly observed in patients with unmutated IGHV gene (10/14), and associated with a more aggressive disease course. In addition, NOTCH1 mutations were almost mutually exclusive with TP53 mutations. In the combined group of NOTCH1 (6.7%) or TP53 (6.2%) mutations, a significant difference in overall survival compared to the wildtype NOTCH1 and TP53 was found (p = 0.002).Conclusions: Both NOTCH1 and TP53 mutations seem to be independent predictive markers for worse outcome in CLL-patients and this study emphasizes the contention that NOTCH1 mutations is a novel risk marker. [ABSTRACT FROM AUTHOR]- Published
- 2013
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8. Distinct transcriptional control in major immunogenetic subsets of chronic lymphocytic leukemia exhibiting subset-biased global DNA methylation profiles.
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Kanduri, Meena, Marincevic, Millaray, Halldórsdóttir, Anna M., Mansouri, Larry, Junevik, Katarina, Ntoufa, Stavroula, Kultima, Hanna Göransson, Isaksson, Anders, Juliusson, Gunnar, Andersson, Per-Ola, Stamatopoulos, Hans Ehrencrona Kostas, and Rosenquist, Richard
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- 2012
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9. Allogeneic hematopoietic stem cell transplant with reduced-intensity conditioning for chronic lymphocytic leukemia in Sweden: does donor T-cell engraftment 3 months after transplant predict survival?
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Machaczka, Maciej, Johansson, Jan-Erik, Remberger, Mats, Hallböök, Helene, Malm, Claes, Lazarevic, Vladimir Lj, Wahlin, Anders, Omar, Hamdy, Juliusson, Gunnar, Kimby, Eva, and Hägglund, Hans
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HEMATOPOIETIC stem cell transplantation ,CHRONIC lymphocytic leukemia ,T cells ,CHIMERISM - Abstract
Thirty-eight adult patients with chronic lymphocytic leukemia (CLL) underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplant (allo-SCT) in Sweden between 1999 and 2007. The cumulative incidences of acute graft-versus-host disease (GVHD) grades II-IV and chronic GVHD were 29% and 47%, respectively. Rates of non-relapse mortality, progression-free survival (PFS) and overall survival (OS) were 18%, 47% and 74% at 1 year, and 21%, 25% and 45% at 5 years, respectively. T-cell chimerism after transplant was measured in 31 out of 34 patients (91%) surviving beyond day +100. Seventeen patients achieved >90% donor T-cell engraftment at 3 months after allo-SCT and, compared with the 12 patients with ≤90% donor T-cell engraftment, they showed favorable PFS at 1 year (82% vs. 33%, p =0.002) and better long-term PFS and OS ( p =0.002 and 0.046, respectively). Donor T-cell engraftment of >90% at 3 months after RIC allo-SCT for CLL seems to predict favorable short-term and long-term outcome. [ABSTRACT FROM AUTHOR]
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- 2012
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10. Verification that common variation at 2q37.1, 6p25.3, 11q24.1, 15q23, and 19q13.32 influences chronic lymphocytic leukaemia risk.
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Crowther-Swanepoel, Dalemari, Mansouri, Mahmoud, Enjuanes, Anna, Vega, Ana, Smedby, Karin E., Ruiz-Ponte, Clara, Jurlander, Jesper, Juliusson, Gunnar, Montserrat, Emilio, Catovsky, Daniel, Campo, Elias, Carracedo, Angel, Rosenquist, Richard, and Houlston, Richard S.
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CHRONIC lymphocytic leukemia ,RISK ,GENOMES - Abstract
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 × 10−15 ), consistent with a polygenic model of disease susceptibility. These data validate the relationship between common variation and risk of CLL. [ABSTRACT FROM AUTHOR]- Published
- 2010
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11. Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk.
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Crowther-Swanepoel, Dalemari, Broderick, Peter, Di Bernardo, Maria Chiara, Dobbins, Sara E., Torres, María, Mansouri, Mahmoud, Ruiz-Ponte, Clara, Enjuanes, Anna, Rosenquist, Richard, Carracedo, Angel, Jurlander, Jesper, Campo, Elias, Juliusson, Gunnar, Montserrat, Emilio, Smedby, Karin E., Dyer, Martin J. S., Matutes, Estella, Dearden, Claire, Sunter, Nicola J., and Hall, Andrew G.
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CHRONIC lymphocytic leukemia ,GENOMICS ,DNA ,LOCUS (Genetics) ,MULTIPLE sclerosis ,CELL division ,GENE frequency - 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 × 10
−9 ), 8q24.21 (rs2456449; OR = 1.26; P = 7.84 × 10−10 ), 15q21.3 (rs7169431; OR = 1.36; P = 4.74 × 10−7 ) and 16q24.1 (rs305061; OR = 1.22; P = 3.60 × 10−7 ). We also found evidence for risk loci at 15q25.2 (rs783540, CPEB1; OR = 1.18; P = 3.67 × 10−6 ) and 18q21.1 (rs1036935; OR = 1.22; P = 2.28 × 10−6 ). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy. [ABSTRACT FROM AUTHOR]- Published
- 2010
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12. Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations.
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Ljungström, Viktor, Cortese, Diego, Young, Emma, Pandzic, Tatjana, Mansouri, Larry, Plevova, Karla, Ntoufa, Stavroula, Baliakas, Panagiotis, Clifford, Ruth, Sutton, Lesley-Ann, Blakemore, Stuart J., Stavroyianni, Niki, Agathangelidis, Andreas, Rossi, Davide, Höglund, Martin, Kotaskova, Jana, Juliusson, Gunnar, Belessi, Chrysoula, Chiorazzi, Nicholas, and Panagiotidis, Panagiotis
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EXOMES , *CHRONIC lymphocytic leukemia , *GENETIC mutation , *DISEASE relapse , *RITUXIMAB - Abstract
Fludarabine, cyclophosphamide, and rituximab (FCR) is first-line treatment of medically fit chronic lymphocytic leukemia (CLL) patients; however, despite good response rates, many patients eventually relapse. Although recent high-throughput studies have identified novel recurrent genetic lesions in adverse prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, and BIRC3), a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases, selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal before treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid, evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared with wild-type RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology. [ABSTRACT FROM AUTHOR]
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- 2016
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13. Lack of association between the MDM2 promoter polymorphism SNP309 and clinical outcome in chronic lymphocytic leukemia
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Kaderi, Mohd Arifin, Mansouri, Mahmoud, Zainuddin, Norafiza, Cahill, Nicola, Gunnarsson, Rebeqa, Jansson, Mattias, Kimby, Eva, Åleskog, Anna, Lundin, Jeanette, Glimelius, Bengt, Melbye, Mads, Juliusson, Gunnar, Jurlander, Jesper, and Rosenquist, Richard
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PROMOTERS (Genetics) , *GENETIC polymorphisms , *CHRONIC lymphocytic leukemia treatment , *HEALTH outcome assessment , *LYMPHOCYTIC leukemia , *BIOMARKERS , *GENETIC mutation , *PROGNOSIS - Abstract
Abstract: 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. [Copyright &y& Elsevier]
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- 2010
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14. The pattern of deoxycytidine- and deoxyguanosine kinase activity in relation to messenger RNA expression in blood cells from untreated patients with B-cell chronic lymphocytic leukemia
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Lotfi, Kourosh, Karlsson, Karin, Fyrberg, Anna, Juliusson, Gunnar, Jonsson, Viggo, Peterson, Curt, Eriksson, Staffan, and Albertioni, Freidoun
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ENZYMES , *PROTEIN kinases , *CHRONIC lymphocytic leukemia , *BLOOD cells - Abstract
Abstract: Deoxycytidine kinase (dCK) and deoxyguanosine kinase (dGK) catalyze the first step in the intracellular cascade of fludarabine (2-fluoroadenine-β-d-arabinofuranoside) and cladribine (2-chlorodeoxyadenosine) phosphorylation, which leads to activation of these prodrugs, commonly used for treatment of chronic lymphocytic leukemia (CLL). Thus, resistance to nucleoside analogues may primarily be due to low levels of deoxynucleoside kinase activity. The purpose of this study was to investigate the activity profiles of dCK and dGK and characterize the possible relationship between the levels of dCK enzymatic activities and mRNA levels in B-CLL cells from untreated patient samples in an attempt to determine the best approach for predicting sensitivity to nucleoside analogues and thereby optimizing treatment of CLL. For this purpose, dCK and dGK analyses were done in blood cells from 59 untreated symptomatic patients with CLL. The dGK activity towards 2-chlorodeoxyadenosine was significantly lower than of dCK (median 73pmol/mgprotein/min (85–121, 95% CI) versus 353pmol/mgprotein/min (331–421)). The median dCK mRNA level was 0.107 (0.096–0.120, 95% CI). There was a lack of correlation between the activities of dCK and dGK, which indicates that these proteins are regulated independently. We also found that the dCK and dGK activity measurement towards their endogenous substrates were comparable to the nucleoside analogues tested. Such variations in enzyme activities and mRNA levels may well explain differences in clinical responses to treatment. There was no correlation between the levels of dCK mRNAs and enzymatic activities using a quantitative real-time PCR procedure. Sequencing of dCK mRNA did not reveal alternate splicing or mutations in the coding region. The relation between activity and mRNA levels was studied by short interfering RNA (siRNA) method, which showed that in the siRNA treated cells the down-regulation of dCK expression, and activity followed each other. However, in control cells the mRNA levels remained stable but the protein activity markedly decreased. These data demonstrate that the dCK activity is not reflected by dCK mRNA expression that indicates a post-translational mechanism(s). [Copyright &y& Elsevier]
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- 2006
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15. Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes
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Véronique Giudicelli, Lesley-Ann Sutton, Panagiotis Baliakas, Anastasia Hadzidimitriou, David Oscier, Kostas Stamatopoulos, Michael Hallek, Eugen Tausch, Marco Montillo, Achilles Anagnostopoulos, Elias Campo, Yorick Sandberg, Silvio Veronese, Šárka Pospíšilová, Dirk Kienle, Karin E. Smedby, Xiao-Jie Yan, Lydia Scarfò, Andreas Agathangelidis, Nikos Darzentas, Richard Rosenquist, Stavroula Ntoufa, Larry Mansouri, Darko Antic, Niki Stavroyianni, Aliki Xochelli, Tait D. Shanafelt, Tatiana Tzenou, Andrey Sudarikov, Charles C. Chu, Anton W. Langerak, Marie-Paule Lefranc, Nicholas Chiorazzi, Eva Minga, Carsten Utoft Niemann, Ioanna Chouvarda, Nikos Maglaveras, Gianluca Gaidano, Maria Chatzouli, Karla Plevová, Mark Catherwood, Hartmut Döhner, Chrysoula Belessi, Myriam Boudjogra, Zadie Davis, Ioannis Kavakiotis, Gunnar Juliusson, Livio Trentin, Frederic Davi, Davide Rossi, Jasmin Bahlo, Diane F. Jelinek, Monica Facco, Christiane Pott, Lone Bredo Pedersen, Panagiotis Panagiotidis, Fie Juhl Vojdeman, Stephan Stilgenbauer, Teodora Karan-Djurasevic, Alba Navarro, Paolo Ghia, Ioannis Vlahavas, Immunology, Xochelli, Aliki, Baliakas, Panagioti, Kavakiotis, Ioanni, Agathangelidis, Andrea, Sutton, Lesley-Ann, Minga, Eva, Ntoufa, Stavroula, Tausch, Eugen, Yan, Xiao-Jie, Shanafelt, Tait, Plevova, Karla, Boudjogra, Myriam, Rossi, Davide, Davis, Zadie, Navarro, Alba, Sandberg, Yorick, Vojdeman, Fie Juhl, Scarfo, Lydia, Stavroyianni, Niki, Sudarikov, Andrey, Veronese, Silvio, Tzenou, Tatiana, Karan-Djurasevic, Teodora, Catherwood, Mark, Kienle, Dirk, Chatzouli, Maria, Facco, Monica, Bahlo, Jasmin, Pott, Christiane, Pedersen, Lone Bredo, Mansouri, Larry, Smedby, Karin E, Chu, Charles C, Giudicelli, Véronique, Lefranc, Marie-Paule, Panagiotidis, Panagioti, Juliusson, Gunnar, Anagnostopoulos, Achille, Vlahavas, Ioanni, Antic, Darko, Trentin, Livio, Montillo, Marco, Niemann, Carsten, Döhner, Hartmut, Langerak, Anton W, Pospisilova, Sarka, Hallek, Michael, Campo, Elia, Chiorazzi, Nichola, Maglaveras, Niko, Oscier, David, Gaidano, Gianluca, Jelinek, Diane F, Stilgenbauer, Stephan, Chouvarda, Ioanna, Darzentas, Niko, Belessi, Chrysoula, Davi, Frederic, Hadzidimitriou, Anastasia, Rosenquist, Richard, Ghia, Paolo, and Stamatopoulos, Kostas
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Male ,0301 basic medicine ,Cancer Research ,Chronic lymphocytic leukemia ,B-cell receptor ,Immunoglobulin Variable Region ,Somatic hypermutation ,Immunogenetics ,Disease ,Biology ,03 medical and health sciences ,hemic and lymphatic diseases ,medicine ,Humans ,Amino Acid Sequence ,breakpoint cluster region ,Chronic Lymphocytic Leukemia B cell receptor BCR Immunoglobulin ,medicine.disease ,ADP-ribosyl Cyclase 1 ,Leukemia, Lymphocytic, Chronic, B-Cell ,3. Good health ,Gene Expression Regulation, Neoplastic ,Leukemia ,030104 developmental biology ,Oncology ,Immunology ,biology.protein ,Female ,Somatic Hypermutation, Immunoglobulin ,Antibody ,Immunoglobulin Heavy Chains - Abstract
Purpose: We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication. Experimental Design: In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34–expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes. Results: We identified shared and subset-specific patterns of somatic hypermutation (SHM) among patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLL. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly (P < 0.05) longer time-to-first-treatment (TTFT; median TTFT: not yet reached) compared with the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively). Conclusions: Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. In addition, the observed distinct genetic aberration landscapes and clinical heterogeneity suggest that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management. Clin Cancer Res; 23(17); 5292–301. ©2017 AACR.
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- 2017
16. Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia
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Zadie Davis, Richard Rosenquist, Chrysoula Belessi, Panagiotis Baliakas, Niki Stavroyianni, Theodoros Moysiadis, Elias Campo, Julio Delgado, Šárka Pospíšilová, Kostas Stamatopoulos, Marta Larrayoz, Davide Rossi, Jonathan C. Strefford, Larry Mansouri, Achilles Anagnostopoulos, Mattias Mattsson, Karin E. Smedby, Diego Cortese, Anastasia Hadzidimitriou, Lesley-Ann Sutton, Neus Villamor, David Oscier, Alba Navarro, Jana Kotašková, Evangelia Stalika, Gianluca Gaidano, Karla Plevová, Mark Catherwood, Gunnar Juliusson, Paolo Ghia, Sabine Jeromin, Oonagh Sheehy, Lydia Scarfò, Andreas Agathangelidis, Emma Young, Helen Parker, Eva Minga, Aliki Xochelli, Claudia Haferlach, Baliakas, Panagioti, Moysiadis, Theodoro, Hadzidimitriou, Anastasia, Xochelli, Aliki, Jeromin, Sabine, Agathangelidis, Andrea, Mattsson, Mattia, Sutton, Lesley-Ann, Minga, Eva, Scarfò, Lydia, Rossi, Davide, Davis, Zadie, Villamor, Neu, Parker, Helen, Kotaskova, Jana, Stalika, Evangelia, Plevova, Karla, Mansouri, Larry, Cortese, Diego, Navarro, Alba, Delgado, Julio, Larrayoz, Marta, Young, Emma, Anagnostopoulos, Achille, Smedby, Karin E., Juliusson, Gunnar, Sheehy, Oonagh, Catherwood, Mark, Strefford, Jonathan C., Stavroyianni, Niki, Belessi, Chrysoula, Pospisilova, Sarka, Oscier, David, Gaidano, Gianluca, Campo, Elia, Haferlach, Claudia, Ghia, Paolo, Rosenquist, Richard, Stamatopoulos, Kostas, and Universitat de Barcelona
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Male ,Oncology ,medicine.medical_specialty ,Pronòstic mèdic ,Chronic lymphocytic leukemia ,Somatic hypermutation ,Relative weight ,Kaplan-Meier Estimate ,Immunogenetics ,Article ,Time-to-Treatment ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,hemic and lymphatic diseases ,Biomarkers, Tumor ,medicine ,Humans ,Chronic Lymphocytic Leukemia ,Leucèmia limfocítica crònica ,Hematologi ,Aged ,Neoplasm Staging ,030304 developmental biology ,Aged, 80 and over ,Chromosome Aberrations ,0303 health sciences ,Hematology ,biology ,business.industry ,medicine.disease ,Prognosis ,Leukemia, Lymphocytic, Chronic, B-Cell ,3. Good health ,Leukemia ,030220 oncology & carcinogenesis ,Mutation ,biology.protein ,Female ,Disease Susceptibility ,Antibody ,business ,Trisomy - Abstract
Chronic lymphocytic leukemia patients with differential somatic hypermutation status of the immunoglobulin heavy variable genes, namely mutated or unmutated, display fundamental clinicobiological differences. Considering this, we assessed prognosis separately within mutated and unmutated chronic lymphocytic leukemia in 3015 patients, hypothesizing that the relative significance of relevant indicators may differ between these two categories. Within Binet-A mutated chronic lymphocytic leukemia patients, besides TP53 abnormalities, trisomy 12 and stereotyped subset #2 membership were equivalently associated with the shortest time-to-first-treatment and a treatment probability at 5- and 10-years after diagnosis of 40% and 55%, respectively; the remaining cases exhibited 5-year and 10-year treatment probability of 12% and 25%, respectively. Within Binet-A unmutated chronic lymphocytic leukemia patients, besides TP53 abnormalities, del(11q) and/or SF3B1 mutations were associated with the shortest time-to-first-trearment (5- and 10-year treatment probability: 78% and 98%, respectively); in the remaining cases, males had a significantly worse prognosis than females. In conclusion, the relative weight of indicators that can accurately risk stratify early-stage chronic lymphocytic leukemia patients differs depending on the somatic hypermutation status of the immunoglobulin heavy variable genes of each patient. This finding highlights the fact that compartmentalized approaches based on immunogenetic features are necessary to refine and tailor prognostication in chronic lymphocytic leukemia.
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- 2019
17. No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(immuno)therapy
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Tatiana Tzenou, Richard Rosenquist, Marie-Paule Lefranc, Karla Plevová, Charles C. Chu, Yorick Sandberg, Gunnar Juliusson, Véronique Giudicelli, Livio Trentin, Mark Catherwood, Frederic Davi, Šárka Pospíšilová, Xiao-Jie Yan, Silvio Veronese, Lesley-Ann Sutton, Carsten Utoft Niemann, Nikos Darzentas, Kostas Stamatopoulos, Achilles Anagnostopoulos, Diane F. Jelinek, David Oscier, Mattias Mattsson, Nicholas Chiorazzi, Karin E. Smedby, Panagiotis Panagiotidis, Chrysoula Belessi, Florence Nguyen-Khac, Marco Montillo, Eva Minga, Paolo Ghia, Anton W. Langerak, Lydia Scarfò, Andreas Agathangelidis, Tait D. Shanafelt, Panagiotis Baliakas, Niki Stavroyianni, Larry Mansouri, Anastasia Hadzidimitriou, Zadie Davis, Fie Juhl Vojdeman, Uppsala Universitet [Uppsala], Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden, Institute of Applied Biosciences, Centre for Research and Technology-Hellas, Thessaloniki, Greece, Department of Immunology, Genetics and Pathology [Uppsala, Sueden] (IGP), Uppsala University, Department of Hematology [Uppsala], Università Vita-Salute San Raffaele, Milan, Italy., Strategic Research Program in CLL, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy, Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden, Università Vita e Salute, San Raffaele, Milano, Italy, Strategic Research Program in CLL, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy., Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK., The Feinstein Institute for Medical Research, CEITEC-Central European Institute of Technology, MasarykBrno, Czech Republic., Central European Institute of Technology [Brno] (CEITEC MU), Brno University of Technology [Brno] (BUT), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Hematology, Rigshospitalet, Copenhagen, Denmark, First Department of Propaedeutic Medicine, University of Athens, Athens, Greece, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Department of Medicine Solna, Clinical Epidemiology Unit, Karolinska Institutet, and Hematology Center, Karolinska University Hospital, Stockholm, Sweden, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hematology and Transplantation, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University and Hospital Department of Hematology, Lund Stem Cell Center, Lund, Sweden, Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece, Universita degli Studi di Padova, Venetian Institute Molecular Medicine (VIMM), Department of Hemato-Oncology, Belfast City Hospital, Belfast, UK, University Hospital Brno, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Immunology, Mayo Clinic, Rochester, MV, USA, Mayo Clinic [Rochester], Hematology Department, Nikea General Hospital, Piraeus, Greece, Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden., Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden, Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece., Institute of Applied Biosciences, Thessaloniki, Greece., Department of Immunology, Baliakas, Panagioti, Mattsson, Mattia, Hadzidimitriou, Anastasia, Minga, Eva, Agathangelidis, Andrea, Sutton, Lesley-Ann, Scarfo, Lydia, Davis, Zadie, Yan, Xiao-Jie, Plevova, Karla, Sandberg, Yorick, Vojdeman, Fie J, Tzenou, Tatiana, Chu, Charles C, Veronese, Silvio, Mansouri, Larry, Smedby, Karin E, Giudicelli, Véronique, Nguyen-Khac, Florence, Panagiotidis, Panagioti, Juliusson, Gunnar, Anagnostopoulos, Achille, Lefranc, Marie-Paule, Trentin, Livio, Catherwood, Mark, Montillo, Marco, Niemann, Carsten U, Langerak, Anton W, Pospisilova, Sarka, Stavroyianni, Niki, Chiorazzi, Nichola, Oscier, David, Jelinek, Diane F, Shanafelt, Tait, Darzentas, Niko, Belessi, Chrysoula, Davi, Frederic, Ghia, Paolo, Rosenquist, Richard, Stamatopoulos, Kostas, and Immunology
- Subjects
Adult ,Male ,chemorefractorine ,Oncology ,medicine.medical_specialty ,Cyclophosphamide ,Chronic lymphocytic leukemia ,[SDV]Life Sciences [q-bio] ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Drug Therapy ,Chemoimmunotherapy ,Internal medicine ,medicine ,Humans ,Chronic Lymphocytic Leukemia ,[INFO]Computer Science [cs] ,stereotyped subsets ,Online Only Articles ,Survival rate ,ComputingMilieux_MISCELLANEOUS ,Aged ,Retrospective Studies ,Aged, 80 and over ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Hematology ,business.industry ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,3. Good health ,Fludarabine ,Survival Rate ,Leukemia ,030220 oncology & carcinogenesis ,Female ,Rituximab ,Immunotherapy ,business ,030215 immunology ,medicine.drug - Abstract
The overall survival (OS) of patients with chronic lymphocytic leukemia (CLL) has improved over the last decades mainly due to advances in the understanding of the disease biology and the introduction of novel therapeutic approaches(1). In the present retrospective study we investigated trends in OS in subgroups of cases defined by genetic and immunogenetic features aiming at addressing the question whether advances in chemoimmunotherapy had a uniform impact across all CLL patients. We found that such advances have translated into prolonged OS in all prognostic subgroups examined except those carrying TP53 abnormalities, as expected, but also those assigned to stereotyped subsets #1 and #2, that are generally devoid of such gene aberrations. This latter finding, reported here for the first time, indicates the need for alternative treatment options for these patients.
- Published
- 2018
18. TP53 Mutations are infrequent in newly diagnosed chronic lymphocytic leukemia
- Author
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Zainuddin, Norafiza, Murray, Fiona, Kanduri, Meena, Gunnarsson, Rebeqa, Smedby, Karin E., Enblad, Gunilla, Jurlander, Jesper, Juliusson, Gunnar, and Rosenquist, Richard
- Subjects
- *
CHRONIC lymphocytic leukemia diagnosis , *GENETIC mutation , *DISEASE progression , *DISEASE prevalence , *COHORT analysis , *PROGNOSIS - Abstract
Abstract: 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. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
19. ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: Enrichment in subset #2 is associated with markedly short telomeres
- Author
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Panagiotis Baliakas, Larry Mansouri, Viktor Ljungström, Richard Rosenquist, Šárka Pospíšilová, Gunnar Juliusson, Frederic Davi, Martin Trbušek, Stavroula Ntoufa, Paolo Ghia, Karin E. Smedby, Chrysoula Belessi, Anton W. Langerak, Lesley-Ann Sutton, Jiri Mayer, Karla Plevová, Kostas Stamatopoulos, Panagiotis Panagiotidis, Tasoula Touloumenidou, Lenka Radová, Emma Young, Jonathan C. Strefford, Zadie Davis, David Oscier, Veronika Navrkalová, Navrkalova, Veronika, Young, Emma, Baliakas, Panagioti, Radova, Lenka, Sutton, Lesley Ann, Plevova, Karla, Mansouri, Larry, Ljungström, Viktor, Ntoufa, Stavroula, Davis, Zadie, Juliusson, Gunnar, Smedby, Karin E., Belessi, Chrysoula, Panagiotidis, Panagioti, Touloumenidou, Tasoula, Davi, Frederic, Langerak, Anton W., Ghia, PAOLO PROSPERO, Strefford, Jonathan C., Oscier, David, Mayer, Jiri, Stamatopoulos, Kosta, Pospisilova, Sarka, Rosenquist, Richard, Trbusek, Martin, and Immunology
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Antigenic selection ,Chronic lymphocytic leukemia ,Ataxia Telangiectasia Mutated Proteins ,Biology ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Stereotyped subset ,Online Only Articles ,Telomere Shortening ,Hematology ,Atm mutation ,Sequence Analysis, DNA ,Telomere ,medicine.disease ,Short telomere ,Leukemia, Lymphocytic, Chronic, B-Cell ,Survival Analysis ,030104 developmental biology ,030220 oncology & carcinogenesis ,Immunology ,Mutation - Abstract
ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: enrichment in subset 2 is associated with markedly short telomeres, ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: enrichment in subset 2 is associated with markedly short telomeres, ATM mutations in major stereotyped subsets of chronic lymphocytic leukemia: enrichment in subset 2 is associated with markedly short telomeres.
- Published
- 2016
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