74 results on '"Hultdin M"'
Search Results
2. T-cell acute lymphoblastic leukemia in patients 1–45 years treated with the pediatric NOPHO ALL2008 protocol
- Author
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Quist-Paulsen, P., Toft, N., Heyman, M., Abrahamsson, J., Griškevičius, L., Hallböök, H., Jónsson, Ó. G., Palk, K., Vaitkeviciene, G., Vettenranta, K., Åsberg, A., Frandsen, T. L., Opdahl, S., Marquart, H. V., Siitonen, S., Osnes, L. T., Hultdin, M., Overgaard, U. M., Wartiovaara-Kautto, U., and Schmiegelow, K.
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- 2020
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3. Minimal residual disease quantification by flow cytometry provides reliable risk stratification in T-cell acute lymphoblastic leukemia
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Modvig, S., Madsen, H. O., Siitonen, S. M., Rosthøj, S., Tierens, A., Juvonen, V., Osnes, L.T.N., Vålerhaugen, H., Hultdin, M., Thörn, I., Matuzeviciene, R., Stoskus, M., Marincevic, M., Fogelstrand, L., Lilleorg, A., Toft, N., Jónsson, O. G., Pruunsild, K., Vaitkeviciene, G., Vettenranta, K., Lund, B., Abrahamsson, J., Schmiegelow, K., and Marquart, H. V.
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- 2019
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4. Correction: Minimal residual disease quantification by flow cytometry provides reliable risk stratification in T-cell acute lymphoblastic leukemia
- Author
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Modvig, S., Madsen, H. O., Siitonen, S. M., Rosthøj, S., Tierens, A., Juvonen, V., Osnes, L. T. N., Vålerhaugen, H., Hultdin, M., Thörn, I., Matuzeviciene, R., Stoskus, M., Marincevic, M., Fogelstrand, L., Lilleorg, A., Toft, N., Jónsson, O. G., Pruunsild, K., Vaitkeviciene, G., Vettenranta, K., Lund, B., Abrahamsson, J., Schmiegelow, K., and Marquart, H. V.
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- 2020
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5. High-risk subtypes of chronic lymphocytic leukemia are detectable as early as 16 years prior to diagnosis
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Kolijn, P.M. Hosnijeh, F.S. Späth, F. Hengeveld, P.J. Agathangelidis, A. Saleh, M. Casabonne, D. Benavente, Y. Jerkeman, M. Agudo, A. Barricarte, A. Besson, C. Sánchez, M.-J. Chirlaque, M.-D. Masala, G. Sacerdote, C. Grioni, S. Schulze, M.B. Nieters, A. Engelfriet, P. Hultdin, M. McKay, J.D. Vermeulen, R.C.H. Langerak, A.W.
- Subjects
immune system diseases ,hemic and lymphatic diseases - Abstract
Chronic lymphocytic leukemia (CLL) is preceded by monoclonal B-cell lymphocytosis (MBL), a CLL precursor state with a prevalence of up to 12% in aged individuals; however, the duration of MBL and the mechanisms of its evolution to CLL remain largely unknown. In this study, we sequenced the B-cell receptor (BcR) immunoglobulin heavy chain (IGH) gene repertoire of 124 patients with CLL and 118 matched controls in blood samples taken up to 22 years prior to diagnosis. Significant skewing in the BcR IGH gene repertoire was detected in the majority of patients, even before the occurrence of lymphocytosis and irrespective of the clonotypic IGH variable gene somatic hypermutation status. Furthermore, we identified dominant clonotypes belonging to major stereotyped subsets associated with poor prognosis up to 16 years before diagnosis in 14 patients with CLL. In 22 patients with longitudinal samples, the skewing of the BcR IGH gene repertoire increased significantly over time to diagnosis or remained stable at high levels. For 14 of 16 patients with available samples at diagnosis, the CLL clonotype was already present in the prediagnostic samples. Overall, our data indicate that the preclinical phase of CLL could be longer than previously thought, even in adverse-prognostic cases. © 2022 American Society of Hematology
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- 2022
6. Bone marrow hyaluronan and reticulin in patients with malignant disorders
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Sundström, G., Hultdin, M., Engström-Laurent, A., and Dahl, I. M. S.
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- 2010
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7. Value of flow cytometry for MRD-based relapse prediction in B-cell precursor ALL in a multicenter setting
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Modvig, S., primary, Hallböök, H., additional, Madsen, H. O., additional, Siitonen, S., additional, Rosthøj, S., additional, Tierens, A., additional, Juvonen, V., additional, Osnes, L. T. N., additional, Vålerhaugen, H., additional, Hultdin, M., additional, Matuzeviciene, R., additional, Stoskus, M., additional, Marincevic, M., additional, Lilleorg, A., additional, Ehinger, M., additional, Norén-Nystrøm, U., additional, Toft, N., additional, Taskinen, M., additional, Jónsson, O. G., additional, Pruunsild, K., additional, Vaitkeviciene, G., additional, Vettenranta, K., additional, Lund, B., additional, Abrahamsson, J., additional, Porwit, A., additional, Schmiegelow, K., additional, and Marquart, H. V., additional
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- 2020
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8. Correction: Minimal residual disease quantification by flow cytometry provides reliable risk stratification in T-cell acute lymphoblastic leukemia
- Author
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Modvig, S., primary, Madsen, H. O., additional, Siitonen, S. M., additional, Rosthøj, S., additional, Tierens, A., additional, Juvonen, V., additional, Osnes, L. T. N., additional, Vålerhaugen, H., additional, Hultdin, M., additional, Thörn, I., additional, Matuzeviciene, R., additional, Stoskus, M., additional, Marincevic, M., additional, Fogelstrand, L., additional, Lilleorg, A., additional, Toft, N., additional, Jónsson, O. G., additional, Pruunsild, K., additional, Vaitkeviciene, G., additional, Vettenranta, K., additional, Lund, B., additional, Abrahamsson, J., additional, Schmiegelow, K., additional, and Marquart, H. V., additional
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- 2019
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9. T-cell acute lymphoblastic leukemia in patients 1–45 years treated with the pediatric NOPHO ALL2008 protocol
- Author
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Quist-Paulsen, P., primary, Toft, N., additional, Heyman, M., additional, Abrahamsson, J., additional, Griškevičius, L., additional, Hallböök, H., additional, Jónsson, Ó. G., additional, Palk, K., additional, Vaitkeviciene, G., additional, Vettenranta, K., additional, Åsberg, A., additional, Frandsen, T. L., additional, Opdahl, S., additional, Marquart, H. V., additional, Siitonen, S., additional, Osnes, L. T., additional, Hultdin, M., additional, Overgaard, U. M., additional, Wartiovaara-Kautto, U., additional, and Schmiegelow, K., additional
- Published
- 2019
- Full Text
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10. Minimal residual disease quantification by flow cytometry provides reliable risk stratification in T-cell acute lymphoblastic leukemia
- Author
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Modvig, S., primary, Madsen, H. O., additional, Siitonen, S. M., additional, Rosthøj, S., additional, Tierens, A., additional, Juvonen, V., additional, Osnes, L.T.N., additional, Vålerhaugen, H., additional, Hultdin, M., additional, Thörn, I., additional, Matuzeviciene, R., additional, Stoskus, M., additional, Marincevic, M., additional, Fogelstrand, L., additional, Lilleorg, A., additional, Toft, N., additional, Jónsson, O. G., additional, Pruunsild, K., additional, Vaitkeviciene, G., additional, Vettenranta, K., additional, Lund, B., additional, Abrahamsson, J., additional, Schmiegelow, K., additional, and Marquart, H. V., additional
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- 2018
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11. Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma
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Mansouri, L. Noerenberg, D. Young, E. Mylonas, E. Abdulla, M. Frick, M. Asmar, F. Ljungström, V. Schneider, M. Yoshida, K. Skaftason, A. Pandzic, T. Gonzalez, B. Tasidou, A. Waldhueter, N. Rivas-Delgado, A. Angelopoulou, M. Ziepert, M. Arends, C.M. Couronné, L. Lenze, D. Baldus, C.D. Bastard, C. Okosun, J. Fitzgibbon, J. Dörken, B. Drexler, H.G. Roos-Weil, D. Schmitt, C.A. Munch-Petersen, H.D. Zenz, T. Hansmann, M.-L. Strefford, J.C. Enblad, G. Bernard, O.A. Ralfkiaer, E. Erlanson, M. Korkolopoulou, P. Hultdin, M. Papadaki, T. Grønbæk, K. Lopez-Guillermo, A. Ogawa, S. Küppers, R. Stamatopoulos, K. Stavroyianni, N. Kanellis, G. Rosenwald, A. Campo, E. Amini, R.-M. Ott, G. Vassilakopoulos, T.P. Hummel, M. Rosenquist, R. Damm, F.
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hemic and lymphatic diseases - Abstract
We recently reported a truncating deletion in the NFKBIE gene, which encodes IκB, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Because preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, we screened a large patient cohort (n 5 1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal zone lymphoma, and T-cell acute lymphoblastic leukemia (
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- 2016
12. Bone marrow hyaluronan and reticulin in patients with malignant disorders
- Author
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Sundström, G., primary, Hultdin, M., additional, Engström-Laurent, A., additional, and Dahl, I. M. S., additional
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- 2009
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13. Association between telomere length and VH gene mutation status in chronic lymphocytic leukaemia: clinical and biological implications
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Hultdin, M, primary, Rosenquist, R, additional, Thunberg, U, additional, Tobin, G, additional, Norrback, K-F, additional, Johnson, A, additional, Sundström, C, additional, and Roos, G, additional
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- 2003
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14. Replication Timing of Human Telomeric DNA and Other Repetitive Sequences Analyzed by Fluorescence in Situ Hybridization and Flow Cytometry
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Hultdin, M., primary, Grönlund, E., additional, Norrback, K.-F., additional, Just, T., additional, Taneja, K., additional, and Roos, G., additional
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- 2001
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15. Telomere analysis by fluorescence in situ hybridization and flow cytometry
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Hultdin, M., primary, Gronlund, E., additional, Norrback, K.- F., additional, Eriksson-Lindstrom, E., additional, Roos, G., additional, and Just, T., additional
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- 1998
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16. Association between telomere length and VH gene mutation status in chronic lymphocytic leukaemia: clinical and biological implications.
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Hultdin, M, Rosenquist, R, Thunberg, U, Tobin, G, Norrback, K-F, Johnson, A, Sundström, C, and Roos, G
- Subjects
- *
IMMUNOGLOBULINS , *GENETIC mutation , *CHRONIC lymphocytic leukemia , *B cells - Abstract
The immunoglobulin V[sub H] gene mutation status can divide B-cell chronic Iymphocytic leukaemia (CLL) into two entities with a different clinical course. Cases with unmutated V[sub H] genes, considered to evolve from pregerminal centre (GC) cells, have a worse outcome compared to cases showing mutated V[sub H] genes, that is, post-GC derived. Also, telomere length has been reported to be of prognostic significance in CLL. Interestingly, telomerase becomes activated during the GC reaction and an elongation of the telomeres occurs in GC B cells. We performed telomere length and V[sub H] gene analysis in a series of 61 CLL cases, in order to investigate if the unique telomere lengthening shown in GC B cells could reflect the telomere status in the two subsets of mutated and unmutated CLL. A novel association was found between V[sub H] gene mutation status and telomere length, since significantly shorter telomeres were demonstrated in the unmutated group compared to the mutated group (mean length 4.3 vs 6.3 kbp). Shorter telomeres also constituted a subgroup with a worse prognosis than cases with longer telomeres (median survival 59 vs 159 months). Furthermore, the Ig gene sequence data revealed that samples with high mutations frequency (> 6%) had long telomeres (∼ 8 kbp). Thus, both the telomere and V[sub H] gene mutation status in CLL appear linked, which may reflect the proliferative history of the clonal cells with regard to the GC reaction. [ABSTRACT FROM AUTHOR]
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- 2003
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17. Replication Timing of Human Telomeric DNA and Other Repetitive Sequences Analyzed by Fluorescence in SituHybridization and Flow Cytometry
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Hultdin, M., Grönlund, E., Norrback, K.-F., Just, T., Taneja, K., and Roos, G.
- Abstract
The replication timing of telomeres seems to differ between species. Yeast telomeres are late replicating, whereas limited data from very few human cell lines have indicated telomere replication throughout S phase. In the present study a series of permanent cell lines and patient samples was investigated using a flow cytometric approach for telomere length determination based on in situhybridization using peptide nucleic acid probes and DNA staining. This method permits selective analysis of cells in specific phases of the cell cycle without perturbation of the cell cycle machinery. The timing of replication of telomeric C3TA2and T2AG3repeats was found to differ between individual samples and could precede or be concomitant with the replication of bulk DNA. Replication of the T2AG3strand seemed to occur somewhat later than that of the C3TA2strand in some samples. (GTG)nand other repetitive sequences generally showed a replication pattern similar to that of the bulk of DNA with slightly individual differences, whereas centromeric DNA repeats consistently replicated within a short time frame in late S phase. The apparent variability in replication timing seen for telomeric DNA might suggest individual differences in firing of replication origins.
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- 2001
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18. Patients with chronic lymphocytic leukemia with mutated VH genes presenting with Binet stage B or C form a subgroup with a poor outcome
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Tobin, G., Thunberg, U., Laurell, A., Karlsson, K., Aleskog, A., Willander, K., Soderberg, O., Merup, M., Vilpo, J., Hultdin, M., Sundstrom, C., Roos, G., and Richard Rosenquist
19. Evaluation of coverage, generalisability and validity of the U-CAN lymphoma biobank in Sweden: A comparison with nationwide registers.
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Forsgren E, Ekberg S, Smedby KE, Nylund P, Sjöblom T, Flogegård M, Sjöström S, Hultdin M, Hallén K, Hellström M, Molin D, Enblad G, and Glimelius I
- Abstract
Validation of biobanks and large cancer cohorts is essential in ensuring high-quality research results. We examined the coverage, generalisability and validity of the lymphoma collection of the Uppsala-Umeå Comprehensive Cancer Consortium (U-CAN) biobank in Sweden, one of the largest cancer biobanks in Europe. Up until 2022, 889 lymphoma patients in U-CAN Uppsala had available samples, and 329 in U-CAN Umeå. Patients diagnosed in the U-CAN Uppsala area 2011-2021 (n = 843) were linked to the nationwide Swedish Lymphoma Register, and a subset diagnosed before 2019 (n = 727) to population-based registers. The coverage was 39% of all lymphoma patients between 2011 and 2019 diagnosed in the U-CAN Uppsala area, with a pandemic decline to 10% during 2020-2021. The patients included had superior overall survival (hazard ratio = 0.70 [95% confidence interval, CI: 0.60-0.82]) than all lymphoma patients in Sweden. They had better performance status, were younger (odds ratio [OR] = 0.21 [95% CI: 0.13-0.34]) and had less comorbidities (OR = 0.66 [95% CI: 0.56-0.78]). However, cause-specific survival and stage distribution were similar. The questionnaire data captured less comorbidities compared to the national registers. Evaluations of biobanks are important, as even population-based biobanks such as U-CAN select younger patients with higher socioeconomical status and better performance status. However, the similar cause-specific survival as in the registries suggests U-CANs usefulness for prognostic biomarker studies., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2024
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20. Semimethylation is a feature of diffuse large B-cell lymphoma, and subgroups with poor prognosis are characterized by global hypomethylation and short telomere length.
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Carlund O, Thörn E, Osterman P, Fors M, Dernstedt A, Forsell MNE, Erlanson M, Landfors M, Degerman S, and Hultdin M
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- Humans, Female, Male, Prognosis, Middle Aged, Aged, Adult, Rituximab therapeutic use, Aged, 80 and over, Cyclophosphamide therapeutic use, Doxorubicin therapeutic use, Vincristine therapeutic use, Prednisone therapeutic use, Telomere genetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Telomere Shortening genetics, Epigenesis, Genetic genetics, CpG Islands genetics, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse mortality, DNA Methylation genetics
- Abstract
Background: Large B-cell lymphoma (LBCL) is the most common lymphoma and is known to be a biologically heterogeneous disease regarding genetic, phenotypic, and clinical features. Although the prognosis is good, one-third has a primary refractory or relapsing disease which underscores the importance of developing predictive biological markers capable of identifying high- and low-risk patients. DNA methylation (DNAm) and telomere maintenance alterations are hallmarks of cancer and aging. Both these alterations may contribute to the heterogeneity of the disease, and potentially influence the prognosis of LBCL., Results: We studied the DNAm profiles (Infinium MethylationEPIC BeadChip) and relative telomere lengths (RTL) with qPCR of 93 LBCL cases: Diffuse large B-cell lymphoma not otherwise specified (DLBCL, n = 66), High-grade B-cell lymphoma (n = 7), Primary CNS lymphoma (n = 8), and transformation of indolent B-cell lymphoma (n = 12). There was a substantial methylation heterogeneity in DLBCL and other LBCL entities compared to normal cells and other B-cell neoplasms. LBCL cases had a particularly aberrant semimethylated pattern (0.15 ≤ β ≤ 0.8) with large intertumor variation and overall low hypermethylation (β > 0.8). DNAm patterns could not be used to distinguish between germinal center B-cell-like (GC) and non-GC DLBCL cases. In cases treated with R-CHOP-like regimens, a high percentage of global hypomethylation (β < 0.15) was in multivariable analysis associated with worse disease-specific survival (DSS) (HR 6.920, 95% CI 1.499-31.943) and progression-free survival (PFS) (HR 4.923, 95% CI 1.286-18.849) in DLBCL and with worse DSS (HR 5.147, 95% CI 1.239-21.388) in LBCL. These cases with a high percentage of global hypomethylation also had a higher degree of CpG island methylation, including islands in promoter-associated regions, than the cases with less hypomethylation. Additionally, telomere length was heterogenous in LBCL, with a subset of the DLBCL-GC cases accounting for the longest RTL. Short RTL was independently associated with worse DSS (HR 6.011, 95% CI 1.319-27.397) and PFS (HR 4.689, 95% CI 1.102-19.963) in LBCL treated with R-CHOP-like regimens., Conclusion: We hypothesize that subclones with high global hypomethylation and hypermethylated CpG islands could have advantages in tumor progression, e.g. by inactivating tumor suppressor genes or promoting treatment resistance. Our findings suggest that cases with high global hypomethylation and thus poor prognosis could be candidates for alternative treatment regimens including hypomethylating drugs., (© 2024. The Author(s).)
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- 2024
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21. Correction: Short leukocyte telomeres predict 25-year Alzheimer's disease incidence in non-APOE ε4-carriers.
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Hackenhaar FS, Josefsson M, Adolfsson AN, Landfors M, Kauppi K, Hultdin M, Adolfsson R, Degerman S, and Pudas S
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- 2024
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22. Genetic drivers in the natural history of chronic lymphocytic leukemia development as early as 16 years before diagnosis.
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Kolijn PM, Späth F, Khouja M, Hengeveld PJ, van der Straten L, Darzentas N, Hultdin M, McKay JD, Pott C, Vermeulen RCH, and Langerak AW
- Subjects
- Humans, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell genetics
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- 2023
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23. DNA methylation variations and epigenetic aging in telomere biology disorders.
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Carlund O, Norberg A, Osterman P, Landfors M, Degerman S, and Hultdin M
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- Epigenesis, Genetic, Telomere genetics, Biology, DNA Methylation, DNA
- Abstract
Telomere Biology Disorders (TBDs) are characterized by mutations in telomere-related genes leading to short telomeres and premature aging but with no strict correlation between telomere length and disease severity. Epigenetic alterations are also markers of aging and we aimed to evaluate whether DNA methylation (DNAm) could be part of the pathogenesis of TBDs. In blood from 35 TBD cases, genome-wide DNAm were analyzed and the cases were grouped based on relative telomere length (RTL): short (S), with RTL close to normal controls, and extremely short (ES). TBD cases had increased epigenetic age and DNAm alterations were most prominent in the ES-RTL group. Thus, the differentially methylated (DM) CpG sites could be markers of short telomeres but could also be one of the mechanisms contributing to disease phenotype since DNAm alterations were observed in symptomatic, but not asymptomatic, cases with S-RTL. Furthermore, two or more DM-CpGs were identified in four genes previously linked to TBD or telomere length (PRDM8, SMC4, VARS, and WNT6) and in three genes that were novel in telomere biology (MAS1L, NAV2, and TM4FS1). The DM-CpGs in these genes could be markers of aging in hematological cells, but they could also be of relevance for the progression of TBD., (© 2023. The Author(s).)
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- 2023
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24. Sixteen-Year Longitudinal Evaluation of Blood-Based DNA Methylation Biomarkers for Early Prediction of Alzheimer's Disease.
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Schäfer Hackenhaar F, Josefsson M, Nordin Adolfsson A, Landfors M, Kauppi K, Porter T, Milicic L, Laws SM, Hultdin M, Adolfsson R, Degerman S, and Pudas S
- Subjects
- Female, Humans, Male, Biomarkers, Epigenesis, Genetic, Prospective Studies, Alzheimer Disease diagnosis, Alzheimer Disease genetics, DNA Methylation
- Abstract
Background: DNA methylation (DNAm), an epigenetic mark reflecting both inherited and environmental influences, has shown promise for Alzheimer's disease (AD) prediction., Objective: Testing long-term predictive ability (>15 years) of existing DNAm-based epigenetic age acceleration (EAA) measures and identifying novel early blood-based DNAm AD-prediction biomarkers., Methods: EAA measures calculated from Illumina EPIC data from blood were tested with linear mixed-effects models (LMMs) in a longitudinal case-control sample (50 late-onset AD cases; 51 matched controls) with prospective data up to 16 years before clinical onset, and post-onset follow-up. Novel DNAm biomarkers were generated with epigenome-wide LMMs, and Sparse Partial Least Squares Discriminant Analysis applied at pre- (10-16 years), and post-AD-onset time-points., Results: EAA did not differentiate cases from controls during the follow-up time (p > 0.05). Three new DNA biomarkers showed in-sample predictive ability on average 8 years pre-onset, after adjustment for age, sex, and white blood cell proportions (p-values: 0.022-<0.00001). Our longitudinally-derived panel replicated nominally (p = 0.012) in an external cohort (n = 146 cases, 324 controls). However, its effect size and discriminatory accuracy were limited compared to APOEɛ4-carriership (OR = 1.38 per 1 SD DNAm score increase versus OR = 13.58 for ɛ4-allele carriage; AUCs = 77.2% versus 87.0%). Literature review showed low overlap (n = 4) across 3275 AD-associated CpGs from 8 published studies, and no overlap with our identified CpGs.
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- 2023
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25. Long-Term Follow-Up of Newborns with 22q11 Deletion Syndrome and Low TRECs.
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Framme JL, Lundqvist C, Lundell AC, van Schouwenburg PA, Lemarquis AL, Thörn K, Lindgren S, Gudmundsdottir J, Lundberg V, Degerman S, Zetterström RH, Borte S, Hammarström L, Telemo E, Hultdin M, van der Burg M, Fasth A, Oskarsdóttir S, and Ekwall O
- Subjects
- Adolescent, DNA, Follow-Up Studies, Humans, Infant, Newborn, Neonatal Screening, Receptors, Antigen, T-Cell genetics, 22q11 Deletion Syndrome, Lymphopenia diagnosis, Severe Combined Immunodeficiency diagnosis
- Abstract
Background: Population-based neonatal screening using T-cell receptor excision circles (TRECs) identifies infants with profound T lymphopenia, as seen in cases of severe combined immunodeficiency, and in a subgroup of infants with 22q11 deletion syndrome (22q11DS)., Purpose: To investigate the long-term prognostic value of low levels of TRECs in newborns with 22q11DS., Methods: Subjects with 22q11DS and low TRECs at birth (22q11Low, N=10), matched subjects with 22q11DS and normal TRECs (22q11Normal, N=10), and matched healthy controls (HC, N=10) were identified. At follow-up (median age 16 years), clinical and immunological characterizations, covering lymphocyte subsets, immunoglobulins, TRECs, T-cell receptor repertoires, and relative telomere length (RTL) measurements were performed., Results: At follow-up, the 22q11Low group had lower numbers of naïve T-helper cells, naïve T-regulatory cells, naïve cytotoxic T cells, and persistently lower TRECs compared to healthy controls. Receptor repertoires showed skewed V-gene usage for naïve T-helper cells, whereas for naïve cytotoxic T cells, shorter RTL and a trend towards higher clonality were found. Multivariate discriminant analysis revealed a clear distinction between the three groups and a skewing towards Th17 differentiation of T-helper cells, particularly in the 22q11Low individuals. Perturbations of B-cell subsets were found in both the 22q11Low and 22q11Normal group compared to the HC group, with larger proportions of naïve B cells and lower levels of memory B cells, including switched memory B cells., Conclusions: This long-term follow-up study shows that 22q11Low individuals have persistent immunologic aberrations and increased risk for immune dysregulation, indicating the necessity of lifelong monitoring., Clinical Implications: This study elucidates the natural history of childhood immune function in newborns with 22q11DS and low TRECs, which may facilitate the development of programs for long-term monitoring and therapeutic choices., (© 2022. The Author(s).)
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- 2022
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26. High-risk subtypes of chronic lymphocytic leukemia are detectable as early as 16 years prior to diagnosis.
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Kolijn PM, Hosnijeh FS, Späth F, Hengeveld PJ, Agathangelidis A, Saleh M, Casabonne D, Benavente Y, Jerkeman M, Agudo A, Barricarte A, Besson C, Sánchez MJ, Chirlaque MD, Masala G, Sacerdote C, Grioni S, Schulze MB, Nieters A, Engelfriet P, Hultdin M, McKay JD, Vermeulen RCH, and Langerak AW
- Subjects
- Aged, B-Lymphocytes, Humans, Immunoglobulin Heavy Chains genetics, Receptors, Antigen, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Lymphocytosis diagnosis, Lymphocytosis genetics
- Abstract
Chronic lymphocytic leukemia (CLL) is preceded by monoclonal B-cell lymphocytosis (MBL), a CLL precursor state with a prevalence of up to 12% in aged individuals; however, the duration of MBL and the mechanisms of its evolution to CLL remain largely unknown. In this study, we sequenced the B-cell receptor (BcR) immunoglobulin heavy chain (IGH) gene repertoire of 124 patients with CLL and 118 matched controls in blood samples taken up to 22 years prior to diagnosis. Significant skewing in the BcR IGH gene repertoire was detected in the majority of patients, even before the occurrence of lymphocytosis and irrespective of the clonotypic IGH variable gene somatic hypermutation status. Furthermore, we identified dominant clonotypes belonging to major stereotyped subsets associated with poor prognosis up to 16 years before diagnosis in 14 patients with CLL. In 22 patients with longitudinal samples, the skewing of the BcR IGH gene repertoire increased significantly over time to diagnosis or remained stable at high levels. For 14 of 16 patients with available samples at diagnosis, the CLL clonotype was already present in the prediagnostic samples. Overall, our data indicate that the preclinical phase of CLL could be longer than previously thought, even in adverse-prognostic cases., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2022
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27. Combination of aneuploidy and high S-phase fraction indicates increased risk of relapse in stage I endometrioid endometrial carcinoma.
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Patthey A, Boman K, Tavelin B, Lindquist D, Lundin E, and Hultdin M
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- Aneuploidy, Female, Flow Cytometry, Humans, Neoplasm Recurrence, Local genetics, Prognosis, S Phase, DNA, Neoplasm, Endometrial Neoplasms genetics
- Abstract
Introduction: Endometrioid endometrial carcinoma is a cancer type with generally excellent prognosis when diagnosed at an early stage, but there is a subset of patients with relapsing disease in spite of early diagnosis and surgical treatment. There is a need to find prognostic markers to identify these patients with increased risk of relapse. Depth of myometrial invasion, histological grade, and presence of lymphovascular invasion are known risk factors. DNA content (ploidy) and proliferation measured as S-phase fraction (SPF) have been discussed as prognostic markers but need additional evaluation., Material and Methods: We evaluated relapse-free survival (RFS) with respect to ploidy and SPF, which was analyzed by flow cytometry on fresh tumor tissue, in a cohort of 1001 women treated for stage I endometrioid endometrial carcinoma in northern Sweden during the period of 1993-2010, with a median follow up time of 12.0 years. Data were obtained from historical records., Results: In simple analysis, both aneuploidy and high SPF were associated to increased risk of relapse with hazard ratios (HR) 2.37 (95% CI 1.52-3.70) and 1.94 (95% CI 1.24-3.02), respectively. Our data also confirmed stage, tumor grade, and ploidy as independent prognostic markers in an age adjusted cox regression multivariable analysis but we did not find SPF to contribute to prognosis. However, the combination of aneuploidy and high SPF identified a group of patients with increased risk of relapse, HR 2.02 (95% CI 1.19-3.44)., Conclusion: In this study, which is the largest study of ploidy and SPF in stage I endometrioid endometrial carcinoma using fresh frozen tissue, aneuploidy was shown to be an independent prognostic marker. Furthermore, the combination of aneuploidy and high SPF could be used to identify patients with increased risk of relapse.
- Published
- 2021
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28. Short leukocyte telomeres predict 25-year Alzheimer's disease incidence in non-APOE ε4-carriers.
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Hackenhaar FS, Josefsson M, Adolfsson AN, Landfors M, Kauppi K, Hultdin M, Adolfsson R, Degerman S, and Pudas S
- Subjects
- Apolipoproteins E genetics, Genotype, Humans, Incidence, Leukocytes, Risk Factors, Telomere, Alzheimer Disease epidemiology, Alzheimer Disease genetics, Apolipoprotein E4 genetics
- Abstract
Background: Leukocyte telomere length (LTL) has been shown to predict Alzheimer's disease (AD), albeit inconsistently. Failing to account for the competing risks between AD, other dementia types, and mortality, can be an explanation for the inconsistent findings in previous time-to-event analyses. Furthermore, previous studies indicate that the association between LTL and AD is non-linear and may differ depending on apolipoprotein E (APOE) ε4 allele carriage, the strongest genetic AD predictor., Methods: We analyzed whether baseline LTL in interaction with APOE ε4 predicts AD, by following 1306 initially non-demented subjects for 25 years. Gender- and age-residualized LTL (rLTL) was categorized into tertiles of short, medium, and long rLTLs. Two complementary time-to-event models that account for competing risks were used; the Fine-Gray model to estimate the association between the rLTL tertiles and the cumulative incidence of AD, and the cause-specific hazard model to assess whether the cause-specific risk of AD differed between the rLTL groups. Vascular dementia and death were considered competing risk events. Models were adjusted for baseline lifestyle-related risk factors, gender, age, and non-proportional hazards., Results: After follow-up, 149 were diagnosed with AD, 96 were diagnosed with vascular dementia, 465 died without dementia, and 596 remained healthy. Baseline rLTL and other covariates were assessed on average 8 years before AD onset (range 1-24). APOE ε4-carriers had significantly increased incidence of AD, as well as increased cause-specific AD risk. A significant rLTL-APOE interaction indicated that short rLTL at baseline was significantly associated with an increased incidence of AD among non-APOE ε4-carriers (subdistribution hazard ratio = 3.24, CI 1.404-7.462, P = 0.005), as well as borderline associated with increased cause-specific risk of AD (cause-specific hazard ratio = 1.67, CI 0.947-2.964, P = 0.07). Among APOE ε4-carriers, short or long rLTLs were not significantly associated with AD incidence, nor with the cause-specific risk of AD., Conclusions: Our findings from two complementary competing risk time-to-event models indicate that short rLTL may be a valuable predictor of the AD incidence in non-APOE ε4-carriers, on average 8 years before AD onset. More generally, the findings highlight the importance of accounting for competing risks, as well as the APOE status of participants in AD biomarker research., (© 2021. The Author(s).)
- Published
- 2021
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29. A novel DNA methylation signature is associated with androgen receptor activity and patient prognosis in bone metastatic prostate cancer.
- Author
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Ylitalo EB, Thysell E, Landfors M, Brattsand M, Jernberg E, Crnalic S, Widmark A, Hultdin M, Bergh A, Degerman S, and Wikström P
- Subjects
- Aged, Aged, 80 and over, Gene Expression Profiling methods, Humans, Male, Middle Aged, Prognosis, Receptors, Androgen genetics, Signal Transduction, Bone Neoplasms genetics, Bone Neoplasms secondary, DNA Methylation genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Receptors, Androgen metabolism
- Abstract
Background: Patients with metastatic prostate cancer (PC) are treated with androgen deprivation therapy (ADT) that initially reduces metastasis growth, but after some time lethal castration-resistant PC (CRPC) develops. A better understanding of the tumor biology in bone metastases is needed to guide further treatment developments. Subgroups of PC bone metastases based on transcriptome profiling have been previously identified by our research team, and specifically, heterogeneities related to androgen receptor (AR) activity have been described. Epigenetic alterations during PC progression remain elusive and this study aims to explore promoter gene methylation signatures in relation to gene expression and tumor AR activity., Materials and Methods: Genome-wide promoter-associated CpG methylation signatures of a total of 94 tumor samples, including paired non-malignant and malignant primary tumor areas originating from radical prostatectomy samples (n = 12), and bone metastasis samples of separate patients with hormone-naive (n = 14), short-term castrated (n = 4) or CRPC (n = 52) disease were analyzed using the Infinium Methylation EPIC arrays, along with gene expression analysis by Illumina Bead Chip arrays (n = 90). AR activity was defined from expression levels of genes associated with canonical AR activity., Results: Integrated epigenome and transcriptome analysis identified pronounced hypermethylation in malignant compared to non-malignant areas of localized prostate tumors. Metastases showed an overall hypomethylation in relation to primary PC, including CpGs in the AR promoter accompanied with induction of AR mRNA levels. We identified a Methylation Classifier for Androgen receptor activity (MCA) signature, which separated metastases into two clusters (MCA positive/negative) related to tumor characteristics and patient prognosis. The MCA positive metastases showed low methylation levels of genes associated with canonical AR signaling and patients had a more favorable prognosis after ADT. In contrast, MCA negative patients had low AR activity associated with hypermethylation of AR-associated genes, and a worse prognosis after ADT., Conclusions: A promoter methylation signature classifies PC bone metastases into two groups and predicts tumor AR activity and patient prognosis after ADT. The explanation for the methylation diversities observed during PC progression and their biological and clinical relevance need further exploration.
- Published
- 2021
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30. Short Leukocyte Telomeres, But Not Telomere Attrition Rates, Predict Memory Decline in the 20-Year Longitudinal Betula Study.
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Pudas S, Josefsson M, Nordin Adolfsson A, Landfors M, Kauppi K, Veng-Taasti LM, Hultdin M, Adolfsson R, and Degerman S
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Cognitive Dysfunction genetics, Female, Humans, Longitudinal Studies, Male, Middle Aged, Neuropsychological Tests, Telomere metabolism, Cognitive Dysfunction metabolism, Leukocytes metabolism, Telomere Shortening
- Abstract
Leukocyte telomere length (LTL) is a proposed biomarker for aging-related disorders, including cognitive decline and dementia. Long-term longitudinal studies measuring intra-individual changes in both LTL and cognitive outcomes are scarce, precluding strong conclusions about a potential aging-related relationship between LTL shortening and cognitive decline. This study investigated associations between baseline levels and longitudinal changes in LTL and memory performance across an up to 20-year follow-up in 880 dementia-free participants from a population-based study (mean baseline age: 56.8 years, range: 40-80; 52% female). Shorter baseline LTL significantly predicted subsequent memory decline (r = .34, 95% confidence interval: 0.06, 0.82), controlling for age, sex, and other relevant covariates. No significant associations were however observed between intra-individual changes in LTL and memory, neither concurrently nor with a 5-year time-lag between LTL shortening and memory decline. These results support the notion of short LTL as a predictive factor for aging-related memory decline, but suggest that LTL dynamics in adulthood and older age may be less informative of cognitive outcomes in aging. Furthermore, the results highlight the importance of long-term longitudinal evaluation of outcomes in biomarker research., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America.)
- Published
- 2021
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31. Regulation of Decay Accelerating Factor Primes Human Germinal Center B Cells for Phagocytosis.
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Dernstedt A, Leidig J, Holm A, Kerkman PF, Mjösberg J, Ahlm C, Henriksson J, Hultdin M, and Forsell MNE
- Subjects
- B-Lymphocytes cytology, Germinal Center cytology, Humans, Positive Regulatory Domain I-Binding Factor 1 immunology, B-Lymphocytes immunology, CD55 Antigens immunology, Gene Expression Regulation immunology, Germinal Center immunology, Lymphocyte Activation, Phagocytosis
- Abstract
Germinal centers (GC) are sites for extensive B cell proliferation and homeostasis is maintained by programmed cell death. The complement regulatory protein Decay Accelerating Factor (DAF) blocks complement deposition on host cells and therefore also phagocytosis of cells. Here, we show that B cells downregulate DAF upon BCR engagement and that T cell-dependent stimuli preferentially led to activation of DAF
lo B cells. Consistent with this, a majority of light and dark zone GC B cells were DAFlo and susceptible to complement-dependent phagocytosis, as compared with DAFhi GC B cells. We could also show that the DAFhi GC B cell subset had increased expression of the plasma cell marker Blimp-1. DAF expression was also modulated during B cell hematopoiesis in the human bone marrow. Collectively, our results reveal a novel role of DAF to pre-prime activated human B cells for phagocytosis prior to apoptosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dernstedt, Leidig, Holm, Kerkman, Mjösberg, Ahlm, Henriksson, Hultdin and Forsell.)- Published
- 2021
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32. Hematopoietic cellular aging is not accelerated during the first 2 years of life in children born preterm.
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Henckel E, Landfors M, Haider Z, Kosma P, Hultdin M, Degerman S, and Bohlin K
- Subjects
- Aging, Case-Control Studies, Child, Preschool, Critical Care, DNA Methylation, Epigenesis, Genetic, Epigenomics, Female, Follow-Up Studies, Hematopoiesis physiology, Humans, Infant, Infant, Newborn, Infant, Premature, Intensive Care Units, Neonatal, Intensive Care, Neonatal, Longitudinal Studies, Male, Polymerase Chain Reaction, Respiratory Tract Diseases virology, Risk Factors, Telomere ultrastructure, Virus Diseases, Cellular Senescence, Inflammation, Oxidative Stress, Premature Birth
- Abstract
Background: Prematurity in itself and exposure to neonatal intensive care triggers inflammatory processes and oxidative stress, leading to risk for disease later in life. The effects on cellular aging processes are incompletely understood., Methods: Relative telomere length (RTL) was measured by qPCR in this longitudinal cohort study with blood samples taken at birth and at 2 years of age from 60 children (16 preterm and 44 term). Viral respiratory infections the first year were evaluated. Epigenetic biological DNA methylation (DNAm) age was predicted based on methylation array data in 23 children (11 preterm and 12 term). RTL change/year and DNAm age change/year was compared in preterm and term during the 2 first years of life., Results: Preterm infants had longer telomeres than term born at birth and at 2 years of age, but no difference in telomere attrition rate could be detected. Predicted epigenetic DNAm age was younger in preterm infants, but rate of DNAm aging was similar in both groups., Conclusions: Despite early exposure to risk factors for accelerated cellular aging, children born preterm exhibited preserved telomeres. Stress during the neonatal intensive care period did not reflect accelerated epigenetic DNAm aging. Early-life aging was not explained by preterm birth., Impact: Preterm birth is associated with elevated disease risk later in life. Preterm children often suffer from inflammation early in life. Stress-related telomere erosion during neonatal intensive care has been proposed. Inflammation-accelerated biological aging in preterm is unknown. We find no accelerated aging due to prematurity or infections during the first 2 years of life.
- Published
- 2020
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33. Combining epigenetic and clinicopathological variables improves specificity in prognostic prediction in clear cell renal cell carcinoma.
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Andersson-Evelönn E, Vidman L, Källberg D, Landfors M, Liu X, Ljungberg B, Hultdin M, Rydén P, and Degerman S
- Subjects
- Biomarkers, Tumor genetics, DNA Methylation genetics, Epigenesis, Genetic, Humans, Prognosis, Carcinoma, Renal Cell diagnosis, Carcinoma, Renal Cell genetics, Kidney Neoplasms diagnosis, Kidney Neoplasms genetics
- Abstract
Background: Metastasized clear cell renal cell carcinoma (ccRCC) is associated with a poor prognosis. Almost one-third of patients with non-metastatic tumors at diagnosis will later progress with metastatic disease. These patients need to be identified already at diagnosis, to undertake closer follow up and/or adjuvant treatment. Today, clinicopathological variables are used to risk classify patients, but molecular biomarkers are needed to improve risk classification to identify the high-risk patients which will benefit most from modern adjuvant therapies. Interestingly, DNA methylation profiling has emerged as a promising prognostic biomarker in ccRCC. This study aimed to derive a model for prediction of tumor progression after nephrectomy in non-metastatic ccRCC by combining DNA methylation profiling with clinicopathological variables., Methods: A novel cluster analysis approach (Directed Cluster Analysis) was used to identify molecular biomarkers from genome-wide methylation array data. These novel DNA methylation biomarkers, together with previously identified CpG-site biomarkers and clinicopathological variables, were used to derive predictive classifiers for tumor progression., Results: The "triple classifier" which included both novel and previously identified DNA methylation biomarkers together with clinicopathological variables predicted tumor progression more accurately than the currently used Mayo scoring system, by increasing the specificity from 50% in Mayo to 64% in our triple classifier at 85% fixed sensitivity. The cumulative incidence of progress (
p CIP5yr ) was 7.5% in low-risk vs 44.7% in high-risk in M0 patients classified by the triple classifier at diagnosis., Conclusions: The triple classifier panel that combines clinicopathological variables with genome-wide methylation data has the potential to improve specificity in prognosis prediction for patients with non-metastatic ccRCC.- Published
- 2020
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34. Prognostic implications of the microenvironment for follicular lymphoma under immunomodulation therapy.
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Menter T, Tzankov A, Zucca E, Kimby E, Hultdin M, Sundström C, Beiske K, Cogliatti S, Banz Y, Cathomas G, Karjalainen-Lindsberg ML, Grobholz R, Mazzucchelli L, Sander B, Hawle H, Hayoz S, and Dirnhofer S
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Lymphoma, Follicular mortality, Male, Middle Aged, Prognosis, Progression-Free Survival, Tumor Microenvironment, Immunomodulation drug effects, Lymphoma, Follicular drug therapy
- Abstract
Follicular lymphoma (FL) constitutes a significant proportion of lymphomas and shows frequent relapses. Beyond conventional chemotherapy, new therapeutic approaches have emerged, focussing on the interplay between lymphoma cells and the microenvironment. Here we report the immunophenotypic investigation of the microenvironment of a clinically well-characterized prospective cohort (study SAKK35/10, NCT01307605) of 154 treatment-naïve FL patients in need of therapy, who have been treated with rituximab only or a combination of rituximab and the immunomodulatory drug lenalidomide/Revlimid® A high ratio of CD4- to CD8-positive T cells (P = 0·009) and increased amounts of PD1
+ tumour-infiltrating T cells (P = 0·007) were associated with inferior progression-free survival in the whole cohort. Interestingly, the prognostic impact of PD1+ T cells and the CD4/CD8 ratio lost its significance in the subgroup treated with R2 . In the latter group, high amounts of GATA3+ T helper (Th2) equivalents were associated with better progression-free survival (P < 0·001). We identified tumour microenvironmental features that allow prognostic stratification with respect to immuno- and combined immuno- and immunomodulatory therapy. Our analysis indicates that lenalidomide may compensate the adverse prognostic implication of higher amounts of CD4+ and, particularly, PD1+ T cells and that it has favourable effects mainly in cases with higher amounts of Th2 equivalents. [Correction added on 11 February 2020, after online publication: The NCT-trial number was previously incorrect and has been updated in this version]., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)- Published
- 2020
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35. DNA methylation and copy number variation profiling of T-cell lymphoblastic leukemia and lymphoma.
- Author
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Haider Z, Landfors M, Golovleva I, Erlanson M, Schmiegelow K, Flægstad T, Kanerva J, Norén-Nyström U, Hultdin M, and Degerman S
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, CpG Islands, Gene Expression Profiling methods, Humans, Infant, Middle Aged, Phenotype, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma classification, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology, Prognosis, Young Adult, Biomarkers, Tumor genetics, DNA Copy Number Variations, DNA Methylation, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Despite having common overlapping immunophenotypic and morphological features, T-cell lymphoblastic leukemia (T-ALL) and lymphoma (T-LBL) have distinct clinical manifestations, which may represent separate diseases. We investigated and compared the epigenetic and genetic landscape of adult and pediatric T-ALL (n = 77) and T-LBL (n = 15) patient samples by high-resolution genome-wide DNA methylation and Copy Number Variation (CNV) BeadChip arrays. DNA methylation profiling identified the presence of CpG island methylator phenotype (CIMP) subgroups within both pediatric and adult T-LBL and T-ALL. An epigenetic signature of 128 differentially methylated CpG sites was identified, that clustered T-LBL and T-ALL separately. The most significant differentially methylated gene loci included the SGCE/PEG10 shared promoter region, previously implicated in lymphoid malignancies. CNV analysis confirmed overlapping recurrent aberrations between T-ALL and T-LBL, including 9p21.3 (CDKN2A/CDKN2B) deletions. A significantly higher frequency of chromosome 13q14.2 deletions was identified in T-LBL samples (36% in T-LBL vs. 0% in T-ALL). This deletion, encompassing the RB1, MIR15A and MIR16-1 gene loci, has been reported as a recurrent deletion in B-cell malignancies. Our study reveals epigenetic and genetic markers that can distinguish between T-LBL and T-ALL, and deepen the understanding of the biology underlying the diverse disease localization.
- Published
- 2020
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36. Cell-of-origin determined by both gene expression profiling and immunohistochemistry is the strongest predictor of survival in patients with diffuse large B-cell lymphoma.
- Author
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Abdulla M, Hollander P, Pandzic T, Mansouri L, Ednersson SB, Andersson PO, Hultdin M, Fors M, Erlanson M, Degerman S, Petersen HM, Asmar F, Grønbaek K, Enblad G, Cavelier L, Rosenquist R, and Amini RM
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Algorithms, Denmark, Gene Expression Profiling, Germinal Center cytology, Humans, Lymphocyte Activation, Lymphoma, Large B-Cell, Diffuse diagnosis, Middle Aged, Retrospective Studies, Survival Analysis, Sweden, Young Adult, B-Lymphocytes cytology, Immunohistochemistry methods, Lymphoma, Large B-Cell, Diffuse mortality, Prognosis
- Abstract
The tumor cells in diffuse large B-cell lymphomas (DLBCL) are considered to originate from germinal center derived B-cells (GCB) or activated B-cells (ABC). Gene expression profiling (GEP) is preferably used to determine the cell of origin (COO). However, GEP is not widely applied in clinical practice and consequently, several algorithms based on immunohistochemistry (IHC) have been developed. Our aim was to evaluate the concordance of COO assignment between the Lymph2Cx GEP assay and the IHC-based Hans algorithm, to decide which model is the best survival predictor. Both GEP and IHC were performed in 359 homogenously treated Swedish and Danish DLBCL patients, in a retrospective multicenter cohort. The overall concordance between GEP and IHC algorithm was 72%; GEP classified 85% of cases assigned as GCB by IHC, as GCB, while 58% classified as non-GCB by IHC, were categorized as ABC by GEP. There were significant survival differences (overall survival and progression-free survival) if cases were classified by GEP, whereas if cases were categorized by IHC only progression-free survival differed significantly. Importantly, patients assigned as non-GCB/ABC both by IHC and GEP had the worst prognosis, which was also significant in multivariate analyses. Double expression of MYC and BCL2 was more common in ABC cases and was associated with a dismal outcome. In conclusion, to determine COO both by IHC and GEP is the strongest outcome predictor to identify DLBCL patients with the worst outcome., (© 2019 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.)
- Published
- 2020
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37. Growth-inhibition of cell lines derived from B cell lymphomas through antagonism of serotonin receptor signaling.
- Author
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Kolan SS, Lidström T, Mediavilla T, Dernstedt A, Degerman S, Hultdin M, Björk K, Marcellino D, and Forsell MNE
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Apoptosis genetics, Apoptosis physiology, Autophagy genetics, Cell Cycle genetics, Cell Cycle physiology, Cell Line, Tumor, Cell Proliferation genetics, Cell Proliferation physiology, DNA Damage genetics, DNA Damage physiology, Humans, Lymphoma, B-Cell genetics, Membrane Potential, Mitochondrial, Middle Aged, Reactive Oxygen Species metabolism, Real-Time Polymerase Chain Reaction, Receptors, Serotonin genetics, Receptors, Serotonin, 5-HT1 genetics, Receptors, Serotonin, 5-HT1 metabolism, Signal Transduction genetics, Signal Transduction physiology, Young Adult, Autophagy physiology, Lymphoma, B-Cell metabolism, Receptors, Serotonin metabolism
- Abstract
A majority of lymphomas are derived from B cells and novel treatments are required to treat refractory disease. Neurotransmitters such as serotonin and dopamine influence activation of B cells and the effects of a selective serotonin 1A receptor (5HT1A) antagonist on growth of a number of B cell-derived lymphoma cell lines were investigated. We confirmed the expression of 5HT1A in human lymphoma tissue and in several well-defined experimental cell lines. We discovered that the pharmacological inhibition of 5HT1A led to the reduced proliferation of B cell-derived lymphoma cell lines together with DNA damage, ROS-independent caspase activation and apoptosis in a large fraction of cells. Residual live cells were found 'locked' in a non-proliferative state in which a selective transcriptional and translational shutdown of genes important for cell proliferation and metabolism occurred (e.g., AKT, GSK-3β, cMYC and p53). Strikingly, inhibition of 5HT1A regulated mitochondrial activity through a rapid reduction of mitochondrial membrane potential and reducing dehydrogenase activity. Collectively, our data suggest 5HT1A antagonism as a novel adjuvant to established cancer treatment regimens to further inhibit lymphoma growth.
- Published
- 2019
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38. An integrated transcriptome analysis in T-cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression.
- Author
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Haider Z, Larsson P, Landfors M, Köhn L, Schmiegelow K, Flaegstad T, Kanerva J, Heyman M, Hultdin M, and Degerman S
- Subjects
- Adolescent, Child, Child, Preschool, CpG Islands, Female, Gene Expression Profiling, Humans, Infant, Male, DNA Methylation, Homeodomain Proteins genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, T-Cell Acute Lymphocytic Leukemia Protein 1 genetics
- Abstract
Classification of pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients into CIMP (CpG Island Methylator Phenotype) subgroups has the potential to improve current risk stratification. To investigate the biology behind these CIMP subgroups, diagnostic samples from Nordic pediatric T-ALL patients were characterized by genome-wide methylation arrays, followed by targeted exome sequencing, telomere length measurement, and RNA sequencing. The CIMP subgroups did not correlate significantly with variations in epigenetic regulators. However, the CIMP+ subgroup, associated with better prognosis, showed indicators of longer replicative history, including shorter telomere length (P = 0.015) and older epigenetic (P < 0.001) and mitotic age (P < 0.001). Moreover, the CIMP+ subgroup had significantly higher expression of ANTP homeobox oncogenes, namely TLX3, HOXA9, HOXA10, and NKX2-1, and novel genes in T-ALL biology including PLCB4, PLXND1, and MYO18B. The CIMP- subgroup, with worse prognosis, was associated with higher expression of TAL1 along with frequent STIL-TAL1 fusions (2/40 in CIMP+ vs 11/24 in CIMP-), as well as stronger expression of BEX1. Altogether, our findings suggest different routes for leukemogenic transformation in the T-ALL CIMP subgroups, indicated by different replicative histories and distinct methylomic and transcriptomic profiles. These novel findings can lead to new therapeutic strategies., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
- Published
- 2019
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39. Novel variants in Nordic patients referred for genetic testing of telomere-related disorders.
- Author
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Norberg A, Rosén A, Raaschou-Jensen K, Kjeldsen L, Moilanen JS, Paulsson-Karlsson Y, Baliakas P, Lohi O, Ahmed A, Kittang AO, Larsson P, Roos G, Degerman S, and Hultdin M
- Subjects
- Adolescent, Adult, Aged, Cell Cycle Proteins genetics, Child, Child, Preschool, Dyskeratosis Congenita pathology, Female, Genetic Testing, Humans, Infant, Male, Middle Aged, Mutation, Nuclear Proteins genetics, Telomere genetics, Telomere-Binding Proteins genetics, Young Adult, Dyskeratosis Congenita genetics, RNA genetics, Telomerase genetics, Telomere Shortening genetics
- Abstract
Telomere-related disorders are a clinically and genetically heterogeneous group of disorders characterized by premature telomere shortening and proliferative failure of a variety of tissues. This study reports the spectrum of telomere-related gene variants and telomere length in Nordic patients referred for genetic testing due to suspected telomere-related disorder. We performed Sanger sequencing of the genes TERT, TERC, DKC1, and TINF2 on 135 unrelated index patients and measured telomere length by qPCR on DNA from peripheral blood leukocytes. We identified pathogenic or likely pathogenic variants in 10 index patients, all of which had short telomeres compared to age-matched healthy controls. Six of the 10 variants were novel; three in TERC (n.69_74dupAGGCGC, n.122_125delGCGG, and n.407_408delinsAA) and three in TERT (p.(D684G), p.(R774*), and p.(*1133Wext*39)). The high proportion of novel variants identified in our study highlights the need for solid interpretation of new variants that may be detected. Measurement of telomere length is a useful approach for evaluating pathogenicity of genetic variants associated with telomere-related disorders.
- Published
- 2018
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40. DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia.
- Author
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Borssén M, Nordlund J, Haider Z, Landfors M, Larsson P, Kanerva J, Schmiegelow K, Flaegstad T, Jónsson ÓG, Frost BM, Palle J, Forestier E, Heyman M, Hultdin M, Lönnerholm G, and Degerman S
- Subjects
- Adolescent, Child, Child, Preschool, CpG Islands, Epigenesis, Genetic, Female, Humans, Infant, Male, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma mortality, Prognosis, Proportional Hazards Models, Survival Analysis, DNA Methylation, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma classification, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics
- Abstract
Background: Few biological markers are associated with survival after relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In pediatric T-cell ALL, we have identified promoter-associated methylation alterations that correlate with prognosis. Here, the prognostic relevance of CpG island methylation phenotype (CIMP) classification was investigated in pediatric BCP-ALL patients., Methods: Six hundred and one BCP-ALL samples from Nordic pediatric patients (age 1-18) were CIMP classified at initial diagnosis and analyzed in relation to clinical data., Results: Among the 137 patients that later relapsed, patients with a CIMP- profile ( n = 42) at initial diagnosis had an inferior overall survival (pOS
5years 33%) compared to CIMP+ patients ( n = 95, pOS5years 65%) ( p = 0.001), which remained significant in a Cox proportional hazards model including previously defined risk factors., Conclusion: CIMP classification is a strong candidate for improved risk stratification of relapsed BCP-ALL., Competing Interests: The regional and/or national ethics committees approved the study, and the patients and/or their guardians provided informed consent in accordance with the Declaration of Helsinki.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.- Published
- 2018
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41. U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
- Author
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Glimelius B, Melin B, Enblad G, Alafuzoff I, Beskow A, Ahlström H, Bill-Axelson A, Birgisson H, Björ O, Edqvist PH, Hansson T, Helleday T, Hellman P, Henriksson K, Hesselager G, Hultdin M, Häggman M, Höglund M, Jonsson H, Larsson C, Lindman H, Ljuslinder I, Mindus S, Nygren P, Pontén F, Riklund K, Rosenquist R, Sandin F, Schwenk JM, Stenling R, Stålberg K, Stålberg P, Sundström C, Thellenberg Karlsson C, Westermark B, Bergh A, Claesson-Welsh L, Palmqvist R, and Sjöblom T
- Subjects
- Humans, Sweden, Biological Specimen Banks organization & administration, Biomarkers, Tumor, Neoplasms
- 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.
- Published
- 2018
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42. Maintained memory in aging is associated with young epigenetic age.
- Author
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Degerman S, Josefsson M, Nordin Adolfsson A, Wennstedt S, Landfors M, Haider Z, Pudas S, Hultdin M, Nyberg L, and Adolfsson R
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Longitudinal Studies, Male, Middle Aged, Aging genetics, Aging psychology, Cognition physiology, DNA Methylation genetics, Epigenesis, Genetic genetics, Memory physiology
- Abstract
Epigenetic alterations during aging have been proposed to contribute to decline in physical and cognitive functions, and accelerated epigenetic aging has been associated with disease and all-cause mortality later in life. In this study, we estimated epigenetic age dynamics in groups with different memory trajectories (maintained high performance, average decline, and accelerated decline) over a 15-year period. Epigenetic (DNA-methylation [DNAm]) age was assessed, and delta age (DNAm age - chronological age) was calculated in blood samples at baseline (age: 55-65 years) and 15 years later in 52 age- and gender-matched individuals from the Betula study in Sweden. A lower delta DNAm age was observed for those with maintained memory functions compared with those with average (p = 0.035) or accelerated decline (p = 0.037). Moreover, separate analyses revealed that DNAm age at follow-up, but not chronologic age, was a significant predictor of dementia (p = 0.019). Our findings suggest that young epigenetic age contributes to maintained memory in aging., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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43. Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma.
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Mansouri L, Noerenberg D, Young E, Mylonas E, Abdulla M, Frick M, Asmar F, Ljungström V, Schneider M, Yoshida K, Skaftason A, Pandzic T, Gonzalez B, Tasidou A, Waldhueter N, Rivas-Delgado A, Angelopoulou M, Ziepert M, Arends CM, Couronné L, Lenze D, Baldus CD, Bastard C, Okosun J, Fitzgibbon J, Dörken B, Drexler HG, Roos-Weil D, Schmitt CA, Munch-Petersen HD, Zenz T, Hansmann ML, Strefford JC, Enblad G, Bernard OA, Ralfkiaer E, Erlanson M, Korkolopoulou P, Hultdin M, Papadaki T, Grønbæk K, Lopez-Guillermo A, Ogawa S, Küppers R, Stamatopoulos K, Stavroyianni N, Kanellis G, Rosenwald A, Campo E, Amini RM, Ott G, Vassilakopoulos TP, Hummel M, Rosenquist R, and Damm F
- Subjects
- Adolescent, Adult, Aged, Disease-Free Survival, Female, Humans, Male, Middle Aged, Survival Rate, Biomarkers, Tumor genetics, Gene Deletion, I-kappa B Proteins genetics, Lymphoma, B-Cell genetics, Lymphoma, B-Cell mortality, Mediastinal Neoplasms genetics, Mediastinal Neoplasms mortality, Proto-Oncogene Proteins genetics
- Abstract
We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBε, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Because preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, we screened a large patient cohort (n = 1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary central nervous system lymphoma (3% to 4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases [22.7%]) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases [27.3%]). NFKBIE-deleted PMBL patients were more often therapy refractory (P = .022) and displayed inferior outcome compared with wild-type patients (5-year survival, 59% vs 78%; P = .034); however, they appeared to benefit from radiotherapy (P =022) and rituximab-containing regimens (P = .074). NFKBIE aberrations remained an independent factor in multivariate analysis (P = .003) and when restricting the analysis to immunochemotherapy-treated patients (P = .008). Whole-exome sequencing and gene expression profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL., (© 2016 by The American Society of Hematology.)
- Published
- 2016
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44. DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia.
- Author
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Borssén M, Haider Z, Landfors M, Norén-Nyström U, Schmiegelow K, Åsberg AE, Kanerva J, Madsen HO, Marquart H, Heyman M, Hultdin M, Roos G, Forestier E, and Degerman S
- Subjects
- Adolescent, Age Factors, Child, Child, Preschool, Disease-Free Survival, Female, Genome-Wide Association Study, Humans, Infant, Male, Neoplasm, Residual, Survival Rate, DNA Methylation, DNA, Neoplasm metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma mortality
- Abstract
Background: Despite increased knowledge about genetic aberrations in pediatric T-cell acute lymphoblastic leukemia (T-ALL), no clinically feasible treatment-stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T-ALL., Procedure: Sixty-five diagnostic T-ALL samples from Nordic pediatric patients treated according to the Nordic Society of Pediatric Hematology and Oncology ALL 2008 (NOPHO ALL 2008) protocol were analyzed by HumMeth450K genome wide DNA methylation arrays. Methylation status was analyzed in relation to clinical data and early T-cell precursor (ETP) phenotype., Results: Two distinct CpG island methylator phenotype (CIMP) groups were identified. Patients with a CIMP-negative profile had an inferior response to treatment compared to CIMP-positive patients (3-year cumulative incidence of relapse (CIR3y ) rate: 29% vs. 6%, P = 0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high-risk T-ALL patients (MRD ≥0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs. CIMP positive 12%; P = 0.02). These groups did not differ regarding ETP phenotype, but the CIMP-negative group was younger (P = 0.02) and had higher white blood cell count at diagnosis (P = 0.004) compared with the CIMP-positive group., Conclusions: CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further risk classification and could confer important information in treatment decision making., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
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45. Detection of central nervous system involvement in childhood acute lymphoblastic leukemia by cytomorphology and flow cytometry of the cerebrospinal fluid.
- Author
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Ranta S, Nilsson F, Harila-Saari A, Saft L, Tani E, Söderhäll S, Porwit A, Hultdin M, Noren-Nyström U, and Heyman M
- Subjects
- Adolescent, Brain Neoplasms diagnosis, Child, Child, Preschool, Female, Humans, Immunophenotyping, Infant, Male, Recurrence, Brain Neoplasms cerebrospinal fluid, Cerebrospinal Fluid cytology, Flow Cytometry methods, Precursor Cell Lymphoblastic Leukemia-Lymphoma cerebrospinal fluid
- Abstract
Background: Therapy directed at the central nervous system (CNS) is an essential part of the treatment for childhood acute lymphoblastic leukemia (ALL). The current evaluation of CNS involvement based on cytomorphological examination of the cerebrospinal fluid (CSF) alone is not as sensitive with low cell counts as flow cytometric immunophenotyping (FCI) of the CSF. However, the importance of low CSF blasts counts at diagnosis is uncertain. We sought to determine the significance of FCI in relation to conventional morphological examination., Procedure: We retrospectively compared FCI of the CSF with cytomorphology at diagnosis or relapse of childhood ALL. All patients were diagnosed 2000-2012 in Stockholm or Umeå, Sweden. Clinical data were collected from medical records and the Nordic leukemia registry. Treatment assignment was based on morphological examination only., Results: The cohort was comprised of 214 patients with ALL. CSF involvement was detected by both methods in 20 patients, in 17 by FCI alone, and in one patient by cytomorphology alone. The relapse rate was higher for patients with negative cytology but positive FCI compared to those without CNS involvement using both methods. The difference was especially marked in the current protocol. However, none of the patients with negative CSF cytology but positive FCI had a CNS relapse., Conclusions: FCI of the CSF increased the detection rate of CNS involvement of ALL approximately two times compared to cytomorphology. Patients with low-level CNS involvement may benefit from additional intensified systemic or CNS-directed therapy, but larger studies are needed., (© 2014 Wiley Periodicals, Inc.)
- Published
- 2015
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46. Novel antibodies reveal inclusions containing non-native SOD1 in sporadic ALS patients.
- Author
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Forsberg K, Jonsson PA, Andersen PM, Bergemalm D, Graffmo KS, Hultdin M, Jacobsson J, Rosquist R, Marklund SL, and Brännström T
- Subjects
- Aged, Aged, 80 and over, Animals, Blotting, Western, Chickens, DNA-Binding Proteins metabolism, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunohistochemistry, Inclusion Bodies immunology, Male, Microscopy, Fluorescence, Middle Aged, Rabbits, Superoxide Dismutase genetics, Superoxide Dismutase-1, Ubiquitin metabolism, Amyotrophic Lateral Sclerosis metabolism, Antibodies immunology, Inclusion Bodies metabolism, Spinal Cord metabolism, Superoxide Dismutase immunology, Superoxide Dismutase metabolism
- Abstract
Mutations in CuZn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) and are found in 6% of ALS patients. Non-native and aggregation-prone forms of mutant SOD1s are thought to trigger the disease. Two sets of novel antibodies, raised in rabbits and chicken, against peptides spaced along the human SOD1 sequence, were by enzyme-linked immunosorbent assay and an immunocapture method shown to be specific for denatured SOD1. These were used to examine SOD1 in spinal cords of ALS patients lacking mutations in the enzyme. Small granular SOD1-immunoreactive inclusions were found in spinal motoneurons of all 37 sporadic and familial ALS patients studied, but only sparsely in 3 of 28 neurodegenerative and 2 of 19 non-neurological control patients. The granular inclusions were by confocal microscopy found to partly colocalize with markers for lysosomes but not with inclusions containing TAR DNA binding protein-43, ubiquitin or markers for endoplasmic reticulum, autophagosomes or mitochondria. Granular inclusions were also found in carriers of SOD1 mutations and in spinobulbar muscular atrophy (SBMA) patients and they were the major type of inclusion detected in ALS patients homozygous for the wild type-like D90A mutation. The findings suggest that SOD1 may be involved in ALS pathogenesis in patients lacking mutations in the enzyme.
- Published
- 2010
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47. Progression of bone marrow fibrosis in patients with essential thrombocythemia and polycythemia vera during anagrelide treatment.
- Author
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Hultdin M, Sundström G, Wahlin A, Lundström B, Samuelsson J, Birgegård G, and Engström-Laurent A
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Disease Progression, Female, Humans, Hyaluronic Acid metabolism, Male, Middle Aged, Polycythemia Vera drug therapy, Primary Myelofibrosis drug therapy, Prognosis, Prospective Studies, Reticulin metabolism, Thrombocythemia, Essential drug therapy, Thrombocytosis, Fibrinolytic Agents therapeutic use, Polycythemia Vera complications, Primary Myelofibrosis etiology, Quinazolines therapeutic use, Thrombocythemia, Essential complications
- Abstract
Anagrelide is a second-line option for reduction of thrombocythemia in patients with chronic myeloproliferative disorders (CMPDs). A multicenter, open, phase II study of anagrelide treatment in 60 patients during 2 yr was performed by the Swedish Myeloproliferative Disorder Study Group. Adequate bone marrow biopsies were obtained from 53 of the CMPD patients [36 essential thrombocythemia (ET), 16 polycythemia vera (PV), 1 chronic idiopathic myelofibrosis (CIMF)] before treatment and compared with biopsies from 30 healthy volunteers and 34 patients with acute myeloid leukemia (AML). Higher reticulin and hyaluronan (HYA) scores were found before anagrelide therapy in the CMPD patients than in the normal controls (p < 0.001 and p < 0.001, respectively) and AML patients (p < 0.001 and p = 0.011, respectively). At the end of the study 30 CMPD patients were still on anagrelide treatment and in 19 of these patients, all diagnosed as ET (n = 16) or PV (n = 3), pretreatment bone marrow biopsies were compared with follow-up samples. After 2 yr of anagrelide therapy the reticulin and HYA scores were significantly higher than before treatment (p = 0.02 and p = 0.002, respectively). The cellularity was significantly higher (p = 0.014), although the number of megakaryocytes did not change significantly. The increase of reticulin and HYA in the bone marrow after 2 yr of treatment with anagrelide indicated progression of fibrosis. Although anagrelide is a valuable drug for reduction of platelet levels, it seems unable to stop progression of bone marrow fibrosis and hypercellularity in ET and PV.
- Published
- 2007
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48. Chronic lymphocytic leukemia with osteolytic Richter's syndrome mimicking myeloma bone disease shows no over-expression of DKK1.
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Lazarevic V, Wahlin A, Hultdin M, Zhan F, and Shaughnessy J
- Subjects
- Aged, Bone Diseases metabolism, Bone Diseases therapy, Humans, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Male, Multiple Myeloma metabolism, Multiple Myeloma therapy, Osteolysis etiology, Syndrome, Bone Diseases diagnosis, Diagnosis, Differential, Intercellular Signaling Peptides and Proteins metabolism, Leukemia, Lymphocytic, Chronic, B-Cell complications, Multiple Myeloma diagnosis
- Published
- 2006
- Full Text
- View/download PDF
49. Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status.
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Grabowski P, Hultdin M, Karlsson K, Tobin G, Aleskog A, Thunberg U, Laurell A, Sundström C, Rosenquist R, and Roos G
- Subjects
- Adult, Aged, Aged, 80 and over, Blotting, Southern, Female, Humans, Immunophenotyping, In Situ Hybridization, Fluorescence, Lymph Nodes pathology, Male, Middle Aged, Models, Statistical, Polymerase Chain Reaction, Prognosis, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Treatment Outcome, Genes, Immunoglobulin, Immunoglobulin Heavy Chains genetics, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Mutation, Telomere ultrastructure
- Abstract
B-cell chronic lymphocytic leukemia (CLL) consists of 2 prognostic entities where cases with mutated immunoglobulin V(H) genes have better outcome than unmutated cases. V(H)-mutated CLLs display longer telomeres compared with unmutated cases and telomere length has been indicated to predict outcome, although the prognostic value of telomere length has not been fully established in CLL. We analyzed telomere length, V(H) gene mutation status, and clinical parameters in a large series of CLL. Telomere length was assessed by quantitative polymerase chain reaction (PCR), giving a very good correlation to telomere length estimated by Southern blotting (P < .001). The prognostic information given by mutation status (n = 282) and telomere length (n = 246) was significant (P < .001, respectively). Telomere length was a prognostic factor for stage A (P = .021) and stage B/C (P = .018) patients, whereas mutation status predicted outcome only in stage A patients (P < .001). Furthermore, mutated CLLs were subdivided by telomere length into 2 groups with different prognoses (P = .003), a subdivision not seen for unmutated cases (P = .232). Interestingly, the V(H)-mutated group with short telomeres had an overall survival close to that of the unmutated cases. Thus, by combining V(H) mutation status and telomere length, an improved subclassification of CLL was achieved identifying previously unrecognized patient groups with different outcomes.
- Published
- 2005
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50. Patients with chronic lymphocytic leukemia with mutated VH genes presenting with Binet stage B or C form a subgroup with a poor outcome.
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Tobin G, Thunberg U, Laurell A, Karlsson K, Aleskog A, Willander K, Söderberg O, Merup M, Vilpo J, Hultdin M, Sundström C, Roos G, and Rosenquist R
- Subjects
- Adult, Disease-Free Survival, Gene Rearrangement, B-Lymphocyte, Heavy Chain, Humans, Mutation, Neoplasm Staging, Somatic Hypermutation, Immunoglobulin, Treatment Outcome, Genes, Immunoglobulin physiology, Immunoglobulin Variable Region genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology
- Abstract
Background and Objectives: The immunoglobulin VH gene mutation status is a strong prognostic indicator in B-cell chronic lymphocytic leukemia (CLL), since unmutated VH genes are correlated with short survival. However, the traditional cut-off level dividing mutated and unmutated cases, i.e. more or less than 2% mutations, has been questioned and other cut-offs have been suggested. We investigated whether an alternative cut-off should be applied and the relation of mutational status to another prognostic marker, Binet staging., Design and Methods: VH gene mutation status was assessed in 332 CLL cases by polymerase chain reaction amplification and nucleotide sequencing and was further correlated with overall survival using different VH mutation cut-offs (1-7%) and Binet stage., Results: After testing different mutation borders, the 2% cut-off remained the best discriminative level for determining prognosis. Interestingly, prognostic stratification was improved by combining the information on VH gene mutation status with that of Binet stage: unmutated cases (all stages, n=151, mutated cases with stage A (n=77), and mutated cases with stage B or C (n=37) had a median survival of 82, 179 and 74 months, respectively., Interpretation and Conclusions: CLL cases displaying mutated VH genes with Binet stage B or C had a survival similar to that of unmutated cases and significantly shorter than that of mutated stage A CLL. Our result reveals clinical heterogeneity within the VH mutated CLL group by inclusion of Binet stage data, a finding which is of importance when considering surrogate marker(s) for VH mutation status.
- Published
- 2005
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