umu.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Hultdin, Magnus
Publications (10 of 23) Show all publications
Haider, Z., Larsson, P., Landfors, M., Köhn, L., Schmiegelow, K., Flaegstad, T., . . . Degerman, S. (2019). An integrated transcriptome analysis in T-cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression. Cancer Medicine, 8(1), 311-324
Open this publication in new window or tab >>An integrated transcriptome analysis in T-cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression
Show others...
2019 (English)In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 8, no 1, p. 311-324Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
BEX1, DNA methylation, HOXA, pediatric acute lymphoblastic leukemia, TAL1
National Category
Cancer and Oncology Hematology Pediatrics Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-156637 (URN)10.1002/cam4.1917 (DOI)000456858100032 ()30575306 (PubMedID)
Funder
The Kempe FoundationsSwedish Childhood Cancer FoundationVästerbotten County CouncilSwedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2019-02-20 Created: 2019-02-20 Last updated: 2019-02-20Bibliographically approved
Abdulla, M., Hollander, P., Pandzic, T., Mansouri, L., Ednersson, S. B., Andersson, P.-O., . . . Amini, R.-M. (2019). 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. American Journal of Hematology
Open this publication in new window or tab >>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
Show others...
2019 (English)In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652Article in journal (Refereed) Epub ahead of print
Abstract [en]

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.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2019
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-165343 (URN)10.1002/ajh.25666 (DOI)000495085000001 ()31659781 (PubMedID)
Funder
Swedish Cancer SocietySwedish Research CouncilVästerbotten County Council
Available from: 2019-11-26 Created: 2019-11-26 Last updated: 2019-11-26
Kolan, S. S., Lidström, T., Mediavilla, T., Dernstedt, A., Degerman, S., Hultdin, M., . . . Forsell, M. N. E. (2019). Growth-inhibition of cell lines derived from B cell lymphomas through antagonism of serotonin receptor signaling. Scientific Reports, 9, Article ID 4276.
Open this publication in new window or tab >>Growth-inhibition of cell lines derived from B cell lymphomas through antagonism of serotonin receptor signaling
Show others...
2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 4276Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-157754 (URN)10.1038/s41598-019-40825-x (DOI)000460924100016 ()30862884 (PubMedID)2-s2.0-85062839295 (Scopus ID)
Available from: 2019-04-08 Created: 2019-04-08 Last updated: 2019-04-08Bibliographically approved
Borssén, M., Nordlund, J., Haider, Z., Landfors, M., Larsson, P., Kanerva, J., . . . Degerman, S. (2018). DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia. Clinical Epigenetics, 10, Article ID 31.
Open this publication in new window or tab >>DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia
Show others...
2018 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 10, article id 31Article in journal (Refereed) Published
Abstract [en]

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, pOS(5years) 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.

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
DNA methylation, BCP-ALL, prognosis, CIMP, relapse, risk stratification
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-146216 (URN)10.1186/s13148-018-0466-3 (DOI)000427080200001 ()29515676 (PubMedID)
Available from: 2018-05-08 Created: 2018-05-08 Last updated: 2019-02-20Bibliographically approved
Norberg, A., Rosén, A., Raaschou-Jensen, K., Kjeldsen, L., Moilanen, J. S., Paulsson-Karisson, Y., . . . Hultdin, M. (2018). Novel variants in Nordic patients referred for genetic testing of telomere-related disorders. European Journal of Human Genetics, 26(6), 858-867
Open this publication in new window or tab >>Novel variants in Nordic patients referred for genetic testing of telomere-related disorders
Show others...
2018 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 26, no 6, p. 858-867Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-149013 (URN)10.1038/s41431-018-0112-8 (DOI)000433424200010 ()29483670 (PubMedID)2-s2.0-85042538231 (Scopus ID)
Available from: 2018-06-15 Created: 2018-06-15 Last updated: 2018-06-15Bibliographically approved
Glimelius, B., Melin, B., Enblad, G., Alafuzoff, I., Beskow, A., Ahlström, H., . . . Sjöblom, T. (2018). U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden. Acta Oncologica, 57(2), 187-194
Open this publication in new window or tab >>U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden
Show others...
2018 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 187-194Article in journal (Refereed) Published
Abstract [en]

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 Umea 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.

Place, publisher, year, edition, pages
Taylor & Francis, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-144850 (URN)10.1080/0284186X.2017.1337926 (DOI)000423473200003 ()28631533 (PubMedID)
Available from: 2018-02-23 Created: 2018-02-23 Last updated: 2018-06-09Bibliographically approved
Degerman, S., Josefsson, M., Nordin Adolfsson, A., Wennstedt, S., Landfors, M., Haider, Z., . . . Adolfsson, R. (2017). Maintained memory in aging is associated with young epigenetic age. Neurobiology of Aging, 55, 167-171
Open this publication in new window or tab >>Maintained memory in aging is associated with young epigenetic age
Show others...
2017 (English)In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 55, p. 167-171Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2017
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:umu:diva-132221 (URN)10.1016/j.neurobiolaging.2017.02.009 (DOI)000405068100018 ()28292535 (PubMedID)
Available from: 2017-03-07 Created: 2017-03-07 Last updated: 2019-05-10Bibliographically approved
Kolan, S. S., Lidström, T., Björk, K., Hultdin, M. & Forsell, M. (2017). Modulation of lymphoma growth by a selective serotonin receptor antagonist. Paper presented at 44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN. Scandinavian Journal of Immunology, 86(4), 343-343
Open this publication in new window or tab >>Modulation of lymphoma growth by a selective serotonin receptor antagonist
Show others...
2017 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 343-343Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
WILEY, 2017
National Category
Immunology
Identifiers
urn:nbn:se:umu:diva-140898 (URN)000411865200222 ()
Conference
44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN
Note

Meeting Abstract: D-31412

Available from: 2017-11-20 Created: 2017-11-20 Last updated: 2018-06-09
Borssén, M., Haider, Z., Landfors, M., Norén-Nyström, U., Schmiegelow, K., Åsberg, A. E., . . . Degerman, S. (2016). DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia. Pediatric Blood & Cancer, 63(7), 1185-1192
Open this publication in new window or tab >>DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia
Show others...
2016 (English)In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, no 7, p. 1185-1192Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
childhood leukemia, DNA methylation, MRD, prognosis, T-ALL, WBC
National Category
Cancer and Oncology Hematology Pediatrics
Identifiers
urn:nbn:se:umu:diva-124837 (URN)10.1002/pbc.25958 (DOI)000380105400008 ()26928953 (PubMedID)
Available from: 2016-10-03 Created: 2016-08-26 Last updated: 2019-05-10Bibliographically approved
Mansouri, L., Noerenberg, D., Young, E., Mylonas, E., Abdulla, M., Frick, M., . . . Damm, F. (2016). Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma. Blood, 128(23), 2666-2670
Open this publication in new window or tab >>Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma
Show others...
2016 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, no 23, p. 2666-2670Article in journal (Refereed) Published
Abstract [en]

We recently reported a truncating deletion in the NFKBIE gene, which encodes IkB epsilon, a negative feedback regulator of NF-kB, 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-kB 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.

National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-131885 (URN)10.1182/blood-2016-03-704528 (DOI)000392652300015 ()27670424 (PubMedID)
Available from: 2017-02-24 Created: 2017-02-24 Last updated: 2018-11-14Bibliographically approved
Organisations

Search in DiVA

Show all publications