| 1. |
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| 2. |
- Jansson, Ann, 1950, et al.
(författare)
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Role of a consensus AP-2 regulatory sequence within the Epstein-Barr Virus LMP1 promoter in EBNA2 mediated transactivation
- 2007
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Ingår i: Virus Genes. - : Springer Science and Business Media LLC. - 0920-8569 .- 1572-994X. ; 35:2, s. 203-14
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Tidskriftsartikel (refereegranskat)abstract
- The Epstein-Barr virus (EBV) tumor-associated latent membrane protein 1 (LMP1) gene expression is transactivated by EBV nuclear antigen 2 (EBNA2) in human B cells. We previously reported that an E-box element at the LMP1 regulatory sequence (LRS) represses transcription of the LMP1 gene through the recruitment of a Max-Mad1-mSin3A complex. In the present study, using deletion/mutation analysis, and electrophoretic mobility shift assays, we show that the promoter region adjacent to the E-box (-59/-67) is required for the full repression conferred by E-box binding proteins. The repressive effect of these factors was overcome by an inhibitor of histone deacetylation, Trichostatin A (TSA), concurring with the reports that histone deacetylation plays an important role in repression mediated by Max-Mad1-mSin3A complex. Furthermore, ChIP analyses showed that histones at the transcriptionally active LMP1 promoter were hyperacetylated, whereas in the absence of transcription they were hypoacetylated. EBNA2 activation of the promoter required a consensus AP-2 sequence in the -103/-95 LRS region. While EMSA results and the low level of AP-2 factors expression in B cells argue against known AP-2 factors binding to this site, several pieces of evidence point to a similar mechanism of promoter activation as seen by AP-2 factors. We conclude that an AP-2 site-binding factor and EBNA2 act in concert to overcome the repression of the LMP1 promoter via the consensus AP-2 site. This activation showed strong correlation with histone hyperacetylation at the promoter, indicating this to be a major mechanism for the EBNA2 mediated LMP1 transactivation.
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| 3. |
- Berglund, Eva Caroline, et al.
(författare)
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A Study Protocol for Validation and Implementation of Whole-Genome and -Transcriptome Sequencing as a Comprehensive Precision Diagnostic Test in Acute Leukemias
- 2022
-
Ingår i: Frontiers in Medicine. - Lausanne, Switzerland : Frontiers Media SA. - 2296-858X. ; 9, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS), with the ability to provide comprehensive genomic information, have become the focal point of research interest as novel techniques that can support precision diagnostics in routine clinical care of patients with various cancer types, including hematological malignancies. This national multi-center study, led by Genomic Medicine Sweden, aims to evaluate whether combined application of WGS and WTS (WGTS) is technically feasible and can be implemented as an efficient diagnostic tool in patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). In addition to clinical impact assessment, a health-economic evaluation of such strategy will be performed. Methods and Analysis: The study comprises four phases (i.e., retrospective, prospective, real-time validation, and follow-up) including approximately 700 adult and pediatric Swedish AML and ALL patients. Results of WGS for tumor (90×) and normal/germline (30×) samples as well as WTS for tumors only will be compared to current standard of care diagnostics. Primary study endpoints are diagnostic efficiency and improved diagnostic yield. Secondary endpoints are technical and clinical feasibility for routine implementation, clinical utility, and health-economic impact. Discussion: Data from this national multi-center study will be used to evaluate clinical performance of the integrated WGTS diagnostic workflow compared with standard of care. The study will also elucidate clinical and health-economic impacts of a combined WGTS strategy when implemented in routine clinical care. Clinical Trial Registration: [https://doi.org/10.1186/ISRCTN66987142], identifier [ISRCTN66987142].
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| 4. |
- Blennow, Kaj, 1958, et al.
(författare)
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No association between the alpha2-macroglobulin (A2M) deletion and Alzheimer's disease, and no change in A2M mRNA, protein, or protein expression.
- 2000
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Ingår i: Journal of neural transmission (Vienna, Austria : 1996). - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 107:8-9, s. 1065-79
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Tidskriftsartikel (refereegranskat)abstract
- A polymorphism consisting of a deletion near the 5' splice site of exon 18 on the alpha2-macroglobulin (A2M) gene (A2M-2) has been suggested to be associated with Alzheimer's disease (AD) in family-based studies. We studied the A2M-2 allele together with the ApoE alleles in a large series on patients with AD (n = 449) and age-matched controls (n = 349). Neuropathologically confirmed diagnoses were available in 199 cases (94 AD and 107 control cases). We found no increase in A2M-2 genotype or allele frequencies in AD (27.5% and 14.6%) versus controls (26.4% and 14.9%). In contrast, a marked increase (p < 0.0001) in ApoE epsilon4 genotype or allele frequencies was found in AD (66.6% and 41.2%) as compared with controls (29.8% and 16.5%), suggesting sufficient statistical power in our sample. No relation was found between the A2M-2 and the ApoE epsilon4 allele. No change in A2M exon 17-18 mRNA size or sequence or A2M protein size was found in cases carrying the A2M-2 deletion, suggesting that there is no biological consequences of the A2M intronic deletion. No change in A2M protein level in cerebrospinal fluid was found in AD, suggesting that the A2M-2 allele does not effect the A2M protein expression in the brain. The lack of an association between the A2M-2 allele and AD in the present study, and the lack of abnormalities in the A2M mRNA or protein suggest that the A2M-2 allele is not associated with AD.
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| 5. |
- Fåhraeus, R, et al.
(författare)
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Response to cAMP levels of the Epstein-Barr virus EBNA2-inducible LMP1 oncogene and EBNA2 inhibition of a PP1-like activity.
- 1994
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Ingår i: The EMBO journal. - 0261-4189. ; 13:24, s. 6041-51
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Tidskriftsartikel (refereegranskat)abstract
- The expression of the Epstein-Barr virus LMP1 oncogene is regulated by viral and non-viral factors in a tissue dependent fashion. The virus encoded transcription factor EBNA2 induces its expression in human B-cells. However, this induction also requires the contribution of cellular and/or other viral factors. In nasopharyngeal carcinoma cells and in cells from Hodgkin's lymphoma, LMP1 gene transcription is independent of viral products. Here we show that the effect of a factor binding to a cAMP responsive-like element (CRE) in the LMP1 gene transcription regulatory sequence (LRS) is essential for efficient promoter activity in the DG75 B-cell line and that elevation of cAMP levels in the cells induces LRS-derived CAT activity in a CRE dependent fashion. Incubation of two EBV-immortalized B-cell lines expressing endogenous EBNA2A with 8-Br cAMP increased the levels of the latency associated 66 kDa LMP1 within 2 h. Interestingly, LMP1 expression in DG75 cells conferred resistance to the inhibitory effect of 8-Br cAMP on cell proliferation. The protein phosphatase 1 and 2A (PP1 and PP2A, respectively) inhibitor okadaic acid also stimulated LRS-CAT activity in DG75 cells. EBNA2A from an EBV-immortalized B-cell line co-immunopurified with a PP1-like protein. An EBNA2A fragment spanning residues 324-436 fused to the GST protein specifically rescued a PP1/PP2A-like component from DG75 cell extracts. This GST-EBNA2A fusion product inhibited a PP1-like activity in nuclear extracts from these cells.
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| 6. |
- Kuchenbauer, Florian, et al.
(författare)
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Comprehensive analysis of mammalian miRNA* species and their role in myeloid cells.
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 118:12, s. 3350-8
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Tidskriftsartikel (refereegranskat)abstract
- Processing of pre-miRNA through Dicer1 generates an miRNA duplex that consists of an miRNA and miRNA* strand. Despite the general view that miRNA*s have no functional role, we further investigated miRNA* species in 10 deep-sequencing libraries from mouse and human tissue. Comparisons of miRNA/miRNA* ratios across the miRNA sequence libraries revealed that 50% of the investigated miRNA duplexes exhibited a highly dominant strand. Conversely, 10% of miRNA duplexes showed a comparable expression of both strands, whereas the remaining 40% exhibited variable ratios across the examined libraries, as exemplified by miR-223/miR-223* in murine and human cell lines. Functional analyses revealed a regulatory role for miR-223* in myeloid progenitor cells, which implies an active role for both arms of the miR-223 duplex. This was further underscored by the demonstration that miR-223 and miR-223* targeted the insulin-like growth factor 1 receptor/phosphatidylinositol 3-kinase axis and that high miR-223* levels were associated with increased overall survival in patients with acute myeloid leukemia. Thus, we found a supporting role for miR-223* in differentiating myeloid cells in normal and leukemic cell states. The fact that the miR-223 duplex acts through both arms extends the complexity of miRNA-directed gene regulation of this myeloid key miRNA.
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| 7. |
- Lundin, Catarina, et al.
(författare)
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High frequency of BTG1 deletions in acute lymphoblastic leukemia in children with down syndrome
- 2012
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Ingår i: Genes, Chromosomes and Cancer. - Malden : Wiley-Blackwell. - 1045-2257 .- 1098-2264. ; 51:2, s. 196-206
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Tidskriftsartikel (refereegranskat)abstract
- Previous cytogenetic studies of myeloid and acute lymphoblastic leukemias in children with Down syndrome (ML-DS and DS-ALL) have revealed significant differences in abnormality patterns between such cases and acute leukemias in general. Also, certain molecular genetic aberrations characterize DS-related leukemias, such as GATA1 mutations in ML-DS and deregulation of the CRLF2 gene in DS-ALL. Whether microdeletions/microduplications also vary between DS and non-DS cases is presently unclear. To address this issue, we performed single nucleotide polymorphism array analyses of eight pediatric ML-DS and 17 B-cell precursor DS-ALL. In the ML-DS cases, a total of 29 imbalances (20 gains and nine losses) and two partial uniparental isodisomies (pUPDs) were detected. None of the 11 small (defined as less than10 Mb) imbalances were recurrent, nor were the pUPDs, whereas of the 18 large aberrations, three were recurrentdup(1q), +8 and +21. In contrast, several frequent changes were identified in the DS-ALL cases, which harbored 82 imbalances (30 gains and 52 losses) and four pUPDs. Of the 40 large changes, 28 were gains and 12 losses, with +X, dup(Xq), dup(1q), del(7p), dup(8q), del(9p), dup(9p), del(12p), dup(17q), and +21 being recurrent. Of the 40 microdeletions identified, several targeted specific genes, with the following being repeatedly deleted: BTG1 and CDKN2A/B (29% of cases), ETV6, IKZF1, PAX5 and SERP2 (18%), and BTLA, INPP4B, P2RY8, and RB1 (12%). Loss of the SERP2 and INPP4B genes, encoding the stress-associated endoplasmic reticulum protein family member 2 and the inositol polyphosphate 4-phosphatase-II, respectively, has previously never been implicated in leukemia. Although deletions of the other genes have been associated with ALL, the high frequency of BTG1 loss is a novel finding. Such deletions may characterize a clinical subgroup of DS-ALL, comprising mainly boys with a high median age. In conclusion, ML-DS and DS-ALL are genetically distinct, with mainly gains in ML-DS and deletions in DS-ALL. Furthermore, DS-ALL is characterized by several recurrent gene deletions, with BTG1 loss being particularly frequent.
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| 8. |
- Schneider, Edith, et al.
(författare)
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MicroRNA-155 is a direct target of Meis1, but not a driver in acute myeloid leukemia.
- 2018
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 103, s. 246-255
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNA-155 (miR-155) is one of the first described oncogenic miRNAs. Although multiple direct targets of miR-155 have been identified, it is not clear how it contributes to the pathogenesis of acute myeloid leukemia. We found miR-155 to be a direct target of Meis1 in murine Hoxa9/Meis1 induced acute myeloid leukemia. The additional overexpression of miR 155 accelerated the formation of acute myeloid leukemia in Hoxa9 as well as in Hoxa9/Meis1 cells in vivo. However, in the absence or after the removal of miR-155, leukemia onset and progression were unaffected. Although, miR-155 accelerated growth and homing as well as impaired differentiation, our data underscore the pathophysiological relevance of miR 155 as an accelerator rather than a driver of leukemogenesis. This further highlights the complexity of the oncogenic program of Meis1 to compensate for the loss of a potent oncogene such as miR-155. These findings are highly relevant to current and developing approaches for targeting miR-155 in acute myeloid leukemia.
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| 9. |
- Schneider, Edith, et al.
(författare)
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MicroRNA-155 is upregulated in MLL-rearranged AML but its absence does not affect leukemia development.
- 2016
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Ingår i: Experimental hematology. - : Elsevier BV. - 1873-2399 .- 0301-472X. ; 44:12, s. 1166-71
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNA-155 (miR-155) is an oncogenic miRNA upregulated in various tumor types and leukemias and has been suggested as a potential drug target. Based on our previous work detecting high miR-155 levels in response to Meis1 overexpression in a murine Hox leukemia model, we show here the relationship among HOXA9, MEIS1, and miR-155 levels in MLL-translocated acute myeloid leukemia (AML) patients. Using mouse bone marrow cells transformed by MLL-fusion genes expressing graduated levels of Meis1, we show a positive correlation between miR-155 and Meis1. However, using a miR-155-knockout mouse model, we show that the absence and the depletion of miR-155 have no effect on leukemia formation or progression. We also show for the first time that miR-155 levels are correlated with MLL translocations, but that miR-155 expression is dispensable for the formation of AML and has no effect on leukemia progression.
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| 10. |
- Sjöblom-Hallén, A, et al.
(författare)
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An ATF/CRE element mediates both EBNA2-dependent and EBNA2-independent activation of the Epstein-Barr virus LMP1 gene promoter.
- 1998
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Ingår i: Journal of virology. - 0022-538X. ; 72:2, s. 1365-76
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Tidskriftsartikel (refereegranskat)abstract
- The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is a viral oncogene whose expression is regulated by both viral and cellular factors. EBV nuclear antigen 2 (EBNA2) is a potent transactivator of LMP1 expression in human B cells, and several EBNA2 response elements have been identified in the promoter regulatory sequence (LRS). We have previously shown that an activating transcription factor/cyclic AMP response element (ATF/CRE) site in LRS is involved in EBNA2 responsiveness. We now establish the importance of the ATF/CRE element by mutational analysis and show that both EBNA2-dependent activation and EBNA2-independent activation of the promoter occur via this site but are mediated by separate sets of factors. An electrophoretic mobility shift assay (EMSA) with specific antibodies showed that the ATF-1, CREB-1, ATF-2 and c-Jun factors bind to the site as ATF-1/CREB-1 and ATF-2/c-Jun heterodimers whereas the Sp1 and Sp3 factors bind to an adjacent Sp site. Overexpression of ATF-1 and CREB-1 in the cells by expression vectors demonstrated that homodimeric as well as heterodimeric forms of the factors transactivate the LMP1 promoter in an EBNA2-independent manner. The homodimers of ATF-2 and c-Jun did not significantly stimulate promoter activity. In contrast, the ATF-2/c-Jun heterodimer had only a minor stimulatory effect in the absence of EBNA2 but induced a strong transactivation of the LMP1 promoter when coexpressed with this protein. Evidence for a direct interaction between the ATF-2/c-Jun heterodimeric complex and EBNA2 was obtained by EMSA and coimmunoprecipitation experiments. Thus, our results suggest that EBNA2-induced transactivation via the ATF/CRE site occurs through a direct contact between EBNA2 and an ATF-2/c-Jun heterodimer. EBNA2-independent promoter activation via this site, on the other hand, is mediated by a heterodimeric complex between the ATF-1 and CREB-1 factors.
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| 11. |
- Zetterberg, Henrik, 1973, et al.
(författare)
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Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos.
- 2002
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Ingår i: European journal of human genetics : EJHG. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 10:2, s. 113-8
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Tidskriftsartikel (refereegranskat)abstract
- The pathogenesis of spontaneous abortion is complex, presumably involving the interaction of several genetic and environmental factors. The methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms are commonly associated with defects in folate dependent homocysteine metabolism and have been implicated as risk factors for recurrent embryo loss in early pregnancy. In the present study we have determined the prevalence of combined MTHFR C677T and A1298C polymorphisms in DNA samples from spontaneously aborted embryos (foetal death between sixth and twentieth week after conception) and adult controls using solid-phase minisequencing technique. There was a significant odds ratio of 14.2 (95% CI 1.78-113) in spontaneously aborted embryos comparing the prevalence of one or more 677T and 1298C alleles vs the wild type combined genotype (677CC/1298AA), indicating that the MTHFR polymorphisms may have a major impact on foetal survival. Combined 677CT/1298CC, 677TT/1298AC or 677TT/1298CC genotypes, which contain three or four mutant alleles, were not detected in any of the groups, suggesting complete linkage disequilibrium between the two polymorphisms. The present finding of high prevalence of mutated MTHFR genotypes in spontaneously aborted embryos emphasises the potential protective role of periconceptional folic acid supplementation.
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| 12. |
- Zetterberg, Henrik, 1973, et al.
(författare)
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Influence of the apolipoprotein E epsilon4 allele on human embryonic development.
- 2002
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Ingår i: Neuroscience letters. - 0304-3940. ; 324:3, s. 189-92
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Tidskriftsartikel (refereegranskat)abstract
- Human apolipoprotein E (apoE) exists in three major isoforms encoded by distinct alleles (APOE epsilon2, epsilon3 and epsilon4) and has important functions in nerve development and repair. Inheritance of the 4 allele is a major risk factor for the development of Alzheimer's disease. To investigate the role of APOE polymorphisms in embryonic development, we analyzed the APOE genotypes of 81 spontaneously aborted embryos and 110 adult controls using a solid-phase minisequencing technique. The epsilon4 allele was significantly less frequent in the spontaneous abortion group than in the control group (P=0.009), while the frequency of epsilon3 was significantly increased (P=0.005), suggesting that epsilon4 may have protective effects during embryogenesis. These protective effects might counterbalance the deleterious age-related effects of the epsilon4 allele in natural selection.
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| 13. |
- Alm, Sofie J., 1988, et al.
(författare)
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Minimal residual disease monitoring in childhood B lymphoblastic leukemia with t(12;21)(p13;q22); ETV6-RUNX1: concordant results using quantitation of fusion transcript and flow cytometry.
- 2017
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Ingår i: International journal of laboratory hematology. - : Wiley. - 1751-553X .- 1751-5521. ; 39:2, s. 121-128
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Tidskriftsartikel (refereegranskat)abstract
- The translocation t(12;21)(p13;q22) resulting in the fusion gene ETV6-RUNX1, is the most frequent gene fusion in childhood B lymphoblastic leukemia. In the Nordic Society of Paediatric Haematology and Oncology ALL-2008 treatment protocol, treatment stratification in B-lineage ALL is based on results of minimal residual disease (MRD) analysis with fluorescence-activated cell sorting (FACS). In this study, we determined whether RT-qPCR of the ETV6-RUNX1 fusion transcript can be a reliable alternative for MRD analysis.Seventy-eight bone marrow samples from 29 children at diagnosis and day 15, 29, and 78 during treatment were analyzed for MRD with FACS and with quantitative reverse transcription polymerase chain reaction (RT-qPCR). Fusion transcript MRD was defined as the ETV6-RUNX1/GUSB ratio at the follow-up time point (day 15/29/78) divided with the ETV6-RUNX1/GUSB ratio at diagnosis (%).MRD analysis with FACS and with RT-qPCR of ETV6-RUNX1 fusion transcript showed strong correlation. All cases showed concordant results at the treatment stratifying time points day 29 and day 78, when comparing the two methods with a cutoff set to 0.1%.RT-qPCR is a valuable addition and could also be an alternative to FACS in cases where FACS is not achievable for MRD analysis.
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| 14. |
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| 15. |
- Andersen, Mette K., et al.
(författare)
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Paediatric B-cell precursor acute lymphoblastic leukaemia with t(1;19)(q23;p13) : clinical and cytogenetic characteristics of 47 cases from the Nordic countries treated according to NOPHO protocols
- 2011
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Ingår i: British Journal of Haematology. - Oxford : Wiley. - 0007-1048 .- 1365-2141. ; 155:2, s. 235-243
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Tidskriftsartikel (refereegranskat)abstract
- The translocation t(1;19)(q23;p13)/der(19) t(1;19) is a risk stratifying aberration in childhood B-cell precursor acute lymphoblastic leukaemia (BCP ALL) in the Nordic countries. We have identified 47 children/adolescents with t(1;19)/der(19) t(1;19)-positive BCP ALL treated on two successive Nordic Society of Paediatric Haematology and Oncology (NOPHO) protocols between 1992 and 2007 and have reviewed the clinical and cytogenetic characteristics of these cases, comprising 1.8% of all cases. The translocation was balanced in 15 cases (32%) and unbalanced in 29 cases (62%). The most common additional chromosome abnormalities were del(9p), i(9q), del(6q), and del(13q). The median age was 7 years, the median white blood cell (WBC) count was 16 x 10(9)/l, and the female/male ratio was 1.2. The predicted event-free survival (EFS) at 5 and 10 years was 0.79, whereas the predicted overall survival (OS) at 5 and 10 years was 0.85 and 0.82, respectively. Nine patients had a bone marrow relapse after a median of 23 months; no patient had a central nervous system relapse. Additional cytogenetic abnormalities, age, gender, WBC count or whether the t(1;19) was balanced or unbalanced did not influence EFS or OS. Compared to cases with t(12,21) and high hyperdiploidy, EFS was similar, but overall survival was worse in patients with t(1;19)/der(19) t(1;19) (P = 0.004).
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| 16. |
- Andreasson, B., et al.
(författare)
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ASXL1 mutations, previous vascular complications and age at diagnosis predict survival in 85 WHO-defined polycythaemia vera patients
- 2020
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 189:5, s. 913-919
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Tidskriftsartikel (refereegranskat)abstract
- Polycythaemia vera (PV) patients have an overall comparatively favourable prognosis, but disease progression is very heterogeneous and life-threatening thrombosis and bleedings are frequent complications in untreated disease. Moreover, transformation to more severe secondary myelofibrosis and acute myeloid leukaemia can occur. The aim of this study was to identify gene mutations that could be used together with clinical data as prognostic markers to guide treatment decisions in PV patients. A well-characterized WHO-defined cohort of PV patients was used. Clinical data and blood values were evaluated and a myeloid sequencing panel was used to screen for additional mutations other than the diagnostic JAK2 V617F and JAK2 exon 12 mutations. In 78% of the PV patients, at least one mutation additional to JAK2 V617F was detected. Additional mutations in genes coding for epigenetic modifiers, like TET2, DNMT3A and ASXL1, were most frequent. When correlated to overall survival, mutations in ASXL1 were significantly associated with inferior survival. In an attempt to obtain prognostic guidance in a larger number of patients, the presence of ASXL1 mutations was combined with age and vascular complications prior to diagnosis. Based on these data we were able to define three risk groups that predicted survival.
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| 17. |
- Arabanian, Laleh S., et al.
(författare)
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The endothelin receptor type A is a downstream target of Hoxa9 and Meis1 in acute myeloid leukemia
- 2018
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Ingår i: Leukemia Research. - : Elsevier BV. - 0145-2126. ; 75, s. 61-68
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Tidskriftsartikel (refereegranskat)abstract
- Endothelin receptor type A (EDNRA) is known as a mediator of cell proliferation and survival. Aberrant regulation of EDNRA has been shown to play a role in tumor growth and metastasis. Using a global gene expression screen, we found that expression of Ednra was upregulated in murine leukemia inducing cells co-expressing Hoxa9 and Meis1 compared to cells only expressing Hoxa9. The aim of this study was to explore the role of Ednra in leukemogenesis further. In a murine bone marrow transplantation model, mice transplanted with cells overexpressing Ednra and Hoxa9 succumbed to leukemia significantly earlier than mice transplanted with cells overexpressing Hoxa9 only. Furthermore, overexpression of Ednra led to increased proliferation and resistance to apoptosis of bone marrow cells in vitro. We could also show that Meis1 binds to the Ednra promoter region, suggesting a regulatory role for Meis1 in Ednra expression. Taken together, our results suggest a role for Ednra in Hoxa9/Meis1-driven leukemogenesis.
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| 18. |
- Argiropoulos, Bob, et al.
(författare)
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Linkage of Meis1 leukemogenic activity to multiple downstream effectors including Trib2 and Ccl3.
- 2008
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Ingår i: Experimental hematology. - : Elsevier BV. - 0301-472X. ; 36:7, s. 845-59
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: MEIS1, a HOX cofactor, collaborates with multiple HOX and NUP98-HOX fusion proteins to accelerate the onset of acute myeloid leukemia (AML) through largely unknown molecular mechanisms. MATERIALS AND METHODS: To further resolve these mechanisms, we conducted a structure-function analysis of MEIS1 and gene-expression profiling, in the context of NUP98-HOXD13 (ND13) leukemogenesis. RESULTS: We show, in a murine bone marrow transplantation model, that the PBX-interaction domain, the homeodomain, and the C-terminal domain of MEIS1, are all required for leukemogenic collaboration with ND13. In contrast, the N-terminal domain of MEIS1 is dispensable for collaboration with ND13, but is required for Flt3 upregulation, indicating additional roles for MEIS1 in induction of leukemia independent of alterations in Flt3 expression. Gene-expression profiling of a cloned ND13 preleukemic cell line transduced with wild-type or Meis1 mutant forms revealed deregulation of multiple genes, including a set not previously implicated as MEIS1 targets. Chromatin immunoprecipitation revealed the in vivo occupancy of MEIS1 on regulatory sequences of Trib2, Flt3, Dlk1, Ccl3, Ccl4, Pf4, and Rgs1. Furthermore, engineered overexpression of Trib2 complements ND13 to induce AML while Ccl3 potentiates the repopulating ability of ND13. CONCLUSION: This study shows that Meis1-induced leukemogenesis with ND13 can occur in the absence of Flt3 upregulation and reveals the existence of other pathways activated by MEIS1 to promote leukemia.
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| 19. |
- Argiropoulos, Bob, et al.
(författare)
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Linkage of the potent leukemogenic activity of Meis1 to cell-cycle entry and transcriptional regulation of cyclin D3.
- 2010
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 115:20, s. 4071-82
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Tidskriftsartikel (refereegranskat)abstract
- MEIS1 is a three-amino acid loop extension class homeodomain-containing homeobox (HOX) cofactor that plays key roles in normal hematopoiesis and leukemogenesis. Expression of Meis1 is rate-limiting in MLL-associated leukemias and potently interacts with Hox and NUP98-HOX genes in leukemic transformation to promote self-renewal and proliferation of hematopoietic progenitors. The oncogenicity of MEIS1 has been linked to its transcriptional activation properties. To further reveal the pathways triggered by Meis1, we assessed the function of a novel engineered fusion form of Meis1, M33-MEIS1, designed to confer transcriptional repression to Meis1 target genes that are otherwise up-regulated in normal and malignant hematopoiesis. Retroviral overexpression of M33-Meis1 resulted in the rapid and complete eradication of M33-Meis1-transduced normal and leukemic cells in vivo. Cell-cycle analysis showed that M33-Meis1 impeded the progression of cells from G(1)-to-S phase, which correlated with significant reduction of cyclin D3 levels and the inhibition of retinoblastoma (pRb) hyperphosphorylation. We identified cyclin D3 as a direct downstream target of MEIS1 and M33-MEIS1 and showed that the G(1)-phase accumulation and growth suppression induced by M33-Meis1 was partially relieved by overexpression of cyclin D3. This study provides strong evidence linking the growth-promoting activities of Meis1 to the cyclin D-pRb cell-cycle control pathway.
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| 20. |
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| 21. |
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| 22. |
- Aurelius, Johan, 1980, et al.
(författare)
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Chronic myeloid leukemic cells trigger poly(ADP-ribose) polymerase-dependent inactivation and cell death in lymphocytes.
- 2013
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Ingår i: Journal of leukocyte biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 93:1, s. 155-160
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Tidskriftsartikel (refereegranskat)abstract
- NK cells and T cells are commonly dysfunctional in CML, and their status may determine the course of disease. We aimed to define the molecular mechanisms of leukemia-induced immunosuppression with focus on the role of ROS and the PARP-1 pathway of cell death. Malignant granulocytes from patients with BCR-ABL-positive CML expressed the oxygen radical-producing enzyme NOX, produced large amounts of ROS, and triggered extensive cell death in NK cells. Inhibition of PARP-1 maintained NK cell viability in cocultures with suppressive leukemic cells. Under conditions of oxidative stress, PARP-1 inhibition upheld the capacity of NK cells to kill myeloid leukemic cells, in addition to restoring the proliferation and cytokine production of NK cells and cytotoxic T cells. Our findings are suggestive of a novel pathway of relevance to immunosuppression in CML.
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| 23. |
- Aurelius, Johan, 1980, et al.
(författare)
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Monocytic AML cells inactivate antileukemic lymphocytes: role of NADPH oxidase/gp91(phox) expression and the PARP-1/PAR pathway of apoptosis.
- 2012
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 119:24, s. 5832-7
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Tidskriftsartikel (refereegranskat)abstract
- Dysfunction of T cells and natural killer (NK) cells has been proposed to determine the course of disease in acute myeloid leukemia (AML), but only limited information is available on the mechanisms of lymphocyte inhibition. We aimed to evaluate to what extent human malignant AML cells use NADPH oxidase-derived reactive oxygen species (ROS) as an immune evasion strategy. We report that a subset of malignant myelomonocytic and monocytic AML cells (French-American-British [FAB] classes M4 and M5, respectively), recovered from blood or BM of untreated AML patients at diagnosis, expressed the NADPH oxidase component gp91(phox). Highly purified FAB M4/M5 AML cells produced large amounts of ROS on activation and triggered poly-[ADP-ribose] polymerase-1-dependent apoptosis in adjacent NK cells, CD4(+) T cells, and CD8(+) T cells. In contrast, immature (FAB class M1) and myeloblastic (FAB class M2) AML cells rarely expressed gp91(phox), did not produce ROS, and did not trigger NK or T-cell apoptosis. Microarray data from 207 AML patients confirmed a greater expression of gp91(phox) mRNA by FAB-M4/M5 AML cells than FAB-M1 cells (P < 10(-11)) or FAB-M2 cells (P < 10(-9)). Our data are suggestive of a novel mechanism by which monocytic AML cells evade cell-mediated immunity.
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| 24. |
- Aurelius, Johan, 1980, et al.
(författare)
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Remission maintenance in acute myeloid leukemia: impact of functional histamine H-2 receptors expressed by leukemic cells
- 2012
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 97:12, s. 1904-1908
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Tidskriftsartikel (refereegranskat)abstract
- Post-consolidation immunotherapy with histamine dihydrochloride and interleukin-2 has been shown to improve leukemia-free survival in acute myeloid leukemia in a phase III trial. For this study, treatment efficacy was determined among 145 trial patients with morphological forms of acute myeloid leukemia as defined by the French-American-British classification. Leukemia-free survival was strongly improved in M4/M5 (myelomonocytic/monocytic) leukemia but not in M2 (myeloblastic) leukemia. We also analyzed histamine H-2 receptor expression by leukemic cells recovered from 26 newly diagnosed patients. H-2 receptors were typically absent from M2 cells but frequently expressed by M4/M5 cells. M4/M5 cells, but not M2 cells, produced reactive oxygen species that triggered apoptosis in adjacent natural killer cells. These events were significantly inhibited by histamine dihydrochloride. Our data demonstrate the presence of functional histamine H2 receptors on human AML cells and suggest that expression of these receptors by leukemic cells may impact on the effectiveness of histamine-based immunotherapy.
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| 25. |
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| 26. |
- Borssen, Magnus, et al.
(författare)
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Promoter DNA methylation pattern identifies prognostic subgroups in childhood T-cell acute lymphoblastic leukemia.
- 2013
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:6
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Tidskriftsartikel (refereegranskat)abstract
- Treatment of pediatric T-cell acute lymphoblastic leukemia (T-ALL) has improved, but there is a considerable fraction of patients experiencing a poor outcome. There is a need for better prognostic markers and aberrant DNA methylation is a candidate in other malignancies, but its potential prognostic significance in T-ALL is hitherto undecided.
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| 27. |
- Campagnoli, Monica, et al.
(författare)
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A novel splicing mutation causes an undescribed type of analbuminemia.
- 2002
-
Ingår i: Biochimica et biophysica acta. - 0006-3002. ; 1586:1, s. 43-9
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Tidskriftsartikel (refereegranskat)abstract
- Analbuminemia is a rare autosomal recessive disorder manifested by the absence or severe reduction of circulating serum albumin in homozygous subjects. In this report we describe a new molecular defect that caused the analbuminemic trait in a newborn of Iraqi origin. When the parents' DNA was analyzed, both subjects were found to be heterozygous for the same mutation found in the infant. All the 14 exon and flanking intron sequences of the albumin gene were amplified via PCR and screened for mutations by SSCP and heteroduplex analysis. A mutation in the DNA region encoding exon 1 and its flanking intron was revealed by the presence of a heteroduplex. The fragment, which was directly DNA sequenced, contains a previously unreported single nucleotide change, consisting in a G to A substitution at nucleotide 118 in the structural gene of the human protein. This mutation, involving the first base of intron 1, destroys the GT dinucleotide consensus sequence found at the 5' end of most intervening sequences and causes the defective pre-mRNA splicing responsible for the analbuminemic trait.
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| 28. |
- Campagnoli, Minchiotti, et al.
(författare)
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Analbuminemia in a Swedish male is caused by the Kayseri mutation (c228_229delAT).
- 2008
-
Ingår i: Clinica chimica acta; international journal of clinical chemistry. - : Elsevier BV. - 0009-8981. ; 396:1-2, s. 89-92
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Analbuminemia is a rare autosomal recessive disorder manifested by the absence, or severe reduction, of circulating serum albumin. Here we report the first case of hereditary analbuminemia in the ethnic Swedish population, and we define the molecular defect that causes the analbuminemic trait. METHODS: Total DNA, extracted from peripheral blood samples from the analbuminemic proband and his parents, was PCR-amplified using oligonucleotide primers designed to amplify the 14 exons, the exon-intron splice junctions, and the 5' and 3' untranslated regions of the albumin gene. The products were screened for mutations by single-strand conformation polymorphism and heteroduplex analyses. The latter allowed the identification of the abnormal fragment, which was then sequenced. RESULTS: The analbuminemic trait of the proband was caused by a homozygous AT deletion at nucleotides c. 228-229, the 91st and 92nd bases of exon 3. This defect, previously identified as Kayseri mutation [M. Galliano, M. Campagnoli, A. Rossi, et al. Molecular diagnosis of analbuminemia: a novel mutation identified in two Amerindian and two Turkish families. Clin Chem 2002;48: 844-849.], produces a frameshift leading to a premature stop, two codons downstream. CONCLUSIONS: The Kayseri mutation appears to be the most common cause of analbuminemia in humans, and is found in individuals belonging to geographically distant, and apparently unrelated ethnic groups.
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| 29. |
- Carlsson, Per-Anders, 1972, et al.
(författare)
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A transient in situ FTIR and XANES study of CO oxidation over Pt/Al2O3 catalysts
- 2004
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Ingår i: Journal of Catalysis. - : Elsevier BV. - 0021-9517 .- 1090-2694. ; 226:2, s. 422-434
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Tidskriftsartikel (refereegranskat)abstract
- We report experimental results for the oxidation of CO over supported Pt/Al2O3 catalysts operating in oxygen excess at atmospheric pressure. To study the reaction kinetics under transient conditions we have employed step changes of the O2 concentration by intermittently switching off the O2 supply at various temperatures ranging from 523 to 623 K. Detailed in situ FTIR and XANES data for CO coverage and the chemical state of Pt, respectively, are presented together with the CO conversion, which in both cases was monitored by mass spectrometry. A red-shift of the vibrational frequency of linearly bonded CO which correlates with a blue-shift of the Pt LIII binding energy indicates that the Pt catalyst initially is partially oxidised and gradually reduced when the O2 supply is switched off. Control experiments with a NO2 oxidised Pt/Al2O3 catalyst support these findings. A hysteresis in the catalytic activity due to the different rates whereby Pt is oxidised and reduced as a function of gas-phase composition is observed. The activation energy for the Pt oxide reduction (decomposition) process is estimated to be about 50 kJ/mol. The results further emphasise that the conventional three-step Langmuir-Hinshelwood (LH) scheme used to interpret CO oxidation on Pt surfaces must be complemented by a Pt oxidation and reduction mechanism during transient conditions. Moreover, FTIR data suggest that during the extinction, the partially oxidised platinum surface is reduced by chemisorbed CO which should be explicitly accounted for in the modeling of the reaction mechanism.
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| 30. |
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| 31. |
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| 32. |
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| 33. |
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| 34. |
- Espersen, A. D. L., et al.
(författare)
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Acute myeloid leukemia (AML) with t(7;12)(q36;p13) is associated with infancy and trisomy 19: Data from Nordic Society for Pediatric Hematology and Oncology (NOPHO-AML) and review of the literature
- 2018
-
Ingår i: Genes Chromosomes & Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 57:7, s. 359-365
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Tidskriftsartikel (refereegranskat)abstract
- The t(7;12)(q36;p13) (MNX1/ETV6) is not included in the WHO classification but has been described in up to 30% of acute myeloid leukemia (AML) in children <2 years and associated with a poor prognosis. We present the clinical and cytogenetics characteristics of AML cases with t(7;12)(p36;p13). A literature review identified 35 patients with this translocation, published between 2000 and 2015. Outcome data were available in 22 cases. The NOPHO-AML (Nordic Society for Pediatric Hematology and Oncology) database contained 651 patients with AML from 1993 to 2014 and seven (1.1%) had the translocation. The t(7;12) was only present in patients <2 years of age (median age 6 months) but none was diagnosed as newborn. These patients constituted 4.3% of the patients <2 years of age. There was a strong association with trisomy 19 (literature: 86%, NOPHO: 100%) and +8 (literature: 19%, NOPHO: 14%). Seventeen of 22 patients from the literature with t(7;12) and four of seven patients from the NOPHO database suffered from relapse. The patients with t(7;12) had a 3-year event free survival of 24% (literature) vs. 43% (NOPHO) and a 3-year overall survival of 42% (literature) vs. 100% (NOPHO). None of the NOPHO patients was treated with hematopoietic stem cell transplantation (HSCT) in first complete remission. Relapse was frequent but the salvage rate using HSCT was high. We conclude that t(7;12)(q36;13) is a unique subgroup of childhood AML with presentation before 2 years of age with most cases being associated with +19.
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| 35. |
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| 36. |
- Fogelstrand, Linda, 1974, et al.
(författare)
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Prognostic Implications of Mutations in NOTCH1 and FBXW7 in Childhood T-ALL Treated According to the NOPHO ALL-1992 and ALL-2000 Protocols
- 2014
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Ingår i: Pediatric Blood & Cancer. - : Wiley-Blackwell. - 1545-5009 .- 1545-5017. ; 61:3, s. 424-430
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Tidskriftsartikel (refereegranskat)abstract
- Background In children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis.Procedure We analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes.Results Forty-seven of the cases (59%) displayed mutations in NOTCH1 and/or FBXW7. There was no difference in overall (P=0.14) or event-free survival (EFS) (P=0.10) in patients with T-ALL with mutation(s) in NOTCH1/FBXW7 compared with patients with T-ALL without mutations in any of these genes. T-ALL carrying NOTCH1 mutations had increased HES1 and MYB mRNA expression (HES1 9.21.9 (mean +/- SEM), MYB 8.7 +/- 0.8 (mean +/- SEM)) compared to T-ALL with wild-type NOTCH1 (HES1 1.8 +/- 0.7, MYB 5.1 +/- 1.2, P=0.02 and 0.008, respectively). In cases of T-ALL with high HES1 expression, improved overall (P=0.02) and EFS (P=0.028) was seen.Conclusions Increased NOTCH activity, reflected by increased HES1 expression, is associated with improved outcome in pediatric T-ALL, but its role as a diagnostic tool or a therapeutic target in future clinical treatment protocols remains to be elucidated. Pediatr Blood Cancer 2014;61:424-430. (c) 2013 Wiley Periodicals, Inc.
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| 37. |
- Frändberg, Sofia, 1972, et al.
(författare)
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Concentration of the CDCP1 protein in human cord plasma may serve as a predictor of hematopoietic stem and progenitor cell content
- 2018
-
Ingår i: Stem Cell Research. - : Elsevier BV. - 1873-5061. ; 29, s. 24-27
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Tidskriftsartikel (refereegranskat)abstract
- Successful hematopoietic stem and progenitor cell (HSPC) transplantation rests upon reliable methods for their enumeration in sources such as cord blood (CB). Methods used today are costly, time consuming and exhaust the limited number of cells needed for transplantation. The aim of this study was to analyze if surplus plasma from CB contains biomarkers that can predict HSPC content in CB. Frozen, surplus plasma from 95 CB units was divided into two groups based on CD34+ cell concentration. Birth weight, gestation age, gender, mode of delivery, collection volume, nucleated cell count and colony forming unit assay results were available. Samples were analyzed with a proximity ligation assay covering 92 different proteins. Two-group t-test with p-values adjusted for false discovery rate (FDR) identified 5 proteins that significantly differed between the two groups. CDCP1 was the most significant (FDR adjusted p-value 0.006). Correlation with CDCP1 concentration was most significant for CD34+ concentration and nucleated cell count. Multivariate analysis showed that CD34 and gender seemed to influence the level of CDCP1. In conclusion, CDCP1 was identified as a potential biomarker of HSPC content in CB. The finding also warrants further investigation for a possible role of CDCP1 in regulating HSPC presence in CB. © 2018
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| 38. |
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| 39. |
- Frändberg, Sofia, 1972, et al.
(författare)
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The aldehyde dehydrogenase cord blood potency assay excludes early apoptotic cells
- 2018
-
Ingår i: Transfusion. - : Wiley. - 0041-1132 .- 1537-2995. ; 58:6, s. 1452-1457
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUNDCord blood units (CBUs) are processed, frozen, and thawed before use in hematopoietic stem cell (HSC) transplantation. The manipulations affect HSC functionality, that is, induce apoptosis and reduce viability. HSC content, commonly expressed as CBU potency, that is, the expected ability of a CBU to restore hematopoiesis, is traditionally approximated through viable CD34+ cells and the colony-forming unit (CFU) cell cultivation assay. Alternative approaches, for example, the aldehyde dehydrogenase (ALDH) enzyme-based assay, are also forthcoming. We hypothesized that the ALDH assay might exclude apoptotic cells since it is based on enzyme activity. To investigate this, we designed a protocol for simultaneous staining of viable and apoptotic CD34+ and ALDH+ cells using 7-aminoactinomycin (7-AAD) and annexin V, in frozen-thawed CBUs. Results were correlated with results from the colony-forming unit-granulocyte/macrophage (CFU-GM) assay. STUDY DESIGN AND METHODSSamples from 57 CBUs were thawed and simultaneously analyzed for CD34+ cells, ALDH+ cells, viability (7-AAD), and apoptosis (annexin V) using flow cytometry. Enumeration of CFUs was also performed. RESULTSNo nonviable and few apoptotic cells (mean 0.7%) were identified in the ALDH+ population compared to the viable CD34+ population (mean 3.6%). The total number of ALDH+ cells correlated better than viable CD34+ cells (r=0. 72 vs. r=0.66; p<0.0001) with the results of the CFU assay. CONCLUSIONThe ALDH assay excludes nonviable and apoptotic cells, and therefore correlates better with CFU enumeration compared to the number of viable CD34+ cells. We propose that the ALDH assay might replace the CFU-GM method in CBU potency measurements.
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| 40. |
- Grauers Wiktorin, Hanna, 1990, et al.
(författare)
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Mutated NPM1 in combination with overexpression of Meis1 or Hoxa9 is not sufficient to induce acute myeloid leukemia
- 2016
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Ingår i: Experimental Hematolgy & Oncology. - : Springer Science and Business Media LLC. - 2162-3619. ; 5
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Acute myeloid leukemia (AML) carrying nucleophosmin 1 (NPM1) mutations (NPMc(+)) is regarded as a separate entity of myeloid neoplasms due to its distinct biological and clinical features. However, NPMc(+) alone displays low leukemogenic activity and cooperating events appear crucial for AML to develop. Dysregulation of homeobox genes, such as HOXA9 and MEIS1, is a common transcriptional signature of NPMc(+) AML. Furthermore, the pathogenic role for NPMc(+) in AML remains incompletely understood. Aim: To elucidate if NPMc(+) collaborates with Meis1 or Hoxa9 in the evolvement of AML. Methods: Murine bone marrow cells were genetically engineered to express mutated NPM1 variant A in combination with overexpression of Meis1 or Hoxa9. The capacity of the transduced cells to transform in vitro and to cause leukemia in vivo was then assessed. Findings and conclusion: There was no synergy between NPMc(+) and Meis1 or Hoxa9 in causing leukemogenic transformation of murine bone marrow cells, or in inducing AML in a transplantation model. Hence, overexpression of Meis1 or Hoxa9 in combination with NPMc(+) expression was not sufficient to generate an NPMc(+) AML mouse model.
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| 41. |
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| 42. |
- Hardling, Mats, et al.
(författare)
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Serial monitoring of BCR-ABL transcripts in chronic myelogenous leukemia (CML) treated with imatinib mesylate
- 2004
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Ingår i: Med Oncol. - 1357-0560. ; 21:4, s. 349-58
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Tidskriftsartikel (refereegranskat)abstract
- Survival among chronic myelogenous leukemia (CML) patients can be linked to the reduction in leukemic cell burden. Treatment with imatinib mesylate results in a high frequency of complete cytogenetic response, which can be further stratified using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). We have serially monitored peripheral blood and bone marrow BCR-ABL transcripts using qRT-PCR in CML patients commencing imatinib therapy, and compared the results with bone marrow cytogenetics. Seventeen patients (aged 25-74 yr) with Philadelphia chromosome positive CML in first chronic phase were treated with imatinib targeting a dose of 400 mg/d. The median follow up is 30 mo (range 9-33 mo). Every third month the product of the BCR-ABL fusion gene was evaluated in both blood and bone marrow specimens by real-time RT-PCR using the TaqMan probe system. In 113 simultaneously obtained blood and bone marrow samples, the BCR-ABL transcript values agreed well with cytogenetic data. Blood and bone marrow specimens gave comparable values for BCR-ABL transcripts. Before start of imatinib therapy there was a considerable variation in BCR-ABL transcripts among the patients, ranging approximately one log (base 10). Similarly, patients with a complete cytogenetic response following imatinib therapy had variable BCR-ABL transcript levels, ranging at least three logs (base 10). The major decline in BCR-ABL transcripts occurred within 6 mo after start of imatinib therapy. The decline in BCR-ABL transcripts, following imatinib therapy, appears to level off at 12-15 mo. Two late responders were identified with a still decreasing level in BCR-ABL transcripts after 24 mo of treatment. It is concluded that BCR-ABL mRNA quantification in peripheral blood is suitable for routine monitoring of the response to treatment and long-term disease status in CML, especially in patients who have achieved a complete cytogenetic response. A plateau in BCR-ABL transcripts seems to have been reached after 12-15 mo of imatinib treatment; however, some "late responders" are seen.
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| 43. |
- Hermansson, Cecilia, et al.
(författare)
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Reduced expression of NLRP3 and MEFV in human ischemic heart tissue.
- 2013
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Ingår i: Biochemical and biophysical research communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 430:1, s. 425-428
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Tidskriftsartikel (refereegranskat)abstract
- The innate immune system and, in particular, activation of the multi-protein complex known as the inflammasome complex are involved in ischemic injury in myocardial cells. The nucleotide-binding leucine-rich repeat-containing pyrin receptor 3 (NLRP3) inflammasome has been linked to inflammation and NLRP3 is especially important for increased inflammation in atherosclerosis, which may lead to myocardial infarction. Here we investigated how inflammasome molecules are affected in human ischemic heart tissue. Surprisingly the important member of the inflammasome complex, NLRP3, displayed markedly decreased levels in human ischemic heart tissue compared with non ischemic control heart tissue. However, subsequent gene analysis revealed mutations in NLRP3 in human ischemic heart tissues but not in non-ischemic control tissue. Gene polymorphisms in the NLRP3 inflammasome have been shown to be associated with increased IL-1β and IL-18 production and severe inflammation. The autoinflammatory disorder familial Mediterranean fever (FMF) is associated with decreased expression of the Mediterranean fever gene (MEFV) and increased inflammation. We also observed reduced expression of MEFV in ischemic versus non-ischemic heart tissue. Further analyses showed a mutation in MEFV in human ischemic heart tissue but not in non-ischemic control tissue. Our data show that defects in the inflammasome and associated proteins may be involved in promoting ischemic heart disease.
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| 44. |
- Heuser, Michael, et al.
(författare)
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Cell of origin in AML: susceptibility to MN1-induced transformation is regulated by the MEIS1/AbdB-like HOX protein complex.
- 2011
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Ingår i: Cancer cell. - : Elsevier BV. - 1878-3686 .- 1535-6108. ; 20:1, s. 39-52
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Tidskriftsartikel (refereegranskat)abstract
- Pathways defining susceptibility of normal cells to oncogenic transformation may be valuable therapeutic targets. We characterized the cell of origin and its critical pathways in MN1-induced leukemias. Common myeloid (CMP) but not granulocyte-macrophage progenitors (GMP) could be transformed by MN1. Complementation studies of CMP-signature genes in GMPs demonstrated that MN1-leukemogenicity required the MEIS1/AbdB-like HOX-protein complex. ChIP-sequencing identified common target genes of MN1 and MEIS1 and demonstrated identical binding sites for a large proportion of their chromatin targets. Transcriptional repression of MEIS1 targets in established MN1 leukemias demonstrated antileukemic activity. As MN1 relies on but cannot activate expression of MEIS1/AbdB-like HOX proteins, transcriptional activity of these genes determines cellular susceptibility to MN1-induced transformation and may represent a promising therapeutic target.
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| 45. |
- Jakobsen Falk, Ingrid, et al.
(författare)
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Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5'-nucleotidase
- 2013
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Ingår i: American Journal of Hematology. - : John Wiley & Sons. - 0361-8609 .- 1096-8652. ; 88:12, s. 1001-1006
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Tidskriftsartikel (refereegranskat)abstract
- De novo acute myeloid leukemia with normal karyotype (NK-AML) comprises a large group of patients with no common cytogenetic alterations and with a large variation in treatment response. Single-nucleotide polymorphisms (SNPs) in genes related to the metabolism of the nucleoside analogue AraC, the backbone in AML treatment, might affect drug sensitivity and treatment outcome. Therefore, SNPs may serve as prognostic biomarkers aiding clinicians in individualized treatment decisions, with the aim of improving patient outcomes. We analyzed polymorphisms in genes encoding cytidine deaminase (CDA 79A>C rs2072671 and −451C>T rs532545), 5′-nucleotidase (cN-II 7A>G rs10883841), and deoxycytidine kinase (DCK 3′UTR 948T>C rs4643786) in 205 de novo NK-AML patients. In FLT3-internal tandem duplication (ITD)-positive patients, the CDA 79C/C and −451T/T genotypes were associated with shorter overall survival compared to other genotypes (5 vs. 24 months, P < 0.001 and 5 vs. 23 months, P = 0.015, respectively), and this was most pronounced in FLT3-ITD-positive/NPM1-positive patients. We observed altered in vitro sensitivity to topoisomerase inhibitory drugs, but not to nucleoside analogues, and a decrease in global DNA methylation in cells carrying both CDA variant alleles. A shorter survival was also observed for the cN-II variant allele, but only in FLT3-ITD-negative patients (25 vs. 31 months, P = 0.075). Our results indicate that polymorphisms in genes related to nucleoside analog drug metabolism may serve as prognostic markers in de novo NK-AML
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| 46. |
- Jakobsen Falk, Ingrid, et al.
(författare)
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Impact of ABCB1 single nucleotide polymorphisms 1236C>T and 2677G>T on overall survival in FLT3 wild-type de novo AML patients with normal karyotype
- 2014
-
Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 167:5, s. 671-680
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Tidskriftsartikel (refereegranskat)abstract
- Drug resistance is a clinically relevant problem in the treatment of acute myeloid leukaemia (AML). We have previously reported a relationship between single nucleotide polymorphisms (SNPs) of ABCB1, encoding the multi-drug transporter P-glycoprotein, and overall survival (OS) in normal karyotype (NK)-AML. Here we extended this material, enabling subgroup analysis based on FLT3 and NPM1 status, to further elucidate the influence of ABCB1 SNPs. De novo NK-AML patients (n = 201) were analysed for 1199G>A, 1236C>T, 2677G>T/A and 3435C>T, and correlations to outcome were investigated. FLT3 wild-type 1236C/C patients have significantly shorter OS compared to patients carrying the variant allele; medians 20 vs. 49 months, respectively, P = 0.017. There was also an inferior outcome in FLT3 wild-type 2677G/G patients compared to patients carrying the variant allele, median OS 20 vs. 35 months, respectively, P = 0.039. This was confirmed in Cox regression analysis. Our results indicate that ABCB1 1236C>T and 2677G>T may be used as prognostic markers to distinguish relatively high risk patients in the intermediate risk FLT3 wild-type group, which may contribute to future individualizing of treatment strategies.
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| 47. |
- Jansson, Jonas, 1973, et al.
(författare)
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On the catalytic activity of Co3O4 in low-temperature CO oxidation
- 2002
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Ingår i: Journal of Catalysis. - : Elsevier BV. - 0021-9517 .- 1090-2694. ; 211:2, s. 387-397
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Tidskriftsartikel (refereegranskat)abstract
- Oxidation of CO over Co3O4 at ambient temperature was studied with flow reactor experiments, and in-situ spectroscopic and structural methods. The catalyst deactivates during the reaction. The rate of deactivation increased with increasing CO or CO2 gas-phase concentration but decreased with increased 02 concentration or increased temperature. Regeneration of the catalyst in 10% O-2/Ar was more efficient than regeneration in Ar alone. The presence of carbonates and surface carbon on the deactivated catalyst was concluded from TPO experiments. None of these species could, however, be correlated with the deactivation of the catalyst. In-situ FTIR showed the presence of surface carbonates, carbonyl, and oxygen species. The change in structure and oxidation state of the catalyst was studied by in-situ XRD, in-situ XANES, XPS, and flow reactor experiments. One possible explanation for the deactivation of the catalyst is a surface reconstruction hindering the redox cycle of the reaction. (C) 2002 Elsevier Science (USA).
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| 48. |
- Johansson, Peter, 1958, et al.
(författare)
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Increased risk for vascular complications in PRV-1 positive patients with essential thrombocythaemia.
- 2003
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Ingår i: British journal of haematology. - 0007-1048. ; 123:3, s. 513-6
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Tidskriftsartikel (refereegranskat)abstract
- Essential thrombocythaemia (ET) is a heterogeneous disorder with respect to plasma erythropoietin concentration at diagnosis and clonality of haematopoiesis. Polycythaemia rubra vera-1 (PRV-1) positivity, i.e. PRV-1 mRNA overexpression, is known to be present in the vast majority of patients with polycythaemia vera and also in some patients with ET. In the present study, PRV-1 expression was quantified by real-time polymerase chain reaction in 70 ET patients; 17 of them (24%) were found to be PRV-1 positive. Ten of the 17 PRV-1 positive ET patients had experienced thromboembolic complications compared with 14 of 53 PRV-1 negative patients, the difference between the two groups being statistically significant (P=0.02). In addition, the frequency of total vascular complications, thromboembolic events and major bleedings, was significantly higher in the group of PRV-1 positive as compared with PRV-1 negative ET patients (P=0.03). The time from diagnosis of ET to the requirement of platelet-lowering therapy was significantly shorter in PRV-1 positive compared with PRV-1 negative ET patients (P=0.014). It can be concluded that PRV-1 positive patients appear to suffer from a more aggressive disorder with increased risk for vascular complications and a greater need for platelet-lowering therapy, compared with PRV-1 negative ET patients.
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| 49. |
- Johansson, Peter, 1958, et al.
(författare)
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The presence of a significant association between elevated PRV-1 mRNA expression and low plasma erythropoietin concentration in essential thrombocythaemia.
- 2003
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Ingår i: European journal of haematology. - 0902-4441. ; 70:6, s. 358-62
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Tidskriftsartikel (refereegranskat)abstract
- Approximately 45% of newly diagnosed patients with essential thrombocythaemia (ET) demonstrate subnormal plasma erythropoietin (EPO) concentrations, which constitutes a risk factor for occlusive vascular events. In 58 ET patients, a possible association between polycythaemia rubra vera-1 (PRV-1) overexpression and subnormal plasma EPO was investigated, which was always measured prior to the institution of platelet lowering agents. At the time when PRV-1 expression was measured, 28 of 58 (48%) ET patients had received platelet lowering treatment. PRV-1 expression was measured by quantitative real-time reverse transcription-polymerase chain reaction assay of mRNA extracted from purified peripheral blood buffy coat. The cycle threshold (CT) value of PRV-1 was determined and was divided with the CT value for the housekeeping GAPDH gene transcript. A quotient <0.93 was defined as PRV-1 positive. Of the ET patients 12 of 58 (21%) were PRV-1 positive and 19 of 58 (33%) demonstrated subnormal plasma EPO. In the 58 ET patients there was a significant association between low plasma EPO and PRV-1 positive results (P = 0.001). The 30 ET patients who had not received any platelet lowering treatment showed a significant (P = 0.005) relation between PRV-1 positivity and subnormal plasma EPO. No such relationship was present in the 28 ET patients who had received prior treatment with the above drugs (P = 0.147).
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- Jones, Dylan T, et al.
(författare)
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Albumin activates the AKT signaling pathway and protects B-chronic lymphocytic leukemia cells from chlorambucil- and radiation-induced apoptosis.
- 2003
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 101:8, s. 3174-80
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Tidskriftsartikel (refereegranskat)abstract
- Activation of the phosphatidylinositol 3- kinase/AKT pathway antagonizes apoptosis in diverse cellular systems. We previously showed that human plasma activated AKT and potently blocked the ability of chlorambucil or gamma radiation to induce apoptosis of B-chronic lymphocytic leukemia (CLL) cells. Here we report experiments that identify albumin as the major component of plasma that blocks CLL cell killing by chlorambucil or radiation. Intact plasma depleted of albumin by chromatography on Cibacron blue-Sepharose or plasma from a subject with analbuminemia failed either to activate AKT or to protect CLL cells from chlorambucil-induced apoptosis. Both functions were restored by re-addition of albumin. The protective action of albumin as well as AKT activation was compromised by the binding of lipids. Fluorescence-activated cell sorter (FACScan) analysis demonstrated the uptake of fluoresceinated albumin by CLL cells. Accumulation of albumin in intracellular vesicles was also shown by confocal microscopy. Indirect inhibition of AKT activation by the phosphatidylinositol 3-kinase inhibitor LY294002 reversed the blockade of chlorambucil-induced killing by plasma albumin. The data suggest that activation of AKT consequent to binding of albumin by CLL cells blocks chlorambucil- and radiation-induced apoptosis. Strategies designed to block albumin-induced antiapoptotic signaling may, therefore, be of value in enhancing cytotoxic drug action on CLL cells.
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