| 1. |
- Ali, Dina, et al.
(author)
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Anti-leukaemic effects induced by APR-246 are dependent on induction of oxidative stress and the NFE2L2/HMOX1 axis that can be targeted by PI3K and mTOR inhibitors in acute myeloid leukaemia cells
- 2016
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In: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 174:1, s. 117-126
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Journal article (peer-reviewed)abstract
- The small molecule APR-246 (PRIMA-1(MET)) is a novel drug that restores the activity of mutated and unfolded TP53 protein. However, the mechanisms of action and potential off-target effects are not fully understood. Gene expression profiling in TP53 mutant KMB3 acute myeloid leukaemia (AML) cells showed that genes which protected cells from oxidative stress to be the most up-regulated. APR-246 exposure also induced reactive oxygen species (ROS) formation and depleted glutathione in AML cells. The genes most up-regulated by APR-246, confirmed by quantitative real time polymerase chain reaction, were heme oxygenase-1 (HMOX1, also termed HO-1), SLC7A11 and RIT1. Up-regulation of HMOX1, a key regulator of cellular response to ROS, was independent of TP53 mutational status. NFE2L2 (also termed Nrf2), a master regulator of HMOX1 expression, showed transcriptional up-regulation and nuclear translocation by APR-246. Down-regulation of NFE2L2 by siRNA in AML cells significantly increased the antitumoural effects of APR-246. The PI3K inhibitor wortmannin and the mTOR inhibitor rapamycin inhibited APR-246-induced nuclear translocation of NFE2L2 and counteracted the protective cellular responses to APR-246, resulting in synergistic cell killing together with APR-246. In conclusion, ROS induction is important for antileukaemic activities of APR-246 and inhibiting the protective response of the Nrf-2/HMOX1 axis using PI3K inhibitors, enhances the antileukaemic effects.
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| 2. |
- Angenendt, Linus, et al.
(author)
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Chromosomal Abnormalities and Prognosis in NPM1-Mutated Acute Myeloid Leukemia : A Pooled Analysis of Individual Patient Data From Nine International Cohorts
- 2019
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In: Journal of Clinical Oncology. - : AMER SOC CLINICAL ONCOLOGY. - 0732-183X .- 1527-7755. ; 37:29, s. 2632-2642
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Journal article (peer-reviewed)abstract
- PURPOSE: Nucleophosmin 1 (NPM1) mutations are associated with a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene (FLT3) is absent (FLT3-ITDneg) or present with a low allelic ratio (FLT3-ITDlow). The 2017 European LeukemiaNet guidelines assume this is true regardless of accompanying cytogenetic abnormalities. We investigated the validity of this assumption.METHODS: We analyzed associations between karyotype and outcome in intensively treated patients with NPM1(mut)/FLT3-ITDneg/low AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers.RESULTS: Among 2,426 patients with NPM1(mut)/FLT3-ITDneg/low AML, 2,000 (82.4%) had a normal and 426 (17.6%) had an abnormal karyotype, including 329 patients (13.6%) with intermediate and 83 patients (3.4%) with adverse-risk chromosomal abnormalities. In patients with NPM1(mut)/FLT3-ITDneg/low AML, adverse cytogenetics were associated with lower complete remission rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; P < .001), inferior 5-year overall (52.4%, 44.8%, 19.5%, respectively; P < .001) and event-free survival (40.6%, 36.0%, 18.1%, respectively; P < .001), and a higher 5-year cumulative incidence of relapse (43.6%, 44.2%, 51.9%, respectively; P = .0012). These associations remained in multivariable mixed-effects regression analyses adjusted for known clinicopathologic risk factors (P < .001 for all end points). In patients with adverse-risk chromosomal aberrations, we found no significant influence of the NPM1 mutational status on outcome.CONCLUSION: Karyotype abnormalities are significantly associated with outcome in NPM1(mut)/FLT3-ITDneg/low AML. When adverse-risk cytogenetics are present, patients with NPM1(mut) share the same unfavorable prognosis as patients with NPM1 wild type and should be classified and treated accordingly. Thus, cytogenetic risk predominates over molecular risk in NPM1(mut)/FLT3-ITDneg/low AML.
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| 3. |
- Berggren, Daniel Moreno, et al.
(author)
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Prognostic scoring systems for myelodysplastic syndromes (MDS) in a population-based setting : a report from the Swedish MDS register
- 2018
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In: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 181:5, s. 614-627
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Journal article (peer-reviewed)abstract
- The myelodysplastic syndromes (MDS) have highly variable outcomes and prognostic scoring systems are important tools for risk assessment and to guide therapeutic decisions. However, few population-based studies have compared the value of the different scoring systems. With data from the nationwide Swedish population-based MDS register we validated the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) and the World Health Organization (WHO) Classification-based Prognostic Scoring System (WPSS). We also present population-based data on incidence, clinical characteristics including detailed cytogenetics and outcome from the register. The study encompassed 1329 patients reported to the register between 2009 and 2013, 14% of these had therapy-related MDS (t-MDS). Based on the MDS register, the yearly crude incidence of MDS in Sweden was 2.9 per 100000 inhabitants. IPSS-R had a significantly better prognostic power than IPSS (P < 0001). There was a trend for better prognostic power of IPSS-R compared to WPSS (P=0.05) and for WPSS compared to IPSS (P=0.07). IPSS-R was superior to both IPSS and WPSS for patients aged <= 70years. Patients with t-MDS had a worse outcome compared to de novo MDS (d-MDS), however, the validity of the prognostic scoring systems was comparable for d-MDS and t-MDS. In conclusion, population-based studies are important to validate prognostic scores in a real-world' setting. In our nationwide cohort, the IPSS-R showed the best predictive power.
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| 4. |
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| 5. |
- Eriksson, Anna, et al.
(author)
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Epigenetic aberrations in acute myeloid leukemia : Early key events during leukemogenesis
- 2015
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In: Experimental Hematology. - : Elsevier BV. - 0301-472X .- 1873-2399. ; 43:8, s. 609-624
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Journal article (peer-reviewed)abstract
- As a result of the introduction of new sequencing technologies, the molecular landscape of acute myeloid leukemia (AML) is rapidly evolving. From karyotyping, which detects only large genomic aberrations of metaphase chromosomes, we have moved into an era when sequencing of each base pair allows us to define the AML genome at highest resolution. This has revealed a new complex landscape of genetic aberrations where addition of mutations in epigenetic regulators has been one of the most important contributions to the understanding of the pathogenesis of AML. These findings, together with new insights into epigenetic mechanisms, have placed dysregulated epigenetic mechanisms at the forefront of AML development. Not only have several new mutations in genes directly involved in epigenetic regulatory mechanisms been discovered, but also previously well-known gene fusions have been found to exert aberrant effects through epigenetic mechanisms. In addition, mutations in epigenetic regulators such as DNMT3A, TET2, and ASXL1 have recently been found to be the earliest known events during AML evolution and to be present as preleukemic lesions before the onset of AML. In this article, we review epigenetic changes in AML also in relation to what is known about their mechanism of action and their prognostic role.
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| 6. |
- Herold, Nikolas, et al.
(author)
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Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies
- 2017
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 23:2, s. 256-263
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Journal article (peer-reviewed)abstract
- The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults'. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP)(2-5), which causes DNA damage through perturbation of DNA synthesis(6). Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment(7-9). Here we demonstrate that the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM domain and HD domain 1 (SAMHD1) promotes the detoxification of intracellular ara-CTP pools. Recombinant SAMHD1 exhibited ara-CTPase activity in vitro, and cells in which SAMHD1 expression was transiently reduced by treatment with the simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive to ara-C-induced cytotoxicity. CRISPR-Cas9-mediated disruption of the gene encoding SAMHD1 sensitized cells to ara-C, and this sensitivity could be abrogated by ectopic expression of wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models of AML lacking SAMHD1 were hypersensitive to ara-C, and treatment ex vivo with Vpx sensitized primary patient derived AML blasts to ara-C. Finally, we identified SAMHD1 as a risk factor in cohorts of both pediatric and adult patients with de novo AML who received ara-C treatment. Thus, SAMHD1 expression levels dictate patient sensitivity to ara-C, providing proof-of-concept that the targeting of SAMHD1 by Vpx could be an attractive therapeutic strategy for potentiating ara-C efficacy in hematological malignancies.
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| 7. |
- Hornung, R, et al.
(author)
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Mediation analysis reveals common mechanisms of RUNX1 point mutations and RUNX1/RUNX1T1 fusions influencing survival of patients with acute myeloid leukemia
- 2018
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 11293-
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Journal article (peer-reviewed)abstract
- Alterations of RUNX1 in acute myeloid leukemia (AML) are associated with either a more favorable outcome in the case of the RUNX1/RUNX1T1 fusion or unfavorable prognosis in the case of point mutations. In this project we aimed to identify genes responsible for the observed differences in outcome that are common to both RUNX1 alterations. Analyzing four AML gene expression data sets (n = 1514), a total of 80 patients with RUNX1/RUNX1T1 and 156 patients with point mutations in RUNX1 were compared. Using the statistical tool of mediation analysis we identified the genes CD109, HOPX, and KIAA0125 as candidates for mediator genes. In an analysis of an independent validation cohort, KIAA0125 again showed a significant influence with respect to the impact of the RUNX1/RUNX1T1 fusion. While there were no significant results for the other two genes in this smaller validation cohort, the observed relations linked with mediation effects (i.e., those between alterations, gene expression and survival) were almost without exception as strong as in the main analysis. Our analysis demonstrates that mediation analysis is a powerful tool in the identification of regulative networks in AML subgroups and could be further used to characterize the influence of genetic alterations.
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| 8. |
- Hulegardh, Erik, et al.
(author)
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Characterization and prognostic features of secondary acute myeloid leukemia in a population-based setting : A report from the Swedish Acute Leukemia Registry
- 2015
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In: American Journal of Hematology. - : Wiley-Blackwell. - 0361-8609 .- 1096-8652. ; 90:3, s. 208-214
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Journal article (peer-reviewed)abstract
- Patients with secondary acute myeloid leukemia (AML) often escape inclusion in clinical trials and thus, population-based studies are crucial for its accurate characterization. In this first large population-based study on secondary AML, we studied AML with an antecedent hematological disease (AHD-AML) or therapy-related AML (t-AML) in the population-based Swedish Acute Leukemia Registry. The study included 3,363 adult patients of which 2,474 (73.6%) had de novo AML, 630 (18.7%) AHD-AML, and 259 (7.7%) t-AML. Secondary AML differed significantly compared to de novo AML with respect to age, gender, and cytogenetic risk. Complete remission (CR) rates were significantly lower but early death rates similar in secondary AML. In a multivariable analysis, AHD-AML (HR 1.51; 95% CI 1.26-1.79) and t-AML (1.72; 1.38-2.15) were independent risk factors for poor survival. The negative impact of AHD-AML and t-AML on survival was highly age dependent with a considerable impact in younger patients, but without independent prognostic value in the elderly. Although patients with secondary leukemia did poorly with intensive treatment, early death rates and survival were significantly worse with palliative treatment. We conclude that secondary AML in a population-based setting has a striking impact on survival in younger AML patients, whereas it lacks prognostic value among the elderly patients. Am. J. Hematol. 90:208-214, 2015.
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| 9. |
- Ilander, M, et al.
(author)
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Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia.
- 2017
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In: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 31:5, s. 1108-1116
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Journal article (peer-reviewed)abstract
- Recent studies suggest that a proportion of chronic myeloid leukemia (CML) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor (TKI) treatment without disease relapse. In this multi-center, prospective clinical trial (EURO-SKI, NCT01596114) we analyzed the function and phenotype of T and NK cells and their relation to successful TKI cessation. Lymphocyte subclasses were measured from 100 imatinib-treated patients at baseline and 1 month after the discontinuation, and functional characterization of NK and T cells was done from 45 patients. The proportion of NK cells was associated with the molecular relapse-free survival as patients with higher than median NK-cell percentage at the time of drug discontinuation had better probability to stay in remission. Similar association was not found with T or B cells or their subsets. In non-relapsing patients the NK-cell phenotype was mature, whereas patients with more naïve CD56(bright) NK cells had decreased relapse-free survival. In addition, the TNF-α/IFN-γ cytokine secretion by NK cells correlated with the successful drug discontinuation. Our results highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents.Leukemia advance online publication, 16 December 2016; doi:10.1038/leu.2016.360.
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| 10. |
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| 11. |
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| 12. |
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| 13. |
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| 14. |
- Khalkar, Prajakta, et al.
(author)
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Selenite and methylseleninic acid epigenetically affects distinct gene sets in myeloid leukemia : A genome wide epigenetic analysis
- 2018
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In: Free Radical Biology & Medicine. - : Elsevier BV. - 0891-5849 .- 1873-4596. ; 117, s. 247-257
-
Journal article (peer-reviewed)abstract
- Selenium compounds have emerged as promising chemotherapeutic agents with proposed epigenetic effects, however the mechanisms and downstream effects are yet to be studied. Here we assessed the effects of the inorganic selenium compound selenite and the organic form methylseleninic acid (MSA) in a leukemic cell line K562, on active (histone H3 lysine 9 acetylation, H3K9ac and histone H3 lysine 4 tri-methylation, H3K4me3) and repressive (histone H3 lysine 9 tri-methylation, H3K9me3) histone marks by Chromatin immunoprecipitation followed by DNA sequencing (ChIP-Seq). Both selenite and MSA had major effects on histone marks but the effects of MSA were more pronounced. Gene ontology analysis revealed that selenite affected genes involved in response to oxygen and hypoxia, whereas MSA affected distinct gene sets associated with cell adhesion and glucocorticoid receptors, also apparent by global gene expression analysis using RNA sequencing. The correlation to adhesion was functionally confirmed by a significantly weakened ability of MSA treated cells to attach to fibronectin and linked to decreased expression of integrin beta 1. A striking loss of cellular adhesion was also confirmed in primary patient AML cells. Recent strategies to enhance the cytotoxicity of chemotherapeutic drugs by disrupting the interaction between leukemic and stromal cells in the bone marrow are of increasing interest; and organic selenium compounds like MSA might be promising candidates. In conclusion, these results provide new insight on the mechanism of action of selenium compounds, and will be of value for the understanding, usage, and development of new selenium compounds as anticancer agents.
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| 15. |
- Lazarevic, Vladimir, et al.
(author)
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Failure matters : unsuccessful cytogenetics and unperformed cytogenetics are associated with a poor prognosis in a population-based series of acute myeloid leukaemia
- 2015
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In: European Journal of Haematology. - Hoboken, USA : Wiley-Blackwell. - 0902-4441 .- 1600-0609. ; 94:5, s. 419-423
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Journal article (peer-reviewed)abstract
- Unsuccessful cytogenetics (UC) in patients with acute myeloid leukaemia (AML) treated on different SWOG trials was recently reported to be associated with increased age and dismal outcome. To ascertain whether this holds true also in unselected patients with AML, we retrieved all cytogenetic reports in cases from the population-based Swedish AML Registry. Between 1997 and 2006, 1737 patients below 80 yr of age without myelosarcoma or acute promyelocytic leukaemia received intensive treatment. The frequencies of UC and unperformed cytogenetics (UPC) were 2.1% and 20%, respectively. The early death rates differed between the cytogenetic subgroups (P = 0.006) with the highest rates in patients with UC (14%) and UPC (12%) followed by high-risk (HR) AML, intermediate risk (IR) and standard risk (SR) cases successfully karyotyped (8.6%, 5.9%, and 5.8%, respectively). The complete remission rate was lower in UC and UPC and HR compared with the other risk groups (P < 0.001). The overall five-year survival rates were 25% for UC and 22% for UPC, whereas the corresponding frequencies for SR, IR and HR AML patients without UC and UPC were 64%, 31% and 15%, respectively. In conclusion, lack of cytogenetic data translates into a poor prognosis.
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| 16. |
- Lehmann, Philipp, et al.
(author)
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Energy and lipid metabolism during direct and diapause development in a pierid butterfly
- 2016
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In: Journal of Experimental Biology. - : The Company of Biologists. - 0022-0949 .- 1477-9145. ; 219:19, s. 3049-3060
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Journal article (peer-reviewed)abstract
- Diapause is a fundamental component of the life-cycle in the majority of insects living in environments characterized by strong seasonality. The present study addresses poorly understood associations and trade-offs between endogenous diapause duration, thermal sensitivity of development, energetic cost of development and cold tolerance. Diapause intensity, metabolic rate trajectories and lipid profiles of directly developing and diapausing animals were studied using pupae and adults of Pieris napi butterflies from a population for which endogenous diapause is well studied. Endogenous diapause was terminated after 3 months and termination required chilling. Metabolic and postdiapause development rates increased with diapause duration, while the metabolic cost of postdiapause development decreased, indicating that once diapause is terminated development proceeds at a low rate even at low temperature. Diapausing pupae had larger lipid stores than the directly developing pupae and lipids constituted the primary energy source during diapause. However, during diapause lipid stores did not decrease. Thus, despite lipid catabolism meeting the low energy costs of the diapausing pupae, primary lipid store utilization did not occur until the onset of growth and metamorphosis in spring. In line with this finding, diapausing pupae contained low amounts of mitochondria-derived cardiolipins, which suggests a low capacity for fatty acid β-oxidation. While ontogenic development had a large effect on lipid and fatty acid profiles, only small changes in these were seen during diapause. The data therefore indicate that the diapause lipidomic phenotype is built early, when pupae are still at high temperature, and retained until diapause post-diapause development.
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| 17. |
- Lehmann, Philipp, et al.
(author)
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Idiosyncratic development of sensory structures in brains of diapausing butterfly pupae : implications for information processing
- 2017
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In: Proceedings of the Royal Society of London. Biological Sciences. - : The Royal Society. - 0962-8452 .- 1471-2954. ; 284:1858
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Journal article (peer-reviewed)abstract
- Diapause is an important escape mechanism from seasonal stress in many insects. A certain minimum amount of time in diapause is generally needed in order for it to terminate. The mechanisms of time-keeping in diapause are poorly understood, but it can be hypothesized that a well-developed neural system is required. However, because neural tissue is metabolically costly to maintain, there might exist conflicting selective pressures on overall brain development during diapause, on the one hand to save energy and on the other hand to provide reliable information processing during diapause. We performed the first ever investigation of neural development during diapause and non-diapause (direct) development in pupae of the butterfly Pieris napi from a population whose diapause duration is known. The brain grew in size similarly in pupae of both pathways up to 3 days after pupation, when development in the diapause brain was arrested. While development in the brain of direct pupae continued steadily after this point, no further development occurred during diapause until temperatures increased far after diapause termination. Interestingly, sensory structures related to vision were remarkably well developed in pupae from both pathways, in contrast with neuropils related to olfaction, which only developed in direct pupae. The results suggest that a well-developed visual system might be important for normal diapause development.
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| 18. |
- Lehmann, Philipp, et al.
(author)
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Metabolome dynamics of diapause in the butterfly Pieris napi: Distinguishing maintenance, termination and post-diapause phases
- 2018
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In: Journal of Experimental Biology. - : The Company of Biologists. - 1477-9145 .- 0022-0949. ; 221:2
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Journal article (peer-reviewed)abstract
- Diapause is a deep resting stage facilitating temporal avoidance of unfavourable environmental conditions, and is used by many insects to adapt their life cycle to seasonal variation. Although considerable work has been invested in trying to understand each of the major diapause stages (induction, maintenance and termination), we know very little about the transitions between stages, especially diapause termination. Understanding diapause termination is crucial for modelling and predicting spring emergence and winter physiology of insects, including many pest insects. In order to gain these insights, we investigated metabolome dynamics across diapause development in pupae of the butterfly Pieris napi, which exhibits adaptive latitudinal variation in the length of endogenous diapause that is uniquely well characterized. By employing a time-series experiment, we show that the whole-body metabolome is highly dynamic throughout diapause and differs between pupae kept at a diapause-terminating (low) temperature and those kept at a diapause-maintaining (high) temperature. We show major physiological transitions through diapause, separate temperature-dependent from temperature-independent processes and identify significant patterns of metabolite accumulation and degradation. Together, the data show that although the general diapause phenotype (suppressed metabolism, increased cold tolerance) is established in a temperature-independent fashion, diapause termination is temperature dependent and requires a cold signal. This revealed several metabolites that are only accumulated under diapause-terminating conditions and degraded in a temperatureunrelated fashion during diapause termination. In conclusion, our findings indicate that some metabolites, in addition to functioning as cryoprotectants, for example, are candidates for having regulatory roles as metabolic clocks or time-keepers during diapause.
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| 19. |
- Lehmann, Philipp, et al.
(author)
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Timing of diapause termination in relation to variation in winter climate
- 2017
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In: Physiological entomology (Print). - : Wiley. - 0307-6962 .- 1365-3032. ; 42:3, s. 232-238
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Journal article (peer-reviewed)abstract
- In temperate insects, winters are typically endured by entering diapause, which comprises a deep resting stage. Correct timing of diapause termination is vital for synchronization of emergence with conspecifics and for mobilizing resources when conditions for growth and reproduction become favourable. Although critical to survival, the intrinsic and extrinsic drivers of diapause termination timing are poorly understood. In the present study, we investigate diapause development under a range of durations (10-24weeks) spent at different temperatures (-2 to 10 degrees C) in the pupal diapausing butterfly Pieris napi Linnaeus (Lepidoptera: Pieridae). We determine: (i) the maximum cold temperature for diapause development; (ii) if pupae in diapause count cold days or cold sums; and (iii) whether diapause termination is distinct or gradual. The results indicate large and idiosyncratic effects of high and low nonlethal temperatures on diapause development in P. napi. Although all temperatures tested lead to diapause termination, a thermal optimum between 2 and 4 degrees C is observed. Lower temperatures lead to decreased eclosion propensity, whereas higher temperatures slow down development and increase emergence desynchronization. These data suggest that, rather than a simple cold-summing process with a distinct diapause termination point, there are trade-offs between time and temperature at the low and high end of the thermal range, resulting in a nonlinear thermal landscape showing a ridge of increasing eclosion propensity at moderate temperatures. The present study suggests that the effects of temperature on diapause development should be included in projections on post-winter phenology models of insects, including pest species.
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| 20. |
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| 21. |
- Liu, Lisa L., et al.
(author)
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Ex Vivo Expanded Adaptive NK Cells Effectively Kill Primary Acute Lymphoblastic Leukemia Cells
- 2017
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In: CANCER IMMUNOLOGY RESEARCH. - 2326-6066 .- 2326-6074. ; 5:8, s. 654-665
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Journal article (peer-reviewed)abstract
- Manipulation of human natural killer (NK) cell repertoires promises more effective strategies for NK cell-based cancer immunotherapy. A subset of highly differentiated NK cells, termed adaptive NK cells, expands naturally in vivo in response to human cytomegalovirus (HCMV) infection, carries unique repertoires of inhibitory killer cell immunoglobulin-like receptors (KIR), and displays strong cytotoxicity against tumor cells. Here, we established a robust and scalable protocol for ex vivo generation and expansion of adaptive NK cells for cell therapy against pediatric acute lymphoblastic leukemia (ALL). Culture of polyclonal NK cells together with feeder cells expressing HLA-E, the ligand for the activating NKG2C receptor, led to selective expansion of adaptive NK cells with enhanced allor-eactivity against HLA-mismatched targets. The ex vivo expanded adaptive NK cells gradually obtained a more differentiated phenotype and were specific and highly efficient killers of allogeneic pediatric T-and precursor B-cell acute lymphoblastic leukemia (ALL) blasts, previously shown to be refractory to killing by autologous NK cells and the NK-cell line NK92 currently in clinical testing. Selective expansion of NK cells that express one single inhibitory KIR for self-HLA class I would allow exploitation of the full potential of NK-cell alloreactivity in cancer immunotherapy. In summary, our data suggest that adaptive NK cells may hold utility for therapy of refractory ALL, either as a bridge to transplant or for patients that lack stem cell donors.
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| 22. |
- Lj Lazarevic, Vladimir, et al.
(author)
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Incidence and prognostic significance of isolated trisomies in adult acute myeloid leukemia : A population-based study from the Swedish AML registry
- 2017
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In: European Journal of Haematology. - : John Wiley & Sons. - 0902-4441 .- 1600-0609. ; 98:5, s. 493-500
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Journal article (peer-reviewed)abstract
- OBJECTIVES AND METHODS: To ascertain the incidence/clinical implications of isolated autosomal trisomies in adult acute myeloid leukemia (AML), all such cases were retrieved from the Swedish AML Registry.RESULTS: Of the 3179 cytogenetically informative AMLs diagnosed January 1997-May 2015, 246 (7.7%) had isolated trisomies. The frequency increased by age (2.4% at age 18-60 years vs. 23% at >60 years; P<.0001); the median age was 69 years. The five most common were +8 (4.0%), +13 (0.9%), +11 (0.8%), +21 (0.7%), and +4 (0.5%). Age and gender, types of AML and treatment, and complete remission and early death rates did not differ between the single trisomy and the intermediate risk (IR) groups or among cases with isolated gains of chromosomes 4, 8, 11, 13, or 21. The overall survival (OS) was similar in the single trisomy (median 1.6 years) and IR groups (1.7 years; P=.251). The OS differed among the most frequent isolated trisomies; the median OS was 2.5 years for +4, 1.9 years for +21, 1.5 years for +8, 1.1 years for +11, and 0.8 years for +13 (P=.013).CONCLUSION: AML with single trisomies, with the exception of +13, should be grouped as IR.
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| 23. |
- Mer, Arvind Singh, et al.
(author)
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Expression levels of long non-coding RNAs are prognostic for AML outcome
- 2018
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In: Journal of Hematology & Oncology. - : BIOMED CENTRAL LTD. - 1756-8722. ; 11
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Journal article (peer-reviewed)abstract
- Background: Long non-coding RNA (lncRNA) expression has been implicated in a range of molecular mechanisms that are central in cancer. However, lncRNA expression has not yet been comprehensively characterized in acute myeloid leukemia (AML). Here, we assess to what extent lncRNA expression is prognostic of AML patient overall survival (OS) and determine if there are indications of lncRNA-based molecular subtypes of AML. Methods: We performed RNA sequencing of 274 intensively treated AML patients in a Swedish cohort and quantified lncRNA expression. Univariate and multivariate time-to-event analysis was applied to determine association between individual lncRNAs with OS. Unsupervised statistical learning was applied to ascertain if lncRNA-based molecular subtypes exist and are prognostic. Results: Thirty-three individual lncRNAs were found to be associated with OS (adjusted p value < 0.05). We established four distinct molecular subtypes based on lncRNA expression using a consensus clustering approach. LncRNA-based subtypes were found to stratify patients into groups with prognostic information (p value < 0.05). Subsequently, lncRNA expression-based subtypes were validated in an independent patient cohort (TCGA-AML). LncRNA subtypes could not be directly explained by any of the recurrent cytogenetic or mutational aberrations, although associations with some of the established genetic and clinical factors were found, including mutations in NPM1, TP53, and FLT3. Conclusion: LncRNA expression-based four subtypes, discovered in this study, are reproducible and can effectively stratify AML patients. LncRNA expression profiling can provide valuable information for improved risk stratification of AML patients.
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| 24. |
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| 25. |
- Nilsson, Christer, et al.
(author)
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Secondary Acute Myeloid Leukemia and the Role of Allogeneic Stem Cell Transplantation in a Population-Based Setting
- 2019
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In: Biology of blood and marrow transplantation. - : Elsevier. - 1083-8791 .- 1523-6536. ; 25:9, s. 1770-1778
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Journal article (peer-reviewed)abstract
- Secondary AML (s-AML), including AML with an antecedent hematologic disorder (AHD-AML) and therapy-related AML (t-AML), constitutes a large proportion of patients with AML and is considered to confer a dismal prognosis. The role of allogeneic hematopoietic cell transplantation (HCT) in patients with s-AML and the extent to which HCT is performed in these patients has been little studied to date. We used the population-based Swedish AML Registry comprising 3337 intensively treated adult patients over a 17-year period to study the role of HCT within the group of patients with s-AML as well as compared with patients with de novo AML. HCT was performed in 576 patients (22%) with de novo AML, in 74 patients (17%) with AHD-AML, and in 57 patients (20%) with t-AML. At 5 years after diagnosis, there were no survivors among patients with previous myeloproliferative neoplasms who did not undergo HCT, and corresponding survival for patients with antecedent myelodysplastic syndromes and t-AML was and 2% and 4%, respectively. HCT was compared with chemotherapy consolidation in s-AML using 3 models: (1) a 200-day landmark analysis, in which HCT was favorable compared with conventional consolidation (P = .04, log-rank test); (2) a multivariable Cox regression with HCT as a time-dependent variable, in which the hazard ratio for mortality was 0.73 (95% confidence interval, 0.64 to 0.83) for HCT and favored HCT in all subgroups; and (3) a propensity score matching analysis, in which the 5-year overall survival (OS) and relapse-free survival in patients with s-AML in first complete remission (CR1) was 48% and 43%, respectively, for patients undergoing HCT versus 20% and 21%, respectively, for those receiving chemotherapy consolidation (P = .01 and .02, respectively, log-rank test). Our observational data suggest that HCT improves survival and offers the only realistic curative treatment option in patients with s-AML.
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| 26. |
- Qu, Ying, et al.
(author)
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Cancer specific changes in DNA methylation reveal aberrant silencing and activation of enhancers in leukemia
- 2017
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 129:7, s. e13-e25
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Journal article (peer-reviewed)abstract
- Acute myeloid leukemia (AML) is characterized by an impaired differentiation process leading to an accumulation of immature blasts in the blood. One feature of cytogenetically normal AML is alterations to the DNA methylome. Here we have analyzed 57 AML patients with normal karyotype using Illuminas 450 k array and show that aberrant DNA methylation is significantly altered at enhancer regions and that the methylation levels at specific enhancers predict overall survival of AML patients. The majority of sites that become differentially methylated in AML occur in regulatory elements of the human genome. Hypermethylation associates with enhancer silencing. In addition, ChIP-seq analyses showed that a subset of hypomethylated sites correlate with enhancer activation, indicated by increased H3K27 acetylation. DNA hypomethylation is not therefore sufficient for enhancer activation. Some sites of hypomethylation occur at weak / poised enhancers marked with H3K4 monomethylation in hematopoietic progenitor cells. Other hypomethylated regions occur at sites inactive in progenitors and reflect the de novo acquisition of AML specific enhancers. Altered enhancer dynamics are reflected in the gene expression of enhancer target genes including genes involved in oncogenesis and blood cell development. This study demonstrates that histone variants and different histone modifications interact with aberrant DNA methylation, causing perturbed enhancer activity in CN-AML that contributes to a leukemic transcriptome.
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| 27. |
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| 28. |
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| 29. |
- Tobiasson, Magnus, et al.
(author)
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Comprehensive mapping of the effects of azacitidine on DNA methylation, repressive/permissive histone marks and gene expression in primary cells from patients with MDS and MDS-related disease
- 2017
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In: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:17, s. 28812-28825
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Journal article (peer-reviewed)abstract
- Azacitidine (Aza) is first-line treatment for patients with high-risk myelodysplastic syndromes (MDS), although its precise mechanism of action is unknown. We performed the first study to globally evaluate the epigenetic effects of Aza on MDS bone marrow progenitor cells assessing gene expression (RNA seq), DNA methylation (Illumina 450k) and the histone modifications H3K18ac and H3K9me3 (ChIP seq). Aza induced a general increase in gene expression with 924 significantly upregulated genes but this increase showed no correlation with changes in DNA methylation or H3K18ac, and only a weak association with changes in H3K9me3. Interestingly, we observed activation of transcripts containing 15 endogenous retroviruses (ERVs) confirming previous cell line studies. DNA methylation decreased moderately in 99% of all genes, with a median beta-value reduction of 0.018; the most pronounced effects seen in heterochromatin. Aza-induced hypomethylation correlated significantly with change in H3K9me3. The pattern of H3K18ac and H3K9me3 displayed large differences between patients and healthy controls without any consistent pattern induced by Aza. We conclude that the marked induction of gene expression only partly could be explained by epigenetic changes, and propose that activation of ERVs may contribute to the clinical effects of Aza in MDS.
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| 30. |
- Wang, Mei, et al.
(author)
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Development and Validation of a Novel RNA Sequencing-Based Prognostic Score for Acute Myeloid Leukemia
- 2018
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In: Journal of the National Cancer Institute. - : OXFORD UNIV PRESS INC. - 0027-8874 .- 1460-2105. ; 110:10, s. 1094-1101
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Journal article (peer-reviewed)abstract
- Background: Recent progress in sequencing technologies allows us to explore comprehensive genomic and transcriptomic information to improve the current European LeukemiaNet (ELN) system of acute myeloid leukemia (AML).Methods: We compared the prognostic value of traditional demographic and cytogenetic risk factors, genomic data in the form of somatic aberrations of 25 AML-relevant genes, and whole-transcriptome expression profiling (RNA sequencing) in 267 intensively treated AML patients (Clinseq-AML). Multivariable penalized Cox models (overall survival [OS]) were developed for each data modality (clinical, genomic, transcriptomic), together with an associated prognostic risk score.Results: Of the three data modalities, transcriptomic data provided the best prognostic value, with an integrated area under the curve (iAUC) of a time-dependent receiver operating characteristic (ROC) curve of 0.73. We developed a prognostic risk score (Clinseq-G) from transcriptomic data, which was validated in the independent The Cancer Genome Atlas AML cohort (RNA sequencing, n = 142, iAUC = 0.73, comparing the high-risk group with the low-risk group, hazard ratio [HR] OS = 2.42, 95% confidence interval [CI] = 1.51 to 3.88). Comparison between Clinseq-G and ELN score iAUC estimates indicated strong evidence in favor of the Clinseq-G model (Bayes factor = 26.78). The proposed model remained statistically significant in multivariable analysis including the ELN and other well-known risk factors (HRos = 2.34, 95% CI = 1.30 to 4.22). We further validated the Clinseq-G model in a second independent data set (n = 458, iAUC = 0.66, adjusted HROS = 2.02, 95% CI = 1.33 to 3.08; adjusted HREFS = 2.10, 95% CI = 1.42 to 3.12).Conclusions: Our results indicate that the Clinseq-G prediction model, based on transcriptomic data from RNA sequencing, outperforms traditional clinical parameters and previously reported models based on genomic biomarkers.
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| 31. |
- Wang, M., et al.
(author)
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Validation of risk stratification models in acute myeloid leukemia using sequencing-based molecular profiling
- 2017
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In: Leukemia. - : NATURE PUBLISHING GROUP. - 0887-6924 .- 1476-5551. ; 31:10, s. 2029-2036
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Journal article (peer-reviewed)abstract
- Risk stratification of acute myeloid leukemia (AML) patients needs improvement. Several AML risk classification models based on somatic mutations or gene-expression profiling have been proposed. However, systematic and independent validation of these models is required for future clinical implementation. We performed whole-transcriptome RNA-sequencing and panel-based deep DNA sequencing of 23 genes in 274 intensively treated AML patients (Clinseq-AML). We also utilized the The Cancer Genome Atlas (TCGA)-AML study (N = 142) as a second validation cohort. We evaluated six previously proposed molecular-based models for AML risk stratification and two revised risk classification systems combining molecular-and clinical data. Risk groups stratified by five out of six models showed different overall survival in cytogenetic normal-AML patients in the Clinseq-AML cohort (P-value < 0.05; concordance index > 40.5). Risk classification systems integrating mutational or gene-expression data were found to add prognostic value to the current European Leukemia Net (ELN) risk classification. The prognostic value varied between models and across cohorts, highlighting the importance of independent validation to establish evidence of efficacy and general applicability. All but one model replicated in the Clinseq-AML cohort, indicating the potential for molecular-based AML risk models. Risk classification based on a combination of molecular and clinical data holds promise for improved AML patient stratification in the future.
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