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- Creignou, Maria, et al.
(författare)
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Early transfusion patterns improve the Molecular International Prognostic Scoring System (IPSS-M) prediction in myelodysplastic syndromes
- 2024
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Ingår i: Journal of Internal Medicine. - : WILEY. - 0954-6820 .- 1365-2796.
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Tidskriftsartikel (refereegranskat)abstract
- Background The Molecular International Prognostic Scoring System (IPSS-M) is the new gold standard for diagnostic outcome prediction in patients with myelodysplastic syndromes (MDS). This study was designed to assess the additive prognostic impact of dynamic transfusion parameters during early follow-up. Methods We retrieved complete transfusion data from 677 adult Swedish MDS patients included in the IPSS-M cohort. Time-dependent erythrocyte transfusion dependency (E-TD) was added to IPSS-M features and analyzed regarding overall survival and leukemic transformation (acute myeloid leukemia). A multistate Markov model was applied to assess the prognostic value of early changes in transfusion patterns. Results Specific clinical and genetic features were predicted for diagnostic and time-dependent transfusion patterns. Importantly, transfusion state both at diagnosis and within the first year strongly predicts outcomes in both lower (LR) and higher-risk (HR) MDSs. In multivariable analysis, 8-month landmark E-TD predicted shorter survival independently of IPSS-M (p < 0.001). A predictive model based on IPSS-M and 8-month landmark E-TD performed significantly better than a model including only IPSS-M. Similar trends were observed in an independent validation cohort (n = 218). Early transfusion patterns impacted both future transfusion requirements and outcomes in a multistate Markov model. Conclusion The transfusion requirement is a robust and available clinical parameter incorporating the effects of first-line management. In MDS, it provides dynamic risk information independently of diagnostic IPSS-M and, in particular, clinical guidance to LR MDS patients eligible for potentially curative therapeutic intervention.
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| 2. |
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| 3. |
- Dolinska, Monika, et al.
(författare)
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Characterization of Bone Marrow Niche in Chronic Myeloid Leukemia Patients Identifies CXCL14 as a New Therapeutic Option
- 2023
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 142:1, s. 73-89
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Tidskriftsartikel (refereegranskat)abstract
- Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long-term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.
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| 4. |
- Dolinska, Monika, et al.
(författare)
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Characterization of the bone marrow niche in patients with chronic myeloid leukemia identifies CXCL14 as a new therapeutic option
- 2023
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 142:1, s. 73-89
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Tidskriftsartikel (refereegranskat)abstract
- Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long -term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.
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| 7. |
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| 8. |
- Tobiasson, Magnus
(författare)
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Clinical and molecular effects of azacitidine in the myelodysplastic syndromes
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The myelodysplastic syndromes (MDS) constitute a heterogeneous group of malignant bone marrow disorders characterized by peripheral cytopenia and increased risk of leukemic progression. In higher-risk MDS, Azacitidine has been shown to prolong survival and modulate the epigenome, although the precise mechanisms by which the drug exerts its effect are unknown. Paper I reports the result from a Nordic study enrolling 30 transfusion-dependent Epo-refractory lower-risk MDS patients. Patients were treated with 6 cycles of Azacitidine and terminated the study if they reached transfusion independence, while non-responding patients received another 3 cycles combined with Epo. Five (21%) and one patient responded after Azacitidine and the combined treatment, respectively, and only 2 patients (10%) responded for more than 6 months. Toxicity was substantial, mainly consisting of infections. We conclude that Azacitidine can be effective in this cohort of patients but that the low response rate and relatively high toxicity precludes its recommendation as standard treatment. Targeted sequencing revealed a high frequency of recurrent MDS mutations without clear relation to response. In paper II we cultured CD34+ progenitors from higher-risk MDS and normal bone marrow (NBM) with or without Azacitidine and studied the effects on DNA methylation and histone acetylation. We showed that the MDS genome at the global level is hypermethylated compared to NBM and that Azacitidine induced profound demethylation. Histone acetylation was decreased by treatment, which theoretically would counteract the transcriptional activation resulting from reduced DNA methylation. To further explore these effects, we repeated the same culture experiment in paper IV to study the effects of Azacitidine on both DNA methylation and gene expression. We confirmed the marked demethylating effect of Azacitidine, and by using RNA seq we could show that Azacitidine significantly increases gene expression but without association with demethylated regions. Interestingly, the repressive histone mark H3K9me3 increased in three demethylated genes without increased expression, providing a potential explanation for the lack of association between demethylation and increased expression. In paper III we searched for factors associated with response to Azacitidine by studying clinical parameters (n=134); mutations (n=90); and DNA methylation (n=42) in patients treated with Azacitidine. Among the clinical variables, only disease duration before treatment predicted for poor response and survival. The group of mutations involved in histone modulation (ASXL1, EZH2, MLL) was associated with prolonged survival, contrasting previous reports on mixed MDS cohorts. Furthermore, DNA methylation profiles differed significantly between responding and non-responding patients. Analysis of 200 differentially methylated regions showed enrichment in pathways involved in differentiation and development. Methylation level of the most significant DMR, the HOXA5/A6-locus, was associated with survival. To summarize, these studies show that epigenetic modifications play a significant role in the pathogenesis and response to treatment in MDS and that further understanding of chromatin modifications will be important in order to develop therapeutic strategies in MDS.
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| 9. |
- Tobiasson, Magnus, et al.
(författare)
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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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Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:17, s. 28812-28825
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Tidskriftsartikel (refereegranskat)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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| 10. |
- Tobiasson, Magnus, et al.
(författare)
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High prevalence of restless legs syndrome among patients with polycytemia vera treated with venesectio
- 2010
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Ingår i: Medical Oncology. - : Springer Science and Business Media LLC. - 1357-0560 .- 1559-131X. ; 27:1, s. 105-107
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Tidskriftsartikel (refereegranskat)abstract
- In order to examine whether symptoms of iron deficiency anemia are due to the iron deficiency itself or the associated anemia, 34 patients with polycytemia vera (PV) treated with venesectio, who had iron deficiency but normal hemoglobin (Hb) levels, were given a questionnaire covering symptoms of iron deficiency including the international RLS-scale and the Fact-fatigue quality of life scale (QoL). We found a prevalence of pica of 11.7%, mouth paresthesias of 5.8% and rest-less legs 29.6% (RLS "normal" prevalence 10%). Thus, the prevalence of RLS is significantly higher in our population. We also saw a significant difference in QoL between patients with and without RLS (P = 0.015) and QoL correlated with the severity of RLS (R = 0.85). In conclusion, RLS seems to be a frequent and serious problem for PV patients treated with venesectio according to standard guidelines.
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