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- Lyberg, Katarina, et al.
(author)
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Histone deacetylase inhibitor SAHA mediates mast cell death and epigenetic silencing of constitutively active D816V KIT in systemic mastocytosis.
- 2017
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In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:6, s. 9647-9659
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Journal article (peer-reviewed)abstract
- Systemic mastocytosis (SM) is a clonal bone marrow disorder, where therapeutical options are limited. Over 90% of the patients carry the D816V point mutation in the KIT receptor that renders this receptor constitutively active. We assessed the sensitivity of primary mast cells (MC) and mast cell lines HMC1.2 (D816V mutated), ROSA (KIT WT) and ROSA (KIT D816V) cells to histone deacetylase inhibitor (HDACi) treatment. We found that of four HDACi, suberoyl anilide hydroxamic acid (SAHA) was the most effective in killing mutated MC. SAHA downregulated KIT, followed by major MC apoptosis. Primary SM patient MC cultured ex vivo were even more sensitive to SAHA than HMC1.2 cells, whereas primary MC from healthy subjects were less affected. There was a correlation between cell death and SM disease severity, where cell death was more pronounced in the case of aggressive SM, with almost 100% cell death among MC from the mast cell leukemia patient. Additionally, ROSA (KIT D816V) was more affected by HDACi than ROSA (KIT WT) cells. Using ChIP qPCR, we found that the level of active chromatin mark H3K18ac/H3 decreased significantly in the KIT region. This epigenetic silencing was seen only in the KIT region and not in control genes upstream and downstream of KIT, indicating that the downregulation of KIT is exerted by specific epigenetic silencing. In conclusion, KIT D816V mutation sensitized MC to HDACi mediated killing, and SAHA may be of value as specific treatment for SM, although the specific mechanism of action requires further investigation.
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| 2. |
- Moreno Berggren, Daniel, et al.
(author)
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Prognostic scoring systems and comorbidities in chronic myelomonocytic leukaemia : a nationwide population-based study
- 2021
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In: British Journal of Haematology. - : John Wiley & Sons. - 0007-1048 .- 1365-2141. ; 192:3, s. 474-483
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Journal article (peer-reviewed)abstract
- Outcomes in chronic myelomonocytic leukaemia (CMML) are highly variable and may be affected by comorbidity. Therefore, prognostic models and comorbidity indices are important tools to estimate survival and to guide clinicians in individualising treatment. In this nationwide population-based study, we assess comorbidities and for the first time validate comorbidity indices in CMML. We also compare the prognostic power of: the revised International Prognostic Scoring System (IPSS-R), CMML-specific prognostic scoring system (CPSS), MD Anderson Prognostic Scoring System (MDAPS) and Mayo score. In this cohort of 337 patients with CMML, diagnosed between 2009 and 2015, the median overall survival was 21 center dot 3 months. Autoimmune conditions were present in 25% of the patients, with polymyalgia rheumatica and Hashimoto's thyroiditis being most common. Of the tested comorbidity indices: the Charlson Comorbidity Index (CCI), Haematopoietic cell transplantation-specific Comorbidity Index (HCT-CI) and Myelodysplastic Syndrome-Specific Comorbidity Index (MDS-CI), CCI had the highest C-index (0 center dot 62) and was the only comorbidity index independently associated with survival in multivariable analyses. When comparing the prognostic power of the scoring systems, the CPSS had the highest C-index (0 center dot 69). In conclusion, using 'real-world' data we found that the CCI and CPSS have the best prognostic power and that autoimmune conditions are overrepresented in CMML.
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| 3. |
- Söderlund, Stina, et al.
(author)
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Proteomic and transcriptomic screening demonstrates increased mast cell-derived CCL23 in systemic mastocytosis
- 2023
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In: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 152:1, s. 205-213
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Journal article (peer-reviewed)abstract
- Background: Systemic mastocytosis (SM) is a heterogeneous group of mast cell-driven diseases diagnosed by bone marrow sampling. However, there are a limited number of available blood disease biomarkers.Objective: Our aim was to identify mast cell-derived proteins that could potentially serve as blood biomarkers for indolent and advanced forms of SM. Methods: We performed a plasma proteomics screening coupled with single-cell transcriptomic analysis in SM patients and healthy subjects.Results: Plasma proteomics screening identified 19 proteins upregulated in indolent disease compared to healthy, and 16 proteins in advanced disease compared to indolent. Among these, 5 proteins, CCL19, CCL23, CXCL13, IL-10, and IL12Rb1, were higher in indolent relative to healthy and in advanced disease compared to indolent. Single-cell RNA sequencing demonstrated that CCL23, IL-10, and IL-6 were selectively produced by mast cells. Notably, plasma CCL23 levels correlated positively with known markers of SM disease severity, namely tryptase levels, percentage bone marrow mast cell infiltration, and IL-6.Conclusion: CCL23 is produced predominantly by mast cells in SM, and CCL23 plasma levels are associated with disease severity, correlating positively with established markers of disease burden, thus suggesting that CCL23 is a specific SM biomarker. In addition, the combination of CCL19, CCL23, CXCL13, IL-10, and IL-12Rb1 may be useful for defining disease stage. (J Allergy Clin Immunol 2023;152:205-13.)
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