24 results on '"van de Loosdrecht, Arjan A."'
Search Results
2. Reduced frequencies and functional impairment of dendritic cell subsets and non-classical monocytes in myelodysplastic syndromes
- Author
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Van Leeuwen-Kerkhoff, Nathalie, primary, Westers, Theresia M., additional, Poddighe, Pino J., additional, Povoleri, Giovanni A.M., additional, Timms, Jessica A., additional, Kordasti, Shahram, additional, De Gruijl, Tanja D., additional, and Van de Loosdrecht, Arjan A., additional
- Published
- 2021
- Full Text
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3. Novel dynamic outcome indicators and clinical endpoints in myelodysplastic syndrome; the European LeukemiaNet MDS Registry and MDS-RIGHT project perspective
- Author
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De Witte, Theo, primary, Malcovati, Luca, additional, Fenaux, Pierre, additional, Bowen, David, additional, Symeonidis, Argiris, additional, Mittelman, Moshe, additional, Stauder, Reinhard, additional, Sanz, Guillermo, additional, Čermák, Jaroslav, additional, Langemeijer, Saskia, additional, Hellström-Lindberg, Eva, additional, Germing, Ulrich, additional, Skov Holm, Mette, additional, Mądry, Krzysztof, additional, Tatic, Aurelia, additional, Medina Almeida, António, additional, Savic, Aleksandar, additional, Mandac Rogulj, Inga, additional, Itzykson, Raphael, additional, Hoeks, Marlijn, additional, Gravdahl Garelius, Hege, additional, Culligan, Dominic, additional, Kotsianidis, Ioannis, additional, Ades, Lionel, additional, Van de Loosdrecht, Arjan A., additional, Van Marrewijk, Corine, additional, Yu, Ge, additional, Crouch, Simon, additional, and Smith, Alex, additional
- Published
- 2020
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4. Thrombomodulin-expressing monocytes are associated with low-risk features in myelodysplastic syndromes and dampen excessive immune activation
- Author
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van Leeuwen-Kerkhoff, Nathalie, primary, Westers, Theresia M., additional, Poddighe, Pino J., additional, de Gruijl, Tanja D., additional, Kordasti, Shahram, additional, and van de Loosdrecht, Arjan A., additional
- Published
- 2019
- Full Text
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5. Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions
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Valent, Peter, primary, Orazi, Attilio, additional, Savona, Michael R., additional, Patnaik, Mrinal M., additional, Onida, Francesco, additional, van de Loosdrecht, Arjan A., additional, Haase, Detlef, additional, Haferlach, Torsten, additional, Elena, Chiara, additional, Pleyer, Lisa, additional, Kern, Wolfgang, additional, Pemovska, Tea, additional, Vladimer, Gregory I., additional, Schanz, Julie, additional, Keller, Alexandra, additional, Lübbert, Michael, additional, Lion, Thomas, additional, Sotlar, Karl, additional, Reiter, Andreas, additional, De Witte, Theo, additional, Pfeilstöcker, Michael, additional, Geissler, Klaus, additional, Padron, Eric, additional, Deininger, Michael, additional, Orfao, Alberto, additional, Horny, Hans-Peter, additional, Greenberg, Peter L., additional, Arber, Daniel A., additional, Malcovati, Luca, additional, and Bennett, John M., additional
- Published
- 2019
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6. The non-erythroid myeloblast count rule in myelodysplastic syndromes: fruitful or futile?
- Author
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van Spronsen, Margot F., primary, Westers, Theresia M., additional, Lissenberg-Witte, Birgit I., additional, Wondergem, Mariëlle, additional, Ossenkoppele, Gert J., additional, and van de Loosdrecht, Arjan A., additional
- Published
- 2019
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7. Labile plasma iron levels predict survival in patients with lower-risk myelodysplastic syndromes
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de Swart, Louise, primary, Reiniers, Chloé, additional, Bagguley, Timothy, additional, van Marrewijk, Corine, additional, Bowen, David, additional, Hellström-Lindberg, Eva, additional, Tatic, Aurelia, additional, Symeonidis, Argiris, additional, Huls, Gerwin, additional, Cermak, Jaroslav, additional, van de Loosdrecht, Arjan A., additional, Garelius, Hege, additional, Culligan, Dominic, additional, Macheta, Mac, additional, Spanoudakis, Michail, additional, Panagiotidis, Panagiotis, additional, Krejci, Marta, additional, Blijlevens, Nicole, additional, Langemeijer, Saskia, additional, Droste, Jackie, additional, Swinkels, Dorine W., additional, Smith, Alex, additional, and de Witte, Theo, additional
- Published
- 2017
- Full Text
- View/download PDF
8. Immunophenotypic analysis of erythroid dysplasia in myelodysplastic syndromes. A report from the IMDSFlow working group
- Author
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Westers, Theresia M., primary, Cremers, Eline M.P., additional, Oelschlaegel, Uta, additional, Johansson, Ulrika, additional, Bettelheim, Peter, additional, Matarraz, Sergio, additional, Orfao, Alberto, additional, Moshaver, Bijan, additional, Brodersen, Lisa Eidenschink, additional, Loken, Michael R., additional, Wells, Denise A., additional, Subirá, Dolores, additional, Cullen, Matthew, additional, te Marvelde, Jeroen G., additional, van der Velden, Vincent H.J., additional, Preijers, Frank W.M.B., additional, Chu, Sung-Chao, additional, Feuillard, Jean, additional, Guérin, Estelle, additional, Psarra, Katherina, additional, Porwit, Anna, additional, Saft, Leonie, additional, Ireland, Robin, additional, Milne, Timothy, additional, Béné, Marie C., additional, Witte, Birgit I., additional, Della Porta, Matteo G., additional, Kern, Wolfgang, additional, and van de Loosdrecht, Arjan A., additional
- Published
- 2016
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9. Implementation of erythroid lineage analysis by flow cytometry in diagnostic models for myelodysplastic syndromes
- Author
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Cremers, Eline M.P., primary, Westers, Theresia M., additional, Alhan, Canan, additional, Cali, Claudia, additional, Visser-Wisselaar, Heleen A., additional, Chitu, Dana A., additional, van der Velden, Vincent H.J., additional, te Marvelde, Jeroen G., additional, Klein, Saskia K., additional, Muus, Petra, additional, Vellenga, Edo, additional, de Greef, Georgina E., additional, Legdeur, Marie-Cecile C.J.C., additional, Wijermans, Pierre W., additional, Stevens-Kroef, Marian J.P.L., additional, Silva-Coelho, Pedro da, additional, Jansen, Joop H., additional, Ossenkoppele, Gert J., additional, and van de Loosdrecht, Arjan A., additional
- Published
- 2016
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10. Expression levels of genes implicated in the working mechanism of lenalidomide predict treatment response in lower risk myelodysplastic syndrome patients.
- Author
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In 't Hout FEM, Scheele TN, Westers TM, Alhan C, Duetz C, Cremers EMP, Visser-Wisselaar HA, Verbrugge A, Chitu DA, Van der Reijden BA, De Graaf AO, Van de Loosdrecht AA, and Jansen JH
- Abstract
Not available.
- Published
- 2024
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11. Reduced frequencies and functional impairment of dendritic cell subsets and non-classical monocytes in myelodysplastic syndromes.
- Author
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Van Leeuwen-Kerkhoff N, Westers TM, Poddighe PJ, Povoleri GAM, Timms JA, Kordasti S, De Gruijl TD, and Van de Loosdrecht AA
- Subjects
- Bone Marrow pathology, Dendritic Cells, Humans, Lymphocyte Activation, Monocytes, Myelodysplastic Syndromes pathology
- Abstract
In myelodysplastic syndromes (MDS) the immune system is involved in pathogenesis as well as in disease progression. Dendritic cells (DC) are key players of the immune system by serving as regulators of immune responses. Their function has been scarcely studied in MDS and most of the reported studies didn't investigate naturally occurring DC subsets. Therefore, we here examined the frequency and function of DC subsets and slan+ non-classical monocytes in various MDS risk groups. Frequencies of DC as well as of slan+ monocytes were decreased in MDS bone marrow compared to normal bone marrow samples. Transcriptional profiling revealed down-regulation of transcripts related to pro-inflammatory pathways in MDS-derived cells as compared to normal bone marrow. Additionally, their capacity to induce T-cell proliferation was impaired. Multidimensional mass cytometry showed that whereas healthy donor-derived slan+ monocytes supported Th1/Th17/Treg differentiation/expansion their MDS-derived counterparts also mediated substantial Th2 expansion. Our findings point to a role for an impaired ability of DC subsets to adequately respond to cellular stress and DNA damage in the immune escape and progression of MDS. As such, it paves the way toward potential novel immunotherapeutic interventions.
- Published
- 2022
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12. Thrombomodulin-expressing monocytes are associated with low-risk features in myelodysplastic syndromes and dampen excessive immune activation.
- Author
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van Leeuwen-Kerkhoff N, Westers TM, Poddighe PJ, de Gruijl TD, Kordasti S, and van de Loosdrecht AA
- Subjects
- Bone Marrow, Disease Progression, Humans, Thrombomodulin genetics, Monocytes, Myelodysplastic Syndromes
- Abstract
The bone marrow of patients with low-risk myelodysplastic syndromes (MDS) is often an inflammatory environment and associated with an active cellular immune response. An active immune response generally contributes to antitumor responses and may prevent disease progression. However, chronic immune stimulation can also induce cell stress, DNA damage and contribute to the pathogenesis of MDS. The protective mechanisms against excessive immune activation are therefore an important aspect of the pathophysiology of MDS and characterizing them may help us to better understand the fine balance between protective and destabilizing inflammation in lower-risk disease. In this study we investigated the role of thrombomodulin (CD141/BDCA-3) expression, a molecule with anti-inflammatory properties, on monocytes in the bone marrow and peripheral blood of MDS patients in different risk groups. Patient-derived classical monocytes showed high expression levels of thrombomodulin, whereas monocytes from healthy donors hardly expressed any thrombomodulin. The presence of thrombomodulin on monocytes from MDS patients correlated with lower-risk disease groups and better overall and leukemia-free survival. Using multidimensional mass cytometry, in an in-vitro setting, we showed that thrombomodulin-positive monocytes could polarize naïve T cells toward cell clusters which are closer to T helper type 2 and T regulatory cell phenotypes and less likely to contribute to effective immune surveillance. In conclusion, the expression of thrombomodulin on classical monocytes is a favorable and early prognostic marker in patients with low-risk MDS and may represent a new mechanism in the protection against disproportionate immune activation., (Copyright© 2020 Ferrata Storti Foundation.)
- Published
- 2020
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13. Labile plasma iron levels predict survival in patients with lower-risk myelodysplastic syndromes.
- Author
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de Swart L, Reiniers C, Bagguley T, van Marrewijk C, Bowen D, Hellström-Lindberg E, Tatic A, Symeonidis A, Huls G, Cermak J, van de Loosdrecht AA, Garelius H, Culligan D, Macheta M, Spanoudakis M, Panagiotidis P, Krejci M, Blijlevens N, Langemeijer S, Droste J, Swinkels DW, Smith A, and de Witte T
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Blood Transfusion methods, Erythropoietin therapeutic use, Female, Humans, Iron Overload etiology, Iron Overload metabolism, Male, Middle Aged, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes therapy, Prognosis, Proportional Hazards Models, Iron metabolism, Myelodysplastic Syndromes blood, Myelodysplastic Syndromes mortality
- Abstract
Red blood cell transfusions remain one of the cornerstones in supportive care of lower-risk patients with myelodysplastic syndromes. We hypothesized that patients develop oxidant-mediated tissue injury through the formation of toxic iron species, caused either by red blood cell transfusions or by ineffective erythropoiesis. We analyzed serum samples from 100 lower-risk patients with myelodysplastic syndromes at six-month intervals for transferrin saturation, hepcidin-25, growth differentiation factor 15, soluble transferrin receptor, non-transferrin bound iron and labile plasma iron in order to evaluate temporal changes in iron metabolism and the presence of potentially toxic iron species and their impact on survival. Hepcidin levels were low in 34 patients with ringed sideroblasts compared to 66 patients without. Increases of hepcidin and non-transferrin bound iron levels were visible early in follow-up of all transfusion-dependent patient groups. Hepcidin levels significantly decreased over time in transfusion-independent patients with ringed sideroblasts. Increased soluble transferrin receptor levels in transfusion-independent patients with ringed sideroblasts confirmed the presence of ineffective erythropoiesis and suppression of hepcidin production in these patients. Detectable labile plasma iron levels in combination with high transferrin saturation levels occurred almost exclusively in patients with ringed sideroblasts and all transfusion-dependent patient groups. Detectable labile plasma iron levels in transfusion-dependent patients without ringed sideroblasts were associated with decreased survival. In conclusion, toxic iron species occurred in all transfusion-dependent patients and in transfusion-independent patients with ringed sideroblasts. Labile plasma iron appeared to be a clinically relevant measure for potential iron toxicity and a prognostic factor for survival in transfusion-dependent patients. clinicaltrials.gov Identifier: 00600860., (Copyright© 2018 Ferrata Storti Foundation.)
- Published
- 2018
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14. Implementation of erythroid lineage analysis by flow cytometry in diagnostic models for myelodysplastic syndromes.
- Author
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Cremers EM, Westers TM, Alhan C, Cali C, Visser-Wisselaar HA, Chitu DA, van der Velden VH, Te Marvelde JG, Klein SK, Muus P, Vellenga E, de Greef GE, Legdeur MC, Wijermans PW, Stevens-Kroef MJ, Silva-Coelho PD, Jansen JH, Ossenkoppele GJ, and van de Loosdrecht AA
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Case-Control Studies, Female, Humans, Immunophenotyping, Male, Middle Aged, Cell Lineage, Erythroid Cells metabolism, Flow Cytometry, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes metabolism
- Abstract
Flow cytometric analysis is a recommended tool in the diagnosis of myelodysplastic syndromes. Current flow cytometric approaches evaluate the (im)mature myelo-/monocytic lineage with a median sensitivity and specificity of ~71% and ~93%, respectively. We hypothesized that the addition of erythroid lineage analysis could increase the sensitivity of flow cytometry. Hereto, we validated the analysis of erythroid lineage parameters recommended by the International/European LeukemiaNet Working Group for Flow Cytometry in Myelodysplastic Syndromes, and incorporated this evaluation in currently applied flow cytometric models. One hundred and sixty-seven bone marrow aspirates were analyzed; 106 patients with myelodysplastic syndromes, and 61 cytopenic controls. There was a strong correlation between presence of erythroid aberrancies assessed by flow cytometry and the diagnosis of myelodysplastic syndromes when validating the previously described erythroid evaluation. Furthermore, addition of erythroid aberrancies to two different flow cytometric models led to an increased sensitivity in detecting myelodysplastic syndromes: from 74% to 86% for the addition to the diagnostic score designed by Ogata and colleagues, and from 69% to 80% for the addition to the integrated flow cytometric score for myelodysplastic syndromes, designed by our group. In both models the specificity was unaffected. The high sensitivity and specificity of flow cytometry in the detection of myelodysplastic syndromes illustrates the important value of flow cytometry in a standardized diagnostic approach. The trial is registered at www.trialregister.nl as NTR1825; EudraCT n.: 2008-002195-10., (Copyright© Ferrata Storti Foundation.)
- Published
- 2017
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15. Immunophenotypic analysis of erythroid dysplasia in myelodysplastic syndromes. A report from the IMDSFlow working group.
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Westers TM, Cremers EM, Oelschlaegel U, Johansson U, Bettelheim P, Matarraz S, Orfao A, Moshaver B, Brodersen LE, Loken MR, Wells DA, Subirá D, Cullen M, Te Marvelde JG, van der Velden VH, Preijers FW, Chu SC, Feuillard J, Guérin E, Psarra K, Porwit A, Saft L, Ireland R, Milne T, Béné MC, Witte BI, Della Porta MG, Kern W, and van de Loosdrecht AA
- Subjects
- Adult, Age Factors, Aged, Aged, 80 and over, Biomarkers, Bone Marrow Cells metabolism, Case-Control Studies, Female, Flow Cytometry, Humans, Immunophenotyping, Male, Middle Aged, Young Adult, Erythroid Cells metabolism, Erythroid Cells pathology, Myelodysplastic Syndromes metabolism, Myelodysplastic Syndromes pathology
- Abstract
Current recommendations for diagnosing myelodysplastic syndromes endorse flow cytometry as an informative tool. Most flow cytometry protocols focus on the analysis of progenitor cells and the evaluation of the maturing myelomonocytic lineage. However, one of the most frequently observed features of myelodysplastic syndromes is anemia, which may be associated with dyserythropoiesis. Therefore, analysis of changes in flow cytometry features of nucleated erythroid cells may complement current flow cytometry tools. The multicenter study within the IMDSFlow Working Group, reported herein, focused on defining flow cytometry parameters that enable discrimination of dyserythropoiesis associated with myelodysplastic syndromes from non-clonal cytopenias. Data from a learning cohort were compared between myelodysplasia and controls, and results were validated in a separate cohort. The learning cohort comprised 245 myelodysplasia cases, 290 pathological, and 142 normal controls; the validation cohort comprised 129 myelodysplasia cases, 153 pathological, and 49 normal controls. Multivariate logistic regression analysis performed in the learning cohort revealed that analysis of expression of CD36 and CD71 (expressed as coefficient of variation), in combination with CD71 fluorescence intensity and the percentage of CD117
+ erythroid progenitors provided the best discrimination between myelodysplastic syndromes and non-clonal cytopenias (specificity 90%; 95% confidence interval: 84-94%). The high specificity of this marker set was confirmed in the validation cohort (92%; 95% confidence interval: 86-97%). This erythroid flow cytometry marker combination may improve the evaluation of cytopenic cases with suspected myelodysplasia, particularly when combined with flow cytometry assessment of the myelomonocytic lineage., (Copyright© Ferrata Storti Foundation.)- Published
- 2017
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16. Risk factors for relapse after allogeneic transplantation in acute myeloid leukemia.
- Author
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Ossenkoppele GJ, Janssen JJ, and van de Loosdrecht AA
- Subjects
- Allografts, Autografts, Disease-Free Survival, Europe epidemiology, Humans, Recurrence, Remission Induction, Risk Factors, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy, Stem Cell Transplantation
- Abstract
Acute myeloid leukemia is a clonal neoplasm derived from myeloid progenitor cells with a varying outcome. The initial goal of treatment is the achievement of complete remission, defined for over 40 years by morphology. However, without additional post-remission treatment the majority of patients relapse. In many cases of acute myeloid leukemia, allogeneic stem cell transplantation offers the best prospects of cure. In 2013, 5608 stem cell transplantations in acute myeloid leukemia were performed in Europe (5228 allogeneic and 380 autologous stem cell transplantations). Most stem cell transplantations are performed in first complete remission. However, despite a considerable reduction in the chance of relapse, in most studies, overall survival benefit of allogeneic stem cell transplantation is modest due to substantial non-relapse mortality. Here we discuss the many factors related to the risk of relapse after allogeneic stem cell transplantation., (Copyright© Ferrata Storti Foundation.)
- Published
- 2016
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17. Regulatory T cells and progenitor B cells are independent prognostic predictors in lower risk myelodysplastic syndromes.
- Author
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Kahn JD, Chamuleau ME, Westers TM, Van de Ven PM, van Dreunen L, van Spronsen M, Ossenkoppele GJ, and van de Loosdrecht AA
- Subjects
- Adult, Aged, Aged, 80 and over, Disease-Free Survival, Female, Follow-Up Studies, Humans, Male, Middle Aged, Predictive Value of Tests, Prognosis, Prospective Studies, Risk Factors, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes immunology, Precursor Cells, B-Lymphoid immunology, T-Lymphocytes, Regulatory immunology
- Published
- 2015
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18. Myelodysplastic syndromes with a deletion 5q display a characteristic immunophenotypic profile suitable for diagnostics and response monitoring.
- Author
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Oelschlaegel U, Westers TM, Mohr B, Kramer M, Parmentier S, Sockel K, Thiede C, Bornhäuser M, Ehninger G, van de Loosdrecht AA, and Platzbecker U
- Subjects
- Antigens, CD genetics, Antigens, CD immunology, Bone Marrow drug effects, Bone Marrow immunology, Bone Marrow pathology, Cohort Studies, Drug Monitoring, Female, Gene Expression, Humans, Immunophenotyping, Lenalidomide, Lymphocytes drug effects, Lymphocytes immunology, Lymphocytes pathology, Male, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes immunology, Myeloid Cells drug effects, Myeloid Cells immunology, Myeloid Cells pathology, Thalidomide therapeutic use, Chromosome Deletion, Chromosomes, Human, Pair 5, Immunologic Factors therapeutic use, Myelodysplastic Syndromes drug therapy, Thalidomide analogs & derivatives
- Published
- 2015
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19. Multicenter validation of a reproducible flow cytometric score for the diagnosis of low-grade myelodysplastic syndromes: results of a European LeukemiaNET study.
- Author
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Della Porta MG, Picone C, Pascutto C, Malcovati L, Tamura H, Handa H, Czader M, Freeman S, Vyas P, Porwit A, Saft L, Westers TM, Alhan C, Cali C, van de Loosdrecht AA, and Ogata K
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Bone Marrow Cells metabolism, Female, Humans, Immunophenotyping, Male, Middle Aged, Myelodysplastic Syndromes pathology, Neoplasm Grading, Reproducibility of Results, Retrospective Studies, Sensitivity and Specificity, Young Adult, Flow Cytometry, Myelodysplastic Syndromes diagnosis
- Abstract
Background: The current World Health Organization classification of myelodysplastic syndromes is based morphological evaluation of bone marrow dysplasia. In clinical practice, the reproducibility of the recognition of dysplasia is usually poor especially in cases that lack specific markers such as ring sideroblasts and clonal cytogenetic abnormalities., Design and Methods: We aimed to develop and validate a flow cytometric score for the diagnosis of myelodysplastic syndrome. Four reproducible parameters were analyzed: CD34(+) myeloblast-related and B-progenitor-related cluster size (defined by CD45 expression and side scatter characteristics CD34(+) marrow cells), myeloblast CD45 expression and granulocyte side scatter value. The study comprised a "learning cohort" (n=538) to define the score and a "validation cohort" (n=259) to confirm its diagnostic value., Results: With respect to non-clonal cytopenias, patients with myelodysplastic syndrome had increased myeloblast-related cluster size, decreased B-progenitor-related cluster size, aberrant CD45 expression and reduced granulocyte side scatter (P<0.001). To define the flow cytometric score, these four parameters were combined in a regression model and the weight for each variable was estimated based on coefficients from that model. In the learning cohort a correct diagnosis of myelodysplastic syndrome was formulated in 198/281 cases (sensitivity 70%), while 18 false-positive results were noted among 257 controls (specificity 93%). Sixty-five percent of patients without specific markers of dysplasia (ring sideroblasts and clonal cytogenetic abnormalities) were correctly classified. A high value of the flow cytometric score was associated with multilineage dysplasia (P=0.001), transfusion dependency (P=0.02), and poor-risk cytogenetics (P=0.04). The sensitivity and specificity in the validation cohort (69% and 92%, respectively) were comparable to those in the learning cohort. The likelihood ratio of the flow cytometric score was 10., Conclusions: A flow cytometric score may help to establish the diagnosis of myelodysplastic syndrome, especially when morphology and cytogenetics are indeterminate.
- Published
- 2012
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20. Class II-associated invariant chain peptide down-modulation enhances the immunogenicity of myeloid leukemic blasts resulting in increased CD4+ T-cell responses.
- Author
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van Luijn MM, Chamuleau ME, Thompson JA, Ostrand-Rosenberg S, Westers TM, Souwer Y, Ossenkoppele GJ, van Ham SM, and van de Loosdrecht AA
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antigen Presentation, Antigens, Differentiation, B-Lymphocyte chemistry, Antigens, Differentiation, B-Lymphocyte genetics, Blast Crisis, Female, Histocompatibility Antigens Class II chemistry, Histocompatibility Antigens Class II genetics, Humans, Leukemia, Myeloid, Acute pathology, Lymphocyte Activation, Male, Middle Aged, Prognosis, RNA, Small Interfering pharmacology, Tumor Cells, Cultured, Young Adult, Antigens, Differentiation, B-Lymphocyte metabolism, CD4-Positive T-Lymphocytes immunology, HLA-DR Antigens immunology, Histocompatibility Antigens Class II metabolism, Leukemia, Myeloid, Acute immunology
- Abstract
Background: Disease recurrence in patients with acute myeloid leukemia may be partially explained by the escape of leukemic blasts from CD4(+) T-cell recognition. The current study investigates the role of aberrant HLA class II antigen presentation on leukemic blasts by determining both the clinical and functional impact of the class II-associated invariant chain peptide (CLIP)., Design and Methods: The levels of expression of CLIP and HLA-DR on blood and bone marrow samples from 207 patients with acute myeloid leukemia were correlated with clinical outcome. Irradiated CLIP(-) and CLIP(+) leukemic blasts were compared for their ability to induce CD4(+) T cells during mixed leukocyte reactions. To discriminate between these blasts, we down-modulated CLIP expression on myeloid leukemic cell lines by RNA interference of the invariant chain, a chaperone protein critically involved in HLA-DR processing, and performed flow cytometric sorting for their isolation from primary acute myeloid leukemia samples., Results: We found that patients with leukemic blasts characterized by a high amount of HLA-DR occupied by CLIP (relative amount of CLIP) had a significantly shortened disease-free survival. The clear reductions in amount of HLA-DR occupied by CLIP on blasts of the THP-1 and Kasumi-1 myeloid leukemic cell lines after treatment with invariant chain short interfering RNA resulted in enhanced rates of allogeneic CD4(+) T-cell proliferation. Similar findings were obtained in an autologous setting, in which there were strong increases in proliferation of remission CD4(+) T cells stimulated with CLIP(-)-sorted leukemic blasts from HLA-DR(+) acute myeloid leukemia patients, in contrast to CLIP(+)-sorted leukemic blasts from the same patients., Conclusions: These data highlight the relevance of CLIP expression on leukemic blasts and the potential of CLIP as a target for immunomodulatory strategies to enhance HLA class II antigen presentation and CD4(+) T-cell reactivity in acute myeloid leukemia.
- Published
- 2010
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21. Standardization of flow cytometry in myelodysplastic syndromes: report from the first European LeukemiaNet working conference on flow cytometry in myelodysplastic syndromes.
- Author
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van de Loosdrecht AA, Alhan C, Béné MC, Della Porta MG, Dräger AM, Feuillard J, Font P, Germing U, Haase D, Homburg CH, Ireland R, Jansen JH, Kern W, Malcovati L, Te Marvelde JG, Mufti GJ, Ogata K, Orfao A, Ossenkoppele GJ, Porwit A, Preijers FW, Richards SJ, Schuurhuis GJ, Subirá D, Valent P, van der Velden VH, Vyas P, Westra AH, de Witte TM, Wells DA, Loken MR, and Westers TM
- Subjects
- Antigens, CD immunology, Flow Cytometry standards, Humans, Immunophenotyping methods, Myelodysplastic Syndromes immunology, Reference Standards, Flow Cytometry methods, Myelodysplastic Syndromes diagnosis
- Abstract
The myelodysplastic syndromes are a group of clonal hematopoietic stem cell diseases characterized by cytopenia(s), dysplasia in one or more cell lineages and increased risk of evolution to acute myeloid leukemia (AML). Recent advances in immunophenotyping of hematopoietic progenitor and maturing cells in dysplastic bone marrow point to a useful role for multiparameter flow cytometry (FCM) in the diagnosis and prognostication of myelodysplastic syndromes. In March 2008, representatives from 18 European institutes participated in a European LeukemiaNet (ELN) workshop held in Amsterdam as a first step towards standardization of FCM in myelodysplastic syndromes. Consensus was reached regarding standard methods for cell sampling, handling and processing. The group also defined minimal combinations of antibodies to analyze aberrant immunophenotypes and thus dysplasia. Examples are altered numbers of CD34(+) precursors, aberrant expression of markers on myeloblasts, maturing myeloid cells, monocytes or erythroid precursors and the expression of lineage infidelity markers. When applied in practice, aberrant FCM patterns correlate well with morphology, the subclassification of myelodysplastic syndromes, and prognostic scoring systems. However, the group also concluded that despite strong evidence for an impact of FCM in myelodysplastic syndromes, further (prospective) validation of markers and immunophenotypic patterns are required against control patient groups as well as further standardization in multi-center studies. Standardization of FCM in myelodysplastic syndromes may thus contribute to improved diagnosis and prognostication of myelodysplastic syndromes in the future.
- Published
- 2009
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22. Immune mediated autologous cytotoxicity against hematopoietic precursor cells in patients with myelodysplastic syndrome.
- Author
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Chamuleau ME, Westers TM, van Dreunen L, Groenland J, Zevenbergen A, Eeltink CM, Ossenkoppele GJ, and van de Loosdrecht AA
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Immunity, Innate, Immunologic Surveillance, Male, Middle Aged, T-Lymphocytes immunology, Autoimmunity, Cytotoxicity, Immunologic immunology, Hematopoietic Stem Cells immunology, Myelodysplastic Syndromes immunology
- Abstract
Background: An activated immune system has been observed in patients with myelodysplastic syndrome but its exact contribution to disease development and control is not fully clarified. On the one hand an activated and skewed T-cell repertoire has been reported, but on the other hand, decreased natural killer cell function has been found. Immune activation could reflect undesired autoimmune reactions against normal hematopoietic precursor cells as well as effective immune-surveillance against dysplastic clones., Design and Methods: We have investigated immune effector cells (lymphocyte subsets, lymphocyte activation markers, and natural killer cells) of 40 low and intermediate risk myelodysplastic syndrome patients and compared them to those of 10 age-matched healthy donors. Furthermore, we have analyzed the cytotoxic capacity of effector cells against autologous bone marrow hematopoietic precursor cells of 8 myelodysplastic syndrome patients and 2 healthy donors., Results: In myelodysplastic syndrome patients, we have found an activated state of lymphocytes, determined by increased percentages of effector T cells with cytotoxic profile, more skewing of the T-cell receptor Vbeta (TCR-Vbeta) repertoire, and decreased frequencies of regulatory T cells, when compared to healthy donors. The percentage of natural killer cells did not differ between myelodysplastic syndrome patients and healthy donors, but natural killer cells of myelodysplastic syndrome patients expressed increased levels of granzyme B. Finally, we have demonstrated non-MHC restricted autologous cytotoxicity up to 90% against aberrant hematopoietic precursor cells, presumably mediated by natural killer cells., Conclusions: Our data point to a role for active immune-surveillance in myelodysplastic syndrome, as demonstrated by activated T cells and TCR-Vss skewing. Autologous cytotoxicity against hematopoietic precursor cells was natural killer cell dependent, which points to an additional role for the innate immune system in immune-surveillance of myelodysplastic syndrome patients.
- Published
- 2009
- Full Text
- View/download PDF
23. High INDO (indoleamine 2,3-dioxygenase) mRNA level in blasts of acute myeloid leukemic patients predicts poor clinical outcome.
- Author
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Chamuleau ME, van de Loosdrecht AA, Hess CJ, Janssen JJ, Zevenbergen A, Delwel R, Valk PJ, Löwenberg B, and Ossenkoppele GJ
- Subjects
- Adolescent, Adult, Aged, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Middle Aged, Prognosis, RNA, Messenger analysis, RNA, Neoplasm analysis, Young Adult, Indoleamine-Pyrrole 2,3,-Dioxygenase genetics, Leukemia, Myeloid, Acute pathology, Predictive Value of Tests
- Abstract
Indoleamine 2,3-dioxygenase degrades the amino acid tryptophan which is essential for T cells. Tryptophan depletion causes T-cell cycle arrest and solid tumors that express high levels of indoleamine 2,3-dioxygenase can create immune suppression. Recently, blasts of patients with acute myeloid leukemia were shown to express indoleamine 2,3-dioxygenase. We determined INDO (encoding gene for indoleamine 2,3-dioxygenase) mRNA expression in leukemic blasts of 286 patients with acute myeloid leukemia by gene-expression profiling. Results were validated by quantitative polymerase chain reaction analysis in blasts of an independent cohort of 71 patients. High INDO expression was correlated to significantly shortened overall and relapse-free survival. Correlation of INDO expression to relevant known prognostic factors and survival identified high INDO expression as a strong negative independent predicting variable for overall and relapse-free survival. Inhibition of indoleamine 2,3-dioxygenase expressed by myeloid leukemic blasts may result in breaking immune tolerance and offers new therapeutic options for patients with acute myeloid leukemia.
- Published
- 2008
- Full Text
- View/download PDF
24. Leukemia-derived dendritic cells: towards clinical vaccination protocols in acute myeloid leukemia.
- Author
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Houtenbos I, Westers TM, Ossenkoppele GJ, and van de Loosdrecht AA
- Subjects
- Cancer Vaccines administration & dosage, Humans, Cancer Vaccines therapeutic use, Dendritic Cells immunology, Dendritic Cells transplantation, Leukemia, Myeloid, Acute immunology, Leukemia, Myeloid, Acute prevention & control
- Abstract
The ability of acute myeloid leukemic (AML) blasts to differentiate into leukemic dendritic cells (DC) thus acquiring the potential to present known and unknown leukemic antigens efficiently, holds promise as a possible new treatment for AML patients with minimal residual disease. Recent advances in culture methods have made the clinical use of leukemic DC feasible. However, additional measures appear to be essential in order to potentiate vaccines and to overcome the intrinsic tolerant state of the patients immune system. This review describes ways to improve AML-DC vaccines and discusses critical aspects concerning the development of clinical vaccination protocols.
- Published
- 2006
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