Induction of myelodysplasia by myeloid-derived suppressor cells.
Xianghong Chen,Erika A. Eksioglu,Junmin Zhou,Ling Zhang,Julie Y. Djeu,Nicole Fortenbery,Pearlie K. Epling-Burnette,Sandra van Bijnen,Harry Dolstra,John P. Cannon,Je-In Youn,Sarah S. Donatelli,Dahui Qin,Theo de Witte,Jianguo Tao,Huaquan Wang,Pingyan Cheng,Dmitry I. Gabrilovich,Alan F. List,Sheng Wei +19 more
TLDR
It is reported that myeloid-derived suppressor cells (MDSC), which are classically linked to immunosuppression, inflammation, and cancer, were markedly expanded in the bone marrow of MDS patients and played a pathogenetic role in the development of ineffective hematopoiesis.Abstract:
Myelodysplastic syndromes (MDS) are age-dependent stem cell malignancies that share biological features of activated adaptive immune response and ineffective hematopoiesis. Here we report that myeloid-derived suppressor cells (MDSC), which are classically linked to immunosuppression, inflammation, and cancer, were markedly expanded in the bone marrow of MDS patients and played a pathogenetic role in the development of ineffective hematopoiesis. These clonally distinct MDSC overproduce hematopoietic suppressive cytokines and function as potent apoptotic effectors targeting autologous hematopoietic progenitors. Using multiple transfected cell models, we found that MDSC expansion is driven by the interaction of the proinflammatory molecule S100A9 with CD33. These 2 proteins formed a functional ligand/receptor pair that recruited components to CD33’s immunoreceptor tyrosine-based inhibition motif (ITIM), inducing secretion of the suppressive cytokines IL-10 and TGF-β by immature myeloid cells. S100A9 transgenic mice displayed bone marrow accumulation of MDSC accompanied by development of progressive multilineage cytopenias and cytological dysplasia. Importantly, early forced maturation of MDSC by either all-trans-retinoic acid treatment or active immunoreceptor tyrosine-based activation motif–bearing (ITAM-bearing) adapter protein (DAP12) interruption of CD33 signaling rescued the hematologic phenotype. These findings indicate that primary bone marrow expansion of MDSC driven by the S100A9/CD33 pathway perturbs hematopoiesis and contributes to the development of MDS.read more
Citations
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Elevated Calprotectin and Abnormal Myeloid Cell Subsets Discriminate Severe from Mild COVID-19.
Aymeric Silvin,Nicolas Chapuis,Garett Dunsmore,Anne-Gaëlle Goubet,Agathe Dubuisson,Lisa Derosa,Carole Almire,Clémence Hénon,Olivier Kosmider,Nathalie Droin,Philippe Rameau,Cyril Catelain,Alexia Alfaro,Charles Dussiau,Chloé Friedrich,Elise Sourdeau,Nathalie Marin,T.-A. Szwebel,Delphine Cantin,Luc Mouthon,Didier Borderie,Marc Deloger,Delphine Bredel,Severine Mouraud,Damien Drubay,Muriel Andrieu,Anne-Sophie Lhonneur,Véronique Saada,Annabelle Stoclin,Christophe Willekens,Fanny Pommeret,Frank Griscelli,Lai Guan Ng,Zheng Zhang,Pierre Bost,Pierre Bost,Ido Amit,Fabrice Barlesi,Aurélien Marabelle,Frédéric Pène,Bertrand Gachot,Fabrice Andre,Fabrice Andre,Laurence Zitvogel,Laurence Zitvogel,Laurence Zitvogel,Florent Ginhoux,Florent Ginhoux,Florent Ginhoux,Michaela Fontenay,Eric Solary,Eric Solary +51 more
TL;DR: It is shown that calprotectin plasma level and a routine flow cytometry assay detecting decreased frequencies of non-classical monocytes could discriminate patients who develop a severe COVID-19 form, suggesting a predictive value that deserves prospective evaluation.
Journal ArticleDOI
Mesenchymal Inflammation Drives Genotoxic Stress in Hematopoietic Stem Cells and Predicts Disease Evolution in Human Pre-leukemia.
Noemi A. Zambetti,Zhen Ping,Si Chen,Keane Jared Guillaume Kenswil,Maria Athina Mylona,Mathijs A. Sanders,Remco Hoogenboezem,Eric Bindels,Maria Niken Adisty,Paulina M. H. van Strien,Cindy S. van der Leije,Theresia M. Westers,Eline M. P. Cremers,Chiara Milanese,Pier G. Mastroberardino,Johannes P.T.M. van Leeuwen,Bram C. J. van der Eerden,Ivo P. Touw,Taco W. Kuijpers,Roland Kanaar,Arjan A. van de Loosdrecht,Thomas Vogl,Marc H.G.P. Raaijmakers +22 more
TL;DR: P perturbation of mesenchymal cells in a mouse model of the pre-leukemic disorder Shwachman-Diamond syndrome induces mitochondrial dysfunction, oxidative stress, and activation of DNA damage responses in hematopoietic stem and progenitor cells.
Journal ArticleDOI
The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype
Ashley A. Basiorka,Kathy L. McGraw,Erika A. Eksioglu,Xianghong Chen,Joseph O. Johnson,Ling Zhang,Qing Zhang,Brittany A. Irvine,Thomas Cluzeau,David A. Sallman,Eric Padron,Rami S. Komrokji,Lubomir Sokol,Rebecca C. Coll,Avril A. B. Robertson,Mark E. Cooper,John L. Cleveland,Luke A. J. O'Neill,Sheng Wei,Alan F. List +19 more
TL;DR: Alarmins and founder gene mutations in MDSs license a common redox-sensitive inflammasome circuit, which suggests new avenues for therapeutic intervention.
Journal ArticleDOI
CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets.
Michelle K. Gleason,Julie A. Ross,Erica D. Warlick,Troy C. Lund,Michael R. Verneris,Andres Wiernik,Stephen R. Spellman,Michael Haagenson,Alexander J. Lenvik,Mark R. Litzow,Pearlie K. Epling-Burnette,Bruce R. Blazar,Louis M. Weiner,Daniel J. Weisdorf,Daniel A. Vallera,Jeffrey S. Miller +15 more
TL;DR: The data suggest that the CD16xCD33 BiKE functions against both CD33(+) MDS and MDSC targets and may be therapeutically beneficial for MDS patients.
Journal ArticleDOI
Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9
Rebekka K. Schneider,Rebekka K. Schneider,Monica Schenone,Mónica S. Ventura Ferreira,Rafael Kramann,Cailin E. Joyce,Christina R. Hartigan,Fabian Beier,Tim H. Brümmendorf,Ulrich Germing,Uwe Platzbecker,Guntram Büsche,Ruth Knüchel,Michelle C. Chen,Christopher S Waters,Edwin Chen,Lisa P. Chu,Carl D. Novina,R. Coleman Lindsley,R. Coleman Lindsley,Steven A. Carr,Benjamin L. Ebert,Benjamin L. Ebert +22 more
TL;DR: The data link Rps14 haploinsufficiency in del(5q) MDS to activation of the innate immune system and induction of S100A8-S100A9 expression, leading to a p53-dependent erythroid differentiation defect.
References
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Myeloid-derived suppressor cells as regulators of the immune system.
TL;DR: The origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit are discussed.
Journal ArticleDOI
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TL;DR: The characterization and suppressive mechanisms used by myeloid-derived suppressor cells to block tumor immunity are reviewed and the mechanisms by which inflammation promotes tumor progression through the induction of MDSC are described.
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TL;DR: The postulated functions of the recently discovered CD33-related Siglecs are discussed and the factors that seem to be driving their rapid evolution are considered.
Journal ArticleDOI
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TL;DR: A phenotypical and functional analysis of several surface molecules previously suggested to be involved in MDSC-mediated suppression of T cells indicate that suppressive features of M DSC is caused not by expansion of a specific subset but more likely represent a functional state of these cells.
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