Inflammatory profile of lower risk myelodysplastic syndromes.
MDS
NLRP3 inflammasome
cytokines
inflammation
Journal
British journal of haematology
ISSN: 1365-2141
Titre abrégé: Br J Haematol
Pays: England
ID NLM: 0372544
Informations de publication
Date de publication:
21 May 2024
21 May 2024
Historique:
received:
22
12
2023
accepted:
06
05
2024
medline:
22
5
2024
pubmed:
22
5
2024
entrez:
21
5
2024
Statut:
aheadofprint
Résumé
The precise link between inflammation and pathogenesis of myelodysplastic syndrome (MDS) is yet to be fully established. We developed a novel method to measure ASC/NLRP3 protein specks which are specific for the NLRP3 inflammasome only. We combined this with cytokine profiling to characterise various inflammatory markers in a large cohort of patients with lower risk MDS in comparison to healthy controls and patients with defined autoinflammatory disorders (AIDs). The ASC/NLRP3 specks were significantly elevated in MDS patients compared to healthy controls (p < 0.001) and these levels were comparable to those found in patients with AIDs. The distribution of protein specks positive only for ASC was different to ASC/NLRP3 ones suggesting that other ASC-containing inflammasome complexes might be important in the pathogenesis of MDS. Patients with MDS-SLD had the lowest levels of interleukin (IL)-1β, tumour necrosis factor (TNF), IL-23, IL-33, interferon (IFN) γ and IFN-α2, compared to other diagnostic categories. We also found that inflammatory cytokine TNF was positively associated with MDS progression to a more aggressive form of disease and IL-6 and IL-1β with time to first red blood cell transfusion. Our study shows that there is value in analysing inflammatory biomarkers in MDS, but their diagnostic and prognostic utility is yet to be fully validated.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Kennedy Trust for Rheumatology Research
Organisme : Cancer Research UK
ID : A29685
Pays : United Kingdom
Organisme : EU 2020 Horizon
ID : 779295
Organisme : National Institute for Health Research
Organisme : Leeds Biomedical Research Centre
Organisme : Novartis Pharmacy B.V. Oncology Europe
Organisme : Amgen Limited
Organisme : Celgene International
Organisme : Janssen Pharmaceutica
Organisme : Takeda Pharmaceuticals International
Informations de copyright
© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
Références
Kouroukli O, Symeonidis A, Foukas P, Maragkou MK, Kourea EP. Bone marrow immune microenvironment in myelodysplastic syndromes. Cancers (Basel). 2022;14(22):5656. https://doi.org/10.3390/cancers14225656
Monlish DA, Bhatt ST, Schuettpelz LG. The role of toll‐like receptors in hematopoietic malignancies. Front Immunol. 2016;7:390. https://doi.org/10.3389/fimmu.2016.00390
Dimicoli S, Wei Y, Bueso‐Ramos C, Yang H, DiNardo C, Jia Y, et al. Overexpression of the toll‐like receptor (TLR) signaling adaptor MYD88, but lack of genetic mutation, in myelodysplastic syndromes. PLoS One. 2013;8(8):e71120. https://doi.org/10.1371/journal.pone.0071120
Basiorka AA, McGraw KL, Eksioglu EA, Chen X, Johnson J, Zhang L, et al. The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype. Blood. 2016;128(25):2960–2975. https://doi.org/10.1182/blood‐2016‐07‐730556
Sallman DA, List A. The central role of inflammatory signaling in the pathogenesis of myelodysplastic syndromes. Blood. 2019;133(10):1039–1048. https://doi.org/10.1182/blood‐2018‐10‐844654
Sano S, Oshima K, Wang Y, MacLauchlan S, Katanasaka Y, Sano M, et al. Tet2‐mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL‐1beta/NLRP3 inflammasome. J Am Coll Cardiol. 2018;71(8):875–886. https://doi.org/10.1016/j.jacc.2017.12.037
McLemore AF, Hou HA, Meyer BS, Lam NB, Ward GA, Aldrich AL, et al. Somatic gene mutations expose cytoplasmic DNA to co‐opt the cGAS/STING/NLRP3 axis in myelodysplastic syndromes. JCI Insight. 2022;7(15):9430. https://doi.org/10.1172/jci.insight.159430
Caiado F, Pietras EM, Manz MG. Inflammation as a regulator of hematopoietic stem cell function in disease, aging, and clonal selection. J Exp Med. 2021;218(7):1541. https://doi.org/10.1084/jem.20201541
Hormaechea‐Agulla D, Matatall KA, Le DT, Kain B, Long X, Kus P, et al. Chronic infection drives Dnmt3a‐loss‐of‐function clonal hematopoiesis via IFNgamma signaling. Cell Stem Cell. 2021;28(8):1428–1442.e6. https://doi.org/10.1016/j.stem.2021.03.002
Schinke C, Giricz O, Li W, Shastri A, Gordon S, Barreyro L, et al. IL8‐CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells. Blood. 2015;125(20):3144–3152. https://doi.org/10.1182/blood‐2015‐01‐621631
Barreyro L, Chlon TM, Starczynowski DT. Chronic immune response dysregulation in MDS pathogenesis. Blood. 2018;132(15):1553–1560. https://doi.org/10.1182/blood‐2018‐03‐784116
Symeonidis A, Kourakli A, Katevas P, Perraki M, Tiniakou M, Matsouka P, et al. Immune function parameters at diagnosis in patients with myelodysplastic syndromes: correlation with the FAB classification and prognosis. Eur J Haematol. 1991;47(4):277–281. https://doi.org/10.1111/j.1600‐0609.1991.tb01571.x
McGonagle D, McDermott MF. A proposed classification of the immunological diseases. PLoS Med. 2006;3(8):e297. https://doi.org/10.1371/journal.pmed.0030297
Montoro J, Gallur L, Merchan B, Molero A, Roldán E, Martínez‐Valle F, et al. Autoimmune disorders are common in myelodysplastic syndrome patients and confer an adverse impact on outcomes. Ann Hematol. 2018;97(8):1349–1356. https://doi.org/10.1007/s00277‐018‐3302‐0
Wolach O, Stone R. Autoimmunity and inflammation in myelodysplastic syndromes. Acta Haematol. 2016;136(2):108–117. https://doi.org/10.1159/000446062
Seguier J, Gelsi‐Boyer V, Ebbo M, Hamidou Z, Charbonnier A, Bernit E, et al. Autoimmune diseases in myelodysplastic syndrome favors patients survival: a case control study and literature review. Autoimmun Rev. 2019;18(1):36–42. https://doi.org/10.1016/j.autrev.2018.07.009
Watad A, Kacar M, Bragazzi NL, Zhou Q, Jassam M, Taylor J, et al. Somatic mutations and the risk of undifferentiated autoinflammatory disease in MDS: an under‐recognized but prognostically important complication. Front Immunol. 2021;12:610019. https://doi.org/10.3389/fimmu.2021.610019
Trowbridge JJ, Starczynowski DT. Innate immune pathways and inflammation in hematopoietic aging, clonal hematopoiesis, and MDS. J Exp Med. 2021;218(7):20201544. https://doi.org/10.1084/jem.20201544
Zhang TY, Dutta R, Benard B, Zhao F, Yin R, Majeti R. IL‐6 blockade reverses bone marrow failure induced by human acute myeloid leukemia. Sci Transl Med. 2020;12(538):5104. https://doi.org/10.1126/scitranslmed.aax5104
Zoumbos N, Symeonidis A, Kourakli A, Katevas P, Matsouka P, Perraki M, et al. Increased levels of soluble interleukin‐2 receptors and tumor necrosis factor in serum of patients with myelodysplastic syndromes. Blood. 1991;77(2):413–414.
Basiorka AA, McGraw KL, Abbas‐Aghababazadeh F, McLemore AF, Vincelette ND, Ward GA, et al. Assessment of ASC specks as a putative biomarker of pyroptosis in myelodysplastic syndromes: an observational cohort study. Lancet Haematol. 2018;5(9):e393–e402. https://doi.org/10.1016/S2352‐3026(18)30109‐1
Wang C, McGraw KL, McLemore AF, Komrokji R, Basiorka AA, Al Ali N, et al. Dual pyroptotic biomarkers predict erythroid response in lower‐risk non‐del(5q) myelodysplastic syndromes treated with lenalidomide and recombinant erythropoietin. Haematologica. 2022;107(3):737–739. https://doi.org/10.3324/haematol.2021.278855
Prochnicki T, Vasconcelos MB, Robinson KS, Klengel C, Ebert T, Gellner AK, et al. Mitochondrial damage activates the NLRP10 inflammasome. Nat Immunol. 2023;24(4):595–603. https://doi.org/10.1038/s41590‐023‐01451‐y
de Swart L, Smith A, Johnston TW, Haase D, Droste J, Fenaux P, et al. Validation of the revised international prognostic scoring system (IPSS‐R) in patients with lower‐risk myelodysplastic syndromes: a report from the prospective European LeukaemiaNet MDS (EUMDS) registry. Br J Haematol. 2015;170(3):372–383. https://doi.org/10.1111/bjh.13450
Yu Z, Fidler TP, Ruan Y, Vlasschaert C, Nakao T, Uddin MM, et al. Genetic modification of inflammation‐ and clonal hematopoiesis‐associated cardiovascular risk. J Clin Invest. 2023;133(18):8597. https://doi.org/10.1172/JCI168597
Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B, Liu Y, et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet. 2014;46(10):1140–1146. https://doi.org/10.1038/ng.3089
Rodriguez‐Meira A, Norfo R, Wen S, Chédeville AL, Rahman H, O'Sullivan J, et al. Single‐cell multi‐omics identifies chronic inflammation as a driver of TP53‐mutant leukemic evolution. Nat Genet. 2023;55(9):1531–1541. https://doi.org/10.1038/s41588‐023‐01480‐1
Adrianzen‐Herrera DA, Sparks AD, Singh R, Alejos‐Castillo D, Batra A, Glushakow‐Smith S, et al. Impact of preexisting autoimmune disease on myelodysplastic syndromes outcomes: a population analysis. Blood Adv. 2023;7:6913–6922. https://doi.org/10.1182/bloodadvances.2023011050
Gonzalez‐Lugo JD, Verma A. Targeting inflammation in lower‐risk MDS. Hematology Am Soc Hematol Educ Program. 2022;2022(1):382–387. https://doi.org/10.1182/hematology.2022000350