Biglycan as a mediator of proinflammatory response and target for MDS and sAML therapy.

Autor:	Vaxevanis CK; Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale) 06112, Germany., Bauer M; Institute of Pathology, Martin Luther University Halle-Wittenberg, Halle (Saale) 06112, Germany., Subbarayan K; Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale) 06112, Germany., Friedrich M; Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale) 06112, Germany., Massa C; Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale) 06112, Germany., Biehl K; Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale) 06112, Germany., Al-Ali HK; Krukenberg Cancer Center Halle, University Hospital Halle, Krukenberg-Krebszentrum, Halle (Saale) 06120, Germany., Wickenhauser C; Institute of Pathology, Martin Luther University Halle-Wittenberg, Halle (Saale) 06112, Germany., Seliger B; Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale) 06112, Germany.; Department of Good Manufacturing Practice (GMP) Development & Advanced Therapy Medicinal Products (ATMP) Design, Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig 04103, Germany.; Medical School Theodor Fontane, Institute of Translational Medicine, Brandenburg an der Havel 14770, Germany.
Jazyk:	angličtina
Zdroj:	Oncoimmunology [Oncoimmunology] 2022 Dec 15; Vol. 12 (1), pp. 2152998. Date of Electronic Publication: 2022 Dec 15 (Print Publication: 2023).
DOI:	10.1080/2162402X.2022.2152998
Abstrakt:	Myelodysplastic syndromes (MDS) and their progression to secondary acute myeloid leukemia (sAML) are associated with an altered protein expression including extracellular matrix (ECM) components thereby promoting an inflammatory environment. Since the role of the proteoglycan biglycan (BGN) as an inflammatory mediator has not yet been investigated in both diseases and might play a role in disease progression, its expression and/or function was determined in cell lines and bone marrow biopsies (BMBs) of MDS and sAML patients and subpopulations of MDS stem cells by Western blot and immunohistochemistry. The bone marrow (BM) microenvironment was analyzed by multispectral imaging, patients' survival by Cox regression. ROC curves were assessed for diagnostic value of BGN. All cell lines showed a strong BGN surface expression in contrast to only marginal expression levels in mononuclear cells and CD34 + cells from healthy donors. In the MDS-L cell line, CD34 - CD33 + and CD34 + CD33 + blast subpopulations exhibited a differential BGN surface detection. Increased BGN mediated inflammasome activity of CD34 - CD33 + TLR4 + cells was observed, which was inhibited by direct targeting of BGN or NLRP3. BGN was heterogeneously expressed in BMBs of MDS and sAML, but was not detected in control biopsies. BGN expression in BMBs positively correlated with MUM1 + and CD8 + , but negatively with CD33 + TLR4 + cell infiltration and was accompanied by a decreased progression-free survival of MDS patients. BGN-mediated inflammasome activation appears to be a crucial mechanism in MDS pathogenesis implicating its use as suitable biomarker and potential therapeutic target. Abbreviations: Ab, antibody; alloSCT, allogenic stem cell transplant; AML, acute myeloid leukemia; BGN, biglycan; BM, bone marrow; BMB, bone marrow biopsy; casp1, caspase 1; CTLA-4, cytotoxic T lymphocyte-associated protein 4; DAMP, danger-associated molecular pattern; ECM, extracellular matrix; FCS, fetal calf serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HD, healthy donor; HSPC, hematopoietic stem and progenitor cell; HSC, hematopoietic stem cell; IFN, interferon; IHC, immunohistochemistry; IL, interleukin; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; MSI, multispectral imaging; NGS, next-generation sequencing; NLRP3, NLR family pyrin domain containing 3; OS, overall survival; PBMC, peripheral blood mononuclear cell; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1, PFS, progression-free survival; PRR, pattern recognition receptor; SC, stem cell; SLRP, small leucine-rich proteoglycan; TGF, transforming growth factor; TIRAP, toll/interleukin 1 receptor domain-containing adapter protein; TLR, toll-like receptor; Treg, regulatory T cell. Competing Interests: The authors declare that they have no conflicts of interest. (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu