ERVs-TLR3-IRF axis is linked to myelodysplastic syndrome pathogenesis
| Autor: | Roberta Taiane Germano de Oliveira, Daniela de Paula Borges, Bruna Ferreira Vitoriano, Mayara Magna de Lima Melo, Leticia Rodrigues Sampaio, João Victor Alves Cordeiro, Silvia Maria Meira Magalhães, Ronald Feitosa Pinheiro |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Male Cancer Research medicine.medical_specialty Myeloid Interferon Regulatory Factor-7 viruses Endogenous retrovirus Biology Pathogenesis Young Adult 03 medical and health sciences 0302 clinical medicine Interferon Internal medicine Biomarkers Tumor medicine Humans Aged Aged 80 and over Hematology Endogenous Retroviruses virus diseases General Medicine Middle Aged Prognosis Molecular biology Toll-Like Receptor 3 Gene Expression Regulation Neoplastic medicine.anatomical_structure Oncology Myelodysplastic Syndromes 030220 oncology & carcinogenesis IRF7 Female Interferon Regulatory Factor-3 IRF3 medicine.drug Interferon regulatory factors |
| Zdroj: | Medical Oncology. 38 |
| ISSN: | 1559-131X 1357-0560 |
| DOI: | 10.1007/s12032-021-01466-1 |
| Popis: | Toll-like receptors are mutated or overexpressed in up to 50% of patients with myelodysplastic syndrome (MDS). Endogenous retroviruses (ERV) trigger TLR3 leading to interferon regulatory genes (IRFs) activation. We evaluated if the ERVs-TLR3-IRF axis activation would be linked to MDS pathogenesis and we also conducted a detailed cancer analysis of the ERVs, TLR3 and IRFs gene expression in 30 cancer types using GEPIA database. Seventy-nine bone marrow samples from patients with MDS were evaluated for cytogenetics and quantitative real‑time PCR of TLR3, ERVK6, ERVW-1, ERV3-1, IRF3 and IRF7. Patients with dyserythropoiesis showed higher TLR3 (p = 0.035), ERVK6 (p = 0.001), ERVW1 (p = 0.045) and ERV3-1 (p = 0.016) expression than patients without dyserythropoiesis. Upregulation of Interferon Regulatory Factors, IRF3 and IRF7, was associated with poor prognostic markers in MDS such as > 10% of blasts (p = 0.003-IRF3; p = 0.009-IRF7), low platelets count (< 50.000/mm3) (p = 0.001-IRF3; p = 0.021-IRF7), transfusion dependence (p = 0.014-IRF3) and chromosomal abnormalities (p = 0.036-IRF7). We found strong correlations between ERVK6-ERVW1 (r = 0.800; r2 = 0.640; p = 0.000), ERVW1-ERV3-1 (r = 0.715; r2 = 0.511; p = 0.000), and IRF7-IRF3 (r = 0.567; r2 = 0.321; p = 0.000) and moderate correlation between ERVK6-ERV3-1(r = 0.485; r2 = 0.235; p = 0.000), ERVW1-IRF7 (r = 0.389; r2 = 0.151; p = 0.001), ERVW1-IRF3 (r = 0.357; r2 = 0.127; p = 0.004), ERV3-1-IRF7 (r = 0.314; r2 = 0.098; p = 0.009), and ERV3-1-IRF3 (r = 0.324; r2 = 0.104; p = 0.007). Using GEPIA Database in 30 cancer types, we detected a typical pattern of upregulation as here presented in MDS. We suggest TLR3 activation by ERVs is linked to MDS pathogenesis leading to bone marrow failure. Abnormal double-stranded RNA (dsRNA) expression of Endogenous Retroviruses (ERV) triggers TLR3 hyperactivation. This induces IRF3, IRF7, and NF-kB to translocate to the nucleus and activate transcription of IFNα/β which binds to the type I-IFN receptor promoting interferon response. Thus, just as TLR4 induces a crucial myeloid shift, the ERVs-TLR3 axis may play an important role in establishing one of the most striking characteristics in MDS, dyserythropoiesis. |
| Databáze: | OpenAIRE |
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