ERVs-TLR3-IRF axis is linked to myelodysplastic syndrome pathogenesis

• Published in: Medical oncology (Northwood, London, England) London, England), 2021-03, Vol.38 (3), p.27-27, Article 27
• Main Authors: de Oliveira, Roberta Taiane Germano, Cordeiro, João Victor Alves, Vitoriano, Bruna Ferreira, de Lima Melo, Mayara Magna, Sampaio, Letícia Rodrigues, de Paula Borges, Daniela, Magalhães, Silvia Maria Meira, Pinheiro, Ronald Feitosa
• Format: Article
• Language: English
• Subjects: Bone marrow; Cancer; Gene expression; Hematology; Interferon; Internal Medicine; Medicine; Medicine & Public Health; Myelodysplastic syndromes; Oncology; Original Paper; Pathogenesis; Pathology
• ISSN: 1357-0560; 1559-131X
• DOI: 10.1007/s12032-021-01466-1

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, E R V K 6 , ERVW-1, E R V 3-1 , IRF 3 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/mm 3 ) ( 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; r 2 = 0.640; p = 0.000), ERVW1-ERV3-1 ( r = 0.715; r 2 = 0.511; p = 0.000), and IRF7-IRF3 ( r = 0.567; r 2 = 0.321; p = 0.000) and moderate correlation between ERVK6 - ERV3-1 ( r = 0.485; r 2 = 0.235; p = 0.000), ERVW1-IRF7 ( r = 0.389; r 2 = 0.151; p = 0.001), ERVW1-IRF3 ( r = 0.357; r 2 = 0.127; p = 0.004), ERV3-1-IRF7 ( r = 0.314; r 2 = 0.098; p = 0.009), and ERV3-1-IRF3 ( r = 0.324; r 2 = 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. Graphic Abstract 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