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

Abstract

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.

Keywords: Endogenous retroviruses; Interferon regulatory genes; Myelodysplastic syndrome; Toll-like receptors.