Expression Profiles of Human Endogenous Retrovirus in Chronic Myeloid Leukemia at Diagnosis and after TKI Therapy

Abstract

INTRODUCTION Chronic Myeloid Leukemia (CML) has become a manageable and possibly curable disease due to the use of Tyrosine Kinase inhibitors (TKI). Although the immune system has been shown to be dysfunctional in newly diagnosed CML patients, TKI therapy may restore the function of the immune cells, and thus, the immune system may play a role in the leukemia control. In this complex immune interplay, the modulation and possible role of Human Endogenous Retroviruses (HERVs) expression is still poorly characterized. HERVs represent ~8% of the human genome and have been repeatedly domesticated by the host for major physiological functions, such as the development of placenta and the shaping of complex networks, including the main antiviral pathways of innate immunity. Accordingly, HERVs are still able to both modulate and be influenced by the host immune system and are thus highly investigated in several pathological contexts of immune dysregulation, such as autoimmunity and cancer. The aim of this study was to evaluate the overall HERV transcription profile in CML patients as compared to healthy controls (HC), to explore the regulatory influence of HERVs and their links to CML immune pathogenesis. METHODS The analysis included 10 HC and a total of 23 CML (11 Male, 7 Female, age range 45-84) being either at diagnosis (5 patients) or after TKI treatment (18 patients) for a minimum of 24 months and a molecular response of MR3 or deeper. Total RNA from peripheral blood cells was deep sequenced to obtain transcriptomic profiles, analyzed for the set of HERVs (~3300) and cellular genes (~60700) expression. RESULTS HERV transcriptome is significantly modulated in CML patients, clearly dividing them from HC. In addition, among CML patients, specific signatures of HERV modulation allows to distinguish actively affected patients from the ones that are in molecular remission after TKI treatment. The latter are also very different from HC in terms of HERV expression, possibly due to residual modulation by the disease and/or the prosecution of TKI therapy. Differential expression analyses allowed to identify a total of 575 and 568 deHERVs significantly modulated between CML patients at diagnosis and HC and between CML treated patients in molecular remission (MR3-MR5) and HC (padj: 3.36e-96 to 0.0098 and 8.32e-69 to 0.0099, respectively). In addition, 267 deHERVs were found comparing the same CML patients at diagnosis and during remission (padj: 5.55e-81 to 0.0099). The differential human gene expression revealed about 5800 dysregulated genes (4782 up and 1019 down, padj: 3.96e-260 to 9.5e-30) in CML pts vs HC. The top overexpressed genes were DDX17, VPS13B, PHIP, SMG1, STK10, LRRFIP1 with under-regulation of RNF213, MIR1276, ZRANB2-AS1, AC138028.4 genes, among others. Pairwise comparisons of 5 CML at diagnosis vs samples after treatment with imatinib resulted in a downregulation of ZNF831, EVL, TXK, HAPLN3, SEPTIN1, TNFRSF25 and upregulation of LTF, MPO, ABCA13, BPI, BCL2L15, ERG, MMP8, DEFA4, ANLN, SCN9A genes. CONCLUSIONS The present study provides the first high-throughput snapshot of HERV transcriptome in CML and identify specific sets of HERVs that can distinguish patients at diagnosis, patients in molecular response to TKI therapies and HC. Patient's gene expression profiles revealed that during molecular remission and under continuous treatments is present a disregulated pathway that is different from healthy individuals. Our results can give insights on the role of HERVs in the biology of CML and may add information useful to select the most effective pathways to target to maximize an advantageous immune response and promote a successful TKI discontinuation. Moreover, the following question is open: is there a potential regulatory role of HERVs in the genomic balance of CML patients? Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal