Chronic immune response dysregulation in MDS pathogenesis

Abstract

Chronic innate immune signaling in hematopoietic cells is widely described in myelodysplastic syndromes (MDS), and innate immune pathway activation, predominantly via pattern recognition receptors, increases the risk of developing MDS. An inflammatory component to MDS has been reported for many years, but only recently has evidence supported a more direct role of chronic innate immune signaling and associated inflammatory pathways in the pathogenesis of MDS. Here we review recent findings and discuss relevant questions related to chronic immune response dysregulation in MDS.

TIFAB Regulates USP15-Mediated p53 Signaling during Stressed and Malignant Hematopoiesis

“…Moreover, deletion of TIFAB in hematopoietic cells recapitulates features of human MDSs, including progressive cytopenias, altered myeloid differentiation, and propensity to develop bone marrow (BM) failure (Bennett et al, 1982;Starczynowski et al, 2010;Steensma, 2015Steensma, , 2018Tefferi and Vardiman, 2009;Weh et al, 1991). Increasing evidence indicates that aberrant innate immune signaling (Barreyro et al, 2018;Fang et al, 2017aFang et al, , 2017bRhyasen et al, 2013;Ribezzo et al, 2019), which we observe in TIFAB-deficient models, is sufficient to induce MDS phenotypes. Although TIFAB is within the deleted region in del(5q) MDSs and AML, it likely has pleotropic functions in hematopoietic cells, yet it remains a poorly characterized member of the TRAF-interacting protein family.…”

Sequential CRISPR gene editing in human iPSCs charts the clonal evolution of leukemia

“…Importantly, while the increased inflammatory responses in the context of TET2 and DNMT3A mutations that have previously been reported were found in mature immune cells, primarily monocytes, our results suggest that innate immunity and inflammatory signaling is already dysregulated at the HSPC level in CH. Interestingly, dysregulation of these pathways in cells early in the hematopoietic hierarchy have been suggested in the case of MDS 31,32 .…”

Dysregulation of interferon regulatory genes reinforces the concept of chronic immune response in myelodysplastic syndrome pathogenesis

“…4 Chronic inflammatory diseases associated with activated innate immune signalizing pathways usually precede MDS, creating the hypothesis that chronic innate immune signalizing in hematopoietic stem cell (HSC) may be related to MDS pathogenesis. 5 Overexpression of immune-related genes in HSC is reported in over 50% of MDS patients. 5 Innate and adaptive immune response are, in many facets, controlled by interferon regulatory factors (IRFs), traditionally described as transcriptional regulators of type I interferons (IFNs) and IFN-inducible genes.…”

“…5 Overexpression of immune-related genes in HSC is reported in over 50% of MDS patients. 5 Innate and adaptive immune response are, in many facets, controlled by interferon regulatory factors (IRFs), traditionally described as transcriptional regulators of type I interferons (IFNs) and IFN-inducible genes. 6 IRF family is composed of nine genes (IRF-1 -IRF-9) which are associated with immunosurveillance, cancer development, and, recently, endogenous retrovirus activation with regulation of PD-1 ligands.…”