Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes

Abstract

Myelodysplastic syndromes (MDSs) are a group of heterogeneous clonal hematologic malignancies that are characterized by defective bone marrow (BM) hematopoiesis and by the occurrence of intramedullary apoptosis. During the past decade, the identification of key genetic and epigenetic alterations in patients has improved our understanding of the pathophysiology of this disease. However, the specific molecular mechanisms leading to the pathogenesis of MDS have largely remained obscure. Recently, essential evidence supporting the direct role of innate immune abnormalities in MDS has been obtained, including the identification of multiple key regulators that are overexpressed or constitutively activated in BM hematopoietic stem and progenitor cells. Mounting experimental results indicate that the dysregulation of these molecules leads to abnormal hematopoiesis, unbalanced cell death and proliferation in patients' BM, and has an important role in the pathogenesis of MDS. Furthermore, there is compelling evidence that the deregulation of innate immune and inflammatory signaling also affects other cells from the immune system and the BM microenvironment, which establish aberrant associations with hematopoietic precursors and contribute to the MDS phenotype. Therefore, the deregulation of innate immune and inflammatory signaling should be considered as one of the driving forces in the pathogenesis of MDS. In this article, we review and update the advances in this field, summarizing the results from the most recent studies and discussing their clinical implications.

Multipotent adult progenitor cells improve the hematopoietic function in myelodysplasia

“…Decreased stromal support, together with mounting evidence of a deregulated immune system, are believed to play an important role in the pathogenesis of MDS [31]. However, it has also been hypothesized that the immune/inflammatory suppression of hematopoiesis in MDS may serve to inhibit the proliferation of the malignant clonal cells and that removal of such inhibition may lead to progression to acute myeloid leukemia [32].…”

Serum Vitamin D Levels in Patients with Myelodysplastic Syndromes: A Retrospective Single-Center Analysis

“…Regarding MDS, particularly lower-risk MDS are thought to be subjected to innate immune activation driving ineffective hematopoiesis and apoptosis [24] which might be reflected by markedly low serum 25(OH)-D3 concentrations in the realm of VD deficiency. Higher-risk MDS have been shown to have gained immune escape mechanisms substantially mediated by T-regulatory lymphocytes [24]. This immune attenuation might be reflected by a higher serum 25(OH)-D3 concentration as observed in our higher-risk MDS patients.…”

Dynamic alterations of bone marrow cytokine landscape of myelodysplastic syndromes patients treated with 5-azacytidine

“…[1][2][3][4] There is growing evidence implicating inflammation-related changes, inhibitory cytokines and increased intramedullary apoptosis as contributors to ineffective hematopoiesis, specifically in the early stages of MDS. [5][6][7] Moreover, several recent studies implicate aberrant BM microenvironment and inflammation-related changes in progression of the MDS. 5,8 MDS has also higher rate of incidence and earlier onset among patients with autoimmune diseases.…”

“…[5][6][7] Moreover, several recent studies implicate aberrant BM microenvironment and inflammation-related changes in progression of the MDS. 5,8 MDS has also higher rate of incidence and earlier onset among patients with autoimmune diseases. 4,[9][10][11] MDS treatment was rather ineffective until recent introduction of two new therapeutic approaches: immunomodulation therapy with lenalidomide and hypomethylating therapy with nucleotide analogs 5-azacytidine (5-AC) and 5-aza-2 0 -deoxycytidine (decitabine).…”