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Editorial theme | Immune dysregulation and genetic mutations associated with MDS pathogenesis

Mar 24, 2021

The pathogenesis of myelodysplastic syndromes (MDS) is heterogeneous, involving inflammation, cytokines, growth factors, the accumulation of genetic damage, and ineffective hematopoiesis. Many studies have investigated potential mechanisms underlying how abnormalities in the innate and adaptive immune systems might modulate the development of MDS, and how MDS-associated mutations and cytogenetic aberrations may affect the tumor microenvironment, however, there remains much to be understood.

Continuing with our Editorial Theme looking at the genetic pathogenesis of MDS, here we share a summary of a review by Anacélia Matos and colleagues, published recently in the Advances in Experimental Medicine and Biology book series, on the recent advances and evidence around immune dysregulation and recurring mutations in MDS.1

Immune dysregulation in MDS

The innate immune system

Activation of the innate immune system involves interactions between pathogen- or danger-associated molecular patterns and Toll-like receptors (TLRs), leading to transcription of pro-inflammatory cytokines such as interleukin (IL)-8. In MDS, TLR pathways are thought to be intrinsically dysregulated in hematopoietic stem and progenitor cells (HSPCs), resulting in excessive TLR signaling and an inflammatory form of programmed cell death (pyroptosis). In addition, higher levels of the inflammatory cytokines tumor necrosis factor (TNF)-α, interferon (IFN)-γ, transforming growth factor (TGF)-β, IL-6, and IL-8 have been observed in patients with MDS, both in the blood and bone marrow (BM). Thus, chronic infections and concurrent inflammatory disorders may exacerbate the MDS clonal advantage and disease progression.

Interestingly, the expression of signaling mediators, Toll-IL-1 receptor domain-contained adaptor protein (TIRAP), and TNF receptor-associated factor-6 (TRAF6) appear to be influenced by haploinsufficiency of micro-RNAs like miR-145 and miR-146a, and genes such as TIFAB in del(5q) MDS, leading to inappropriate TLR activation and IL-6 production. Recurrent mutations associated with MDS, such as those in epigenetic regulators (TET2 and ASXL1) and in components of the spliceosome machinery (SF3B1, SRSF2, and U2AF1), appear to converge on innate immune pathways, resulting in excessive inflammasome activation and production of inflammatory cytokines, like IL-6.

Over 30 cytokines, chemokines, and growth factors in the peripheral blood and BM have been associated with MDS pathogenesis and clinical outcomes. Moreover, inflammatory cytokines seem to play a role in the dysregulation of the immunological environment seen in MDS:

  • In lower-risk MDS, increased levels of apoptosis in the BM are observed, whereas decreased cell death is seen in higher-risk MDS with more aggressive clonal expansion.
  • Greater IFN-γ and IL-6 secretion is seen in lower-risk MDS, whereas immunosuppressive cytokines such as IL-10 are secreted in high-risk MDS.

The adaptive immune system

Although not as well understood, it is likely that the adaptive immune system is also involved in the development of MDS. It has been proposed that the activation and expansion of CD8+ T cells in response to epitopes on MDS stem cells may result in suppression of hematopoiesis:

  • In lower-risk MDS with trisomy 8, the Wilms tumor 1 antigen (WT1) is overexpressed by HSPCs, triggering T-cell suppression of hematopoiesis.
  • As MDS progresses to higher-risk disease, both expansion of regulatory T-cell subsets and increased expression of inhibitory checkpoint proteins occur, allowing evasion of adaptive immunity using mutant MDS clones.

Furthermore, the MDS tumor microenvironment is known to be immunosuppressive, therefore inhibiting activated immune cells and also activating cells with an immunosuppressive phenotype.

MDSCs in the pathogenesis of MDS

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immune cells at different stages of maturation with the following characteristics:

  • Suppressor activity on non-myeloid immune cells such as T, B, and natural killer cells.
  • Modulatory activity on macrophage cytokine production to regulate innate immune responses.
  • Three subsets:
    • Polymorphonuclear or granulocytic MDSCs, making up 70–80% of the whole population
    • Monocytic MDSCs, accounting for 20–30%
    • Early-stage MDSCs, a much smaller fraction
  • Existing predominantly in the BM, but expand in pathological conditions such as cancer, chronic inflammation, or autoimmunity due to sustained and aberrant differentiation of myeloid cells.
  • Expansion is controlled by soluble factors including IL-6, IL-10, IL-1β, and IFN-γ, granulocyte-macrophage colony stimulating factor (CSF), macrophage CSF, granulocytic CSF, vascular endothelial growth factor (VEGF) and TLR ligands, resulting in higher proportions of MDSCs in the circulating blood.

A hypoxic, nutrient-deprived tumor microenvironment, enriched in pro-inflammatory and suppressive cytokines, chemokines, and oxidative agents such as reactive oxygen species (ROS), nitric oxide (NO), and peroxynitrite, further induces activation of local MDSCs. Their ability to suppress immune responses is thought to occur through the expression of suppressive factors such as arginase (ARG1), NO, and ROS:

  • Polymorphonuclear MDSCs produce ROS and ARG1.
  • Monocytic MDSCs produce inducible NO synthase (iNOS).
  • iNOS and ARG1 metabolically convert L-arginine, promoting its depletion and down-regulation of T-cell receptor ζ-chain expression, and leading to suppression of the cell cycle and T-cell immunosuppression.

Therefore, MDSC expansion inhibits proliferation and the antitumor activity of T cells, decreasing cytokine secretion, recruiting regulatory T cells, and prohibiting natural killer cell activation. MDSCs also induce the differentiation of regulatory T cells by secreting IL-10 and TGF-β, as well as stimulating tumor angiogenesis by secreting VEGF and basic fibroblast growth factor. Moreover, clinical and experimental evidence has shown an association between an increase in MDSCs and high cancer prevalence, poor prognosis, and resistance to therapy. Expansion of MDSCs has also been noted within the blood and BM of patients with MDS. Although the underlying mechanisms are not yet known, it has been suggested that MDSCs may suppress the growth of erythroid and myeloid progenitor cells, causing ineffective hematopoiesis. As such, therapies targeting MDSCs with the aim of improving hematopoiesis are currently under investigation.

Clonal pre-MDS states: CHIP and CCUS

Over 40 genes have been identified in which somatic point mutations and small insertions or deletions are associated with MDS pathogenesis (Table 1). Notably, SF3B1 is incorporated into the World Health Organization’s classification of MDS. However, around 10–15% of older adults with no hematologic disease carry acquired somatic mutations that are found in MDS, known as clonal hematopoiesis of indeterminate potential (CHIP). Most will not progress to MDS, however, mutations in certain genes such as DNMT3A, ASXLI, or TP53 seem to be predictors for hematological malignancy and are associated with worse overall survival. Furthermore, the presence of a recurrent mutation alongside unexplained cytopenia (clonal cytopenias of undetermined significance [CCUS]) can be indicative of progression to MDS.

Table 1. Example genes in which lesions are associated with MDS pathogenesis*



RNA splicing regulation


DNA methylation


Chromatin accessibility


Transcription factors


Signal transduction


DNA damage response


DNA, deoxyribonucleic acid.
*Adapted from Matos
et al.1

Mutations in TET2 and DNMT3A show association with inflammation and immune cell alterations in human and murine models, thus linking the accumulation of genetic damage with myeloid-mediated inflammation. As discussed above, mutations affecting RNA splicing, such as SF3B1, SRSF2, and U2AF1, appear to converge on innate immune pathways. Increased ARG1 expression has been found in patients with MDS, suggesting chronic inflammation may generate a myeloid suppressive phenotype, although more studies are required to examine this further.


Understanding the molecular mechanisms underpinning the pathogenesis of MDS remains an ongoing area of research, with increasing evidence supporting a possible link between genetic mutations and immune dysfunction contributing to the development and progression of the disease. It is hoped that greater knowledge surrounding these complex pathways will lead to the identification of novel molecular targets and the potential for new treatment options.

  1. Matos A, Magalhães SMM, Rauh MJ. Immune dysregulation and recurring mutations in myelodysplastic syndromes pathogenesis. In: Advances in Experimental Medicine and Biology. New York: Springer; 2021.Top of Form DOI: 1007/5584_2020_608