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.

Figure 1

Signaling pathways frequently deregulated in MDS. The transmembrane receptors Fas (CD95), TNFR1, TNFR2, Toll-like receptors (TLRs) and IFN-γ receptor (IFNGR) and their associated signal transducers are frequently overexpressed and/or constitutively activated in MDS. Fas/CD95 is specifically engaged by Fas-L/CD95L, which induces caspase-dependent cell death by activating the initiator caspase-8 via its FAS-associated death domain (FADD). TNFR1 and TNFR2 activate the adapter protein TNFR-associated death domain (TRADD), which in turn activates TNFR-associated factors (TRAFs) to ultimately induce the phosphorylation of the mitogen-activated protein kinases (MAPKs) JUN N-terminal kinase (JNK) and/or p38 MAPK, the latter via the receptor-interacting protein (RIP). JNK induces the transcriptional activity of AP-1 and p38 MAPK, in turn, activates other transcription factors (TF) that carry out various functions. TNFR1/2 can also activate the transcription factor NF-κB via IκB kinase (IKK). In addition, TNFR1 can directly induce apoptosis through the death receptor pathway by activating FADD via TRADD, initiating caspase cleavage. TNFR2 lacks a death domain, so its functions are predominately pro-survival. After recognition of pathogen- or damage-associated molecular patterns (PAMPs and DAMPs, respectively), TLRs signal through several specific adapter molecules that ultimately lead to the activation of AP-1, p38 MAPK and NF-κB. Lastly, IFN-γ initiates a transcriptional response mediated by the activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. The transcriptional programs activated by these receptors generally lead to the expression of genes involved in the innate immune response, survival and differentiation but may also lead to the transcription of pro-apoptotic genes.

Figure 2

TLR signaling and its activation in MDS. Receptors and mediators colored in different shades of red represent molecules found to be overexpressed or constitutively activated in MDS. TLRs transduce their signals through two different adapter molecules, myeloid differentiation primary response gene 88 (MyD88) and TIR domain-containing adapter inducing IFN-β (TRIF). Virtually all TLRs signal via MyD88, except for TLR3 (not depicted here), which is an intracellular receptor signaling via TRIF. In addition, TLR4 is the only TLR that can use both mediators. MyD88-driven signaling mediates a rapid and acute pro-inflammatory response through the activation of NF-κB, AP-1 and p38 MAPK-dependent transcription factors. The intracellular receptors TLR7/8 and TLR9 additionally activate interferon-regulatory factor (IRF)-7, which induces the expression of type I IFN. In contrast, TRIF triggers a delayed pro-inflammatory response mediated by NF-κB and IRF-3-dependent type I IFN expression. Herein, TLR2 and TLR4 are depicted as examples of cytoplasmic membrane-bound TLRs, and TLR9 is shown as an example of intracellular TLRs. Abbreviations not defined in the text: Toll-interleukin 1 receptor domain-containing adapter protein (TIRAP), TRIF-related adapter molecule (TRAM), TGF-β activated kinase (TAB), TANK-binding kinase 1 (TBK1), NF-κB-inducing kinase (NIK), ubiquitin (Ub).

Figure 3

Proposed model for the central role of inflammation/innate immunity in the pathogenesis of MDS. (1) The malignant clone or MDS HSC originates in the BM of patients with the characteristic phenotype of aging. The main characteristics of the BM in old individuals are summarized in the box. In this context, the MDS HSC might originate from the genetic/epigenetic changes occurring in susceptible individuals during aging; be generated by exposure to various types of stress, including DNA damage; or could develop after a sustained exposure to inflammatory molecules derived from an existing or past inflammatory condition. (2) Either the changes in gene expression or the pre-exposure to inflammatory molecules trigger the activation of innate immune signaling pathways and the subsequent secretion of cytokines, chemokines and growth factors, which create an inflammatory microenvironment. (3) As a consequence, BM HSCs increase their cycling rates. Also driven by the release of cytokines, HSCs express Fas and other immune receptors on their surface, and CD8⁺, Th17 and NK cells are recruited. (4) The expression of death receptors and the continuous inflammatory signaling induce apoptosis in some HSCs in addition to the T-cell-mediated cytotoxicity. However, it is not clear if the dying HSCs belong to the normal or MDS clone, or to both. (5) Regardless of HSC origin, intramedullary apoptosis decreases the number of functional BM progenitors, which results in a reduced number of fully differentiated cells. In addition, intrinsic defects on the differentiation potential of the MDS clone, and the sustained inflammatory signaling, cause differentiation to be dysregulated and skewed toward the myeloid lineage. (6) The released cytokines and chemokines, and probably also certain cell-to-cell contact proteins, eventually trigger the recruitment of MDSCs to the tumor site and induce profound gene expression changes in the surrounding MSCs. MDSCs exacerbate the defects of differentiation by inducing myeloid skewing and killing erythroid precursors, and they suppress the autoimmune response by CD8⁺ T cells as well as probably participating in the switch to an immunotolerant microenvironment. Likewise, `reprogrammed' MSCs express genes involved in the adaptation to inflammation. (7) The high proliferation rates make MDS HSCs more prone to the accumulation of additional genetic/epigenetic aberrations. In addition, unknown mechanisms lead to a switch in the expression of TNFRs and probably also in the expression of other molecules, which makes malignant cells resistant to apoptosis. (8) Altogether, these alterations confer the MDS clone a survival advantage and contribute to the aberrant proliferation of the clone, which at this point overpopulates the BM. (9) This switch in the cellular processes that prevail in the BM is accompanied by the recruitment of immunomodulatory cells, which are probably triggered by changes in the cytokine/chemokine milieu. Treg cells confer immune resistance to the MDS clone and allow abnormally proliferating cells to escape the immune system. Along with step 8, this event increases the risk of progression to AML.