Innate Immune Signaling in the Myelodysplastic Syndromes

Genome Sciences Centre, British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, Canada.
Hematology/oncology clinics of North America (Impact Factor: 2.3). 04/2010; 24(2):343-59. DOI: 10.1016/j.hoc.2010.02.008
Source: PubMed


Myelodysplastic syndromes (MDS) are heterogeneous clonal hematologic malignancies characterized by cytopenias caused by ineffective hematopoiesis and propensity to progress to acute myeloid leukemia. Innate immunity provides immediate protection against pathogens by coordinating activation of signaling pathways in immune cells. Given the prominent role of the innate immune pathway in regulating hematopoiesis, it is not surprising that aberrant signaling of this pathway is associated with hematologic malignancies. Increased activation of the innate immune pathway may contribute to dysregulated hematopoiesis, dysplasia, and clonal expansion in myelodysplastic syndromes.

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    • "In addition to the expression of pro-inflammatory factors, TLR signaling also induces the expression of microRNAs (miRNAs) which participate in the fine-tuning of the inflammatory response [5], [8], [17]. miRNAs are conserved, non-coding short RNAs that participate in post-transcriptional regulation by binding to mRNAs, generally to their 3′-untranslated region (UTR), and blocking protein expression [18]. "
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    ABSTRACT: Myelodysplastic syndromes (MDS) are characterized by impaired proliferation and differentiation of hematopoietic stem cells. The participation of toll-like receptor (TLR)-mediated signaling in MDS is well documented. Increased TLR signaling leads to the constitutive activation of NF-κB, which mediates inflammation, cell proliferation and apoptosis. In addition, the TLR pathway induces the expression of miRNAs which participate in the fine-tuning of the inflammatory response. miRNAs also regulate other biological processes, including hematopoiesis. miR-125a and miR-125b are known modulators of hematopoiesis and are abnormally expressed in several hematologic malignancies. However, little is known about their role in MDS. NF-κB-activating ability has been described for both miRNAs. We studied the role of miR-125a/miR-125b in MDS and their relationship with TLR signaling and hematopoietic differentiation. Our results indicate that miR-125a is significantly overexpressed in MDS patients and correlates negatively with patient survival. Expression of miR-99b, which is clustered with miR-125a, is also directly correlated with prognosis of MDS. Both miR-125a and miR-99b activated NF-κB in vitro; however, we observed a negative correlation between miR-99b expression and the levels of TLR2, TLR7 and two downstream genes, suggesting that NF-κB activation by the miRNA cluster occurs in the absence of TLR signaling. We also show that TLR7 is negatively correlated with patient survival in MDS. In addition, our data suggest that miR-125a may act as an NF-κB inhibitor upon TLR stimulation. These results indicate that miR-125a is involved in the fine-tuning of NF-κB activity and that its effects may depend on the status of the TLR pathway. Furthermore, we observed that miR-125a inhibits erythroid differentiation in leukemia and MDS cell lines. Therefore, this miRNA could serve as a prognostic marker and a potential therapeutic target in MDS.
    PLoS ONE 04/2014; 9(4):e93404. DOI:10.1371/journal.pone.0093404 · 3.23 Impact Factor
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    • "Although innate immunity responses are mediated mostly by phagocytes such as macrophages and dendritic cells, emerging evidence has suggested that innate immune signalling activation can also directly impact hematopoietic stem and early progenitor cells (HSPCs) [5], [6] and may be involved in the pathogenesis of MDS [7]. For instance, mir-145 and 146a are two microRNAs that have been shown to target the innate immune signal adaptors TIRAP and TRAF6 respectively [7]. Loss of these two microRNAs is involved in the 5q- syndrome subtype of MDS and overexpression of TRIAP and TRAF6 is associated with transformation to acute leukemia or marrow failure in a murine transplant system [8]. "
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    ABSTRACT: MYD88 is a key mediator of Toll-like receptor innate immunity signaling. Oncogenically active MYD88 mutations have recently been reported in lymphoid malignancies, but has not been described in MDS. To characterize MYD88 in MDS, we sequenced the coding region of the MYD88 gene in 40 MDS patients. No MYD88 mutation was detected. We next characterized MYD88 expression in bone marrow CD34+ cells (N = 64). Increased MYD88 RNA was detected in 40% of patients. Patients with higher MYD88 expression in CD34+ cells had a tendency for shorter survival compared to the ones with lower MYD88, which was significant when controlled for IPSS and age. We then evaluated effect of MYD88 blockade in the CD34+ cells of patients with lower-risk MDS. Colony formation assays indicated that MYD88 blockade using a MYD88 inhibitor resulted in increased erythroid colony formation. MYD88 blockade also negatively regulated the secretion of interleukin-8. Treatment of MDS CD34+ cells with an IL-8 antibody also increased formation of erythroid colonies. These results indicate that MYD88 plays a role in the pathobiology of MDS and may have prognostic and therapeutic value in the management of patients with this disease.
    PLoS ONE 08/2013; 8(8):e71120. DOI:10.1371/journal.pone.0071120 · 3.23 Impact Factor
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    • "Although IRAK1 mRNA is overexpressed in a subset of MDS patients, the level of expression rarely exceeds 2-fold. However, deletion and reduced expression of miR-146a is a common event in MDSs as it resides within the deleted region on chr 5q and its expression is reduced in a large subset of normal karyotype MDSs (Starczynowski et al., 2010, 2011b). TRAF6 and IRAK1 are two targets of miR-146a, and germline knockout of miR-146a results in derepression of TRAF6 and IRAK1 protein (Boldin et al., 2011; Zhao et al., 2011). "
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    ABSTRACT: Myelodysplastic syndromes (MDSs) arise from a defective hematopoietic stem/progenitor cell. Consequently, there is an urgent need to develop targeted therapies capable of eliminating the MDS-initiating clones. We identified that IRAK1, an immune-modulating kinase, is overexpressed and hyperactivated in MDSs. MDS clones treated with a small molecule IRAK1 inhibitor (IRAK1/4-Inh) exhibited impaired expansion and increased apoptosis, which coincided with TRAF6/NF-κB inhibition. Suppression of IRAK1, either by RNAi or with IRAK1/4-Inh, is detrimental to MDS cells, while sparing normal CD34(+) cells. Based on an integrative gene expression analysis, we combined IRAK1 and BCL2 inhibitors and found that cotreatment more effectively eliminated MDS clones. In summary, these findings implicate IRAK1 as a drugable target in MDSs.
    Cancer cell 07/2013; 24(1):90-104. DOI:10.1016/j.ccr.2013.05.006 · 23.52 Impact Factor
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