TLR2/6 signaling promotes the expansion of premalignant hematopoietic stem and progenitor cells in the NUP98–HOXD13 mouse model of MDS

Abstract

Toll-like receptor 2 (TLR2) expression is increased on hematopoietic stem and progenitor cells (HSPCs) of patients with myelodysplastic syndromes (MDS), and enhanced TLR2 signaling is thought to contribute to MDS pathogenesis. Notably, TLR2 heterodimerizes with TLR1 or TLR6, and while high TLR2 is associated with lower-risk disease, high TLR6, but not TLR1, correlates with higher-risk disease. This raises the possibility of heterodimer-specific effects of TLR2 signaling in MDS, and in the work described here, we tested the effects of specific modulation of TLR1/2 versus TLR2/6 signaling on premalignant HSPCs. Indeed, chronic stimulation of TLR2/6, but not TLR1/2, accelerates leukemic transformation in the NHD13 mouse model of MDS, and conversely, loss of TLR6, but not TLR1, slows this process. TLR2/6 stimulation expands premalignant HSPCs, and chimeric mouse studies revealed that cell-autonomous signaling contributes to this expansion. Finally, TLR2/6 stimulation is associated with an enrichment of Myc and mTORC1 activities. While Myc inhibition partially suppressed the TLR2/6 agonist-mediated expansion of premalignant HSPCs, inhibition of mTORC1 exacerbated it, suggesting that these pathways play opposite roles in regulating the effects of TLR2/6 ligation on HSPCs. Together, these data reveal heterodimer-specific effects of TLR2 signaling on premalignant HSPCs, with TLR2/6 signaling promoting their expansion and leukemic transformation.

Innate immune pathways and inflammation in hematopoietic aging, clonal hematopoiesis, and MDS

“…Functionally, TLR2-F217S results in enhanced activation of downstream signaling, including NF-κB activity after TLR2 agonist treatment, suggesting that aberrant ligand-receptor activation in MDS HSPCs can also contribute to disease. TLR2 forms a heterodimer with TLR1 or TLR6, and while overexpression of TLR2 is associated with lower-risk disease, increased expression of TLR6, but not TLR1, correlates with higher-risk disease ( Monlish et al, 2020 ). In a mouse model of MDS driven by the NUP98-HOXD13 fusion (NHD13), TLR2 ligand exposure results in cell-autonomous TLR2 signaling that promotes the cell death of premalignant NHD13-HSPCs.…”

“…In contrast, deletion of TLR6, but not TLR1, delays transformation from MDS to AML. Mechanistically, TLR2/6 stimulation leads to cell-intrinsic and cell-autonomous expansion of premalignant HSPCs ( Monlish et al, 2020 ).…”

New Frontiers in Monoclonal Antibodies for the Targeted Therapy of Acute Myeloid Leukemia and Myelodysplastic Syndromes

“…TLR2, also known as CD282, is a member of the Toll-like receptor family and is expressed on the surface of various cells, including HSCs and hematopoietic progenitor cells (HSPCs), and plays a fundamental role in pathogen recognition and in the activation of innate immunity [ 61 ]. Overexpression of TLR2 leads to upregulation of the IL-8 molecular pathway, which is often dysregulated in MDS patients [ 62 , 63 ].…”

Diagnosis of Myelodysplastic Syndromes: From Immunological Observations to Clinical Applications

“…The expression of immune-related genes in HSPCs was reported to be frequently increased in MDS patients [ 45 ]. TLRs were reported to be overexpressed on HSCs and progenitor cells of MDS patients compared with controls but with specific patterns along the course of the disease, therefore suggesting that TLR expression likely influences the pathogenesis of MDS in lower-risk patients [ 46 , 47 , 48 , 49 , 50 ]. An increased level of the DAMP S100A8/9, an endogenous ligand of TLR4, and downstream activation of the NLRP3 inflammasome are also well described in MDS mainly in low-risk patients [ 51 , 52 , 53 , 54 , 55 ].…”