Loss of Toll-like receptor 2 results in accelerated leukemogenesis in the NUP98-HOXD13 mouse model of MDS

Monlish, Darlene; Bhatt, Sima T.; Duncavage, Eric J.; Greenberg, Zev J.; Keller, John L.; Romine, Molly; Yang, Wei; Aplan, Peter D.; Walter, Matthew J.; Schuettpelz, Laura G.

doi:10.1182/blood-2017-08-801944

Cited by 12 publications

(19 citation statements)

References 18 publications

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“…5 Somewhat unexpectedly, a recent study suggests that TLR2 signaling has a protective role against leukemic transformation in a mouse model of MDS. 37 Mice expressing NUP98-HOXD13 (NHD13 mice) developed leukemia more rapidly when crossed with Tlr2-or MyD88-deficient mice. In the NHD13 model, TLR2 appears to be important for the MDS phase of the disease, but its loss may accelerate transformation to acute myeloid leukemia (AML).…”

Section: Functional Evidence Of Innate Immune Signaling Dysregulationmentioning

confidence: 99%

Chronic immune response dysregulation in MDS pathogenesis

Barreyro

Chlon

Starczynowski

2018

Blood

172

166

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Chronic innate immune signaling in hematopoietic cells is widely described in myelodysplastic syndromes (MDS), and innate immune pathway activation, predominantly via pattern recognition receptors, increases the risk of developing MDS. An inflammatory component to MDS has been reported for many years, but only recently has evidence supported a more direct role of chronic innate immune signaling and associated inflammatory pathways in the pathogenesis of MDS. Here we review recent findings and discuss relevant questions related to chronic immune response dysregulation in MDS.

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Section: Functional Evidence Of Innate Immune Signaling Dysregulationmentioning

confidence: 99%

Chronic immune response dysregulation in MDS pathogenesis

Barreyro

Chlon

Starczynowski

2018

Blood

172

166

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“…However, co-transduction of an activated NUP98-HOXD13 fusion gene and MN1 alone is able to induce AML in engrafted mice [165]. More recently, it has been demonstrated that the loss of Toll-like receptor 2 too is able to accelerate leukemic progression in NUP98-HOXD13 mouse model [166]. During leukemic progression, the presence of the fusion transcript NUP98-HOXD13 is associated with other hematopoietic disorders, such as myelodysplastic syndrome (MDS), chronic myeloid leukemia and blast crisis.…”

Section: Hoxd13mentioning

confidence: 99%

Paralogous HOX13 Genes in Human Cancers

Botti

Cillo

Cecio

et al. 2019

Cancers

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Hox genes (HOX in humans), an evolutionary preserved gene family, are key determinants of embryonic development and cell memory gene program. Hox genes are organized in four clusters on four chromosomal loci aligned in 13 paralogous groups based on sequence homology (Hox gene network). During development Hox genes are transcribed, according to the rule of “spatio-temporal collinearity”, with early regulators of anterior body regions located at the 3’ end of each Hox cluster and the later regulators of posterior body regions placed at the distal 5’ end. The onset of 3’ Hox gene activation is determined by Wingless-type MMTV integration site family (Wnt) signaling, whereas 5’ Hox activation is due to paralogous group 13 genes, which act as posterior-inhibitors of more anterior Hox proteins (posterior prevalence). Deregulation of HOX genes is associated with developmental abnormalities and different human diseases. Paralogous HOX13 genes (HOX A13, HOX B13, HOX C13 and HOX D13) also play a relevant role in tumor development and progression. In this review, we will discuss the role of paralogous HOX13 genes regarding their regulatory mechanisms during carcinogenesis and tumor progression and their use as biomarkers for cancer diagnosis and treatment.

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“…We previously reported that young adult NHD13 mice have increased surface TLR2 on their hematopoietic stem and progenitor (c-Kit+Sca-1+Lineage- [KSL]) cells compared with WT littermates [ 19 ]. Using flow cytometry, we determined that surface expression of the TLR2 binding partners, TLR1 and TLR6, is also increased on KSL cells of the NHD13 mice compared with WT littermates ( Figure 1A , B ; Supplementary Figure E1 , online only, available at www.exphem.org ).…”

Section: Resultsmentioning

confidence: 99%

“…This well-characterized transgenic MDS model expresses the NUP98-HOXD13 fusion from the hematopoietic Vav-1 promoter and exhibits many of the salient features of human MDS including cytopenias, bone marrow dysplasia, and transformation to acute leukemia [ 18 ]. Notably, the HSPCs of the NHD13 mice, like those of humans with MDS, have increased expression of TLR2, and we recently reported that complete loss of TLR2 or the TLR signaling adaptor MyD88 is associated with earlier leukemic transformation in the NHD13 mice [ 19 ]. Mechanistic studies revealed that loss of TLR2 resulted in a reduction of activated caspase-1 and lower rates of cell death in preleukemic HSPCs [ 19 ].…”

mentioning

confidence: 99%

“…Notably, the HSPCs of the NHD13 mice, like those of humans with MDS, have increased expression of TLR2, and we recently reported that complete loss of TLR2 or the TLR signaling adaptor MyD88 is associated with earlier leukemic transformation in the NHD13 mice [ 19 ]. Mechanistic studies revealed that loss of TLR2 resulted in a reduction of activated caspase-1 and lower rates of cell death in preleukemic HSPCs [ 19 ]. Together, these data suggest that some TLR signaling may be protective against the progression of MDS to acute leukemia, and are consistent with patient data indicating that high TLR2 expression correlates with lower-risk disease and better overall survival [ 3 , 11 ].…”

mentioning

confidence: 99%

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

Monlish

Greenberg

Bhatt

et al. 2020

Experimental Hematology

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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.

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Loss of Toll-like receptor 2 results in accelerated leukemogenesis in the NUP98-HOXD13 mouse model of MDS

Cited by 12 publications

References 18 publications

Chronic immune response dysregulation in MDS pathogenesis

Chronic immune response dysregulation in MDS pathogenesis

Paralogous HOX13 Genes in Human Cancers

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

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