TLR7 ligation augments hematopoiesis in Rps14 deficiency via paradoxical inflammatory signalling
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ABSTRACT:
PROVIDER: PRJNA713782 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13938338_1.fastq.gz | Fastqsanger.gz | |||
| SRR13938338_2.fastq.gz | Fastqsanger.gz | |||
| SRR13938339_1.fastq.gz | Fastqsanger.gz | |||
| SRR13938339_2.fastq.gz | Fastqsanger.gz | |||
| SRR13938340_1.fastq.gz | Fastqsanger.gz |
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Project description:Myelodysplastic syndrome (MDS) is a haematological malignancy characterised by blood cytopenias and predisposition to acute myeloid leukaemia. We developed a model of MDS using zebrafish using knockout of Rps14, the primary mediator of the anaemia associated with del (5q) MDS. These mutant animals develop bone marrow failure with dysplastic features. We conducted an in vivo small molecule screen to identify compounds that ameliorate the MDS phenotype, identifying imiquimod, an agonist of TLR7. We conducted RNA-seq analysis of both treated and untreated animals to define the mechanism of imiquimod in alleviating anaemia. We find imiquimod alleviates anaemia by promoting haematopoietic stem and progenitor cell expansion and erythroid differentiation, the mechanism of which is dependent on TLR7 ligation. TLR7 activation in this setting paradoxically promoted an anti-inflammatory gene signature suggesting crosstalk between pro-inflammatory pathways endogenous to Rps14 loss and TLR7 pathway activation.
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Project description:Myelodysplastic syndrome (MDS) is a hematological malignancy characterized by blood cytopenias and predisposition to acute myeloid leukemia (AML). Therapies for MDS are lacking, particularly those that have an impact in the early stages of disease. We developed a model of MDS in zebrafish with knockout of Rps14, the primary mediator of the anemia associated with del(5q) MDS. These mutant animals display dose- and age-dependent abnormalities in hematopoiesis, culminating in bone marrow failure with dysplastic features. We used Rps14 knockdown to undertake an in vivo small-molecule screening, to identify compounds that ameliorate the MDS phenotype, and we identified imiquimod, an agonist of Toll-like receptor-7 (TLR7) and TLR8. Imiquimod alleviates anemia by promoting hematopoietic stem and progenitor cell expansion and erythroid differentiation, the mechanism of which is dependent on TLR7 ligation and Myd88. TLR7 activation in this setting paradoxically promoted an anti-inflammatory gene signature, indicating cross talk via TLR7 between proinflammatory pathways endogenous to Rps14 loss and the NF-κB pathway. Finally, in highly purified human bone marrow samples from anemic patients, imiquimod led to an increase in erythroid output from myeloerythroid progenitors and common myeloid progenitors. Our findings have both specific implications for the development of targeted therapeutics for del(5q) MDS and wider significance identifying a potential role for TLR7 ligation in modifying anemia.
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