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bioRxiv · 10.1101/2020.07.06.175000

TLR7 ligation augments haematopoiesis in Rps14 (uS11) deficiency via paradoxical suppression of inflammatory signalling and enhanced differentiation

Pena, O. C.·Lubin, A.·Rowell, J.·Hockings, C. A.·Jung, Y.·Hoade, Y.·Dace, P.·Valdivia, L. E.·Tuschl, K.·Böiers, C.·Virgilio, M. C.·Richardson, S.·Payne, E. M.
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Abstract

Myelodysplastic syndrome (MDS) is a haematological malignancy characterised by blood cytopenias and predisposition to acute myeloid leukaemia (AML). Therapies for MDS are lacking, particularly those that impact the early stages of disease. 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 display dose- and age-dependent abnormalities in haematopoiesis, culminating in bone marrow failure with dysplastic features. We utilized rps14 knockdown to undertake an in vivo small molecule screen to identify compounds that ameliorate the MDS phenotype, identifying imiquimod, an agonist of TLR7 and TLR8. 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. Finally, we show that in highly purified human bone marrow samples from anaemic patients, imiquimod leads to an increase in erythroid output from myelo-erythroid 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 anaemia.Competing Interest StatementThe authors have declared no competing interest.View Full Text

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Pena, O. C., Lubin, A., Rowell, J., Hockings, C. A., Jung, Y., Hoade, Y., Dace, P., Valdivia, L. E., Tuschl, K., Böiers, C., Virgilio, M. C., Richardson, S., Payne, E. M.. 2020-07-06. TLR7 ligation augments haematopoiesis in Rps14 (uS11) deficiency via paradoxical suppression of inflammatory signalling and enhanced differentiation. https://doi.org/10.1101/2020.07.06.175000

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