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TLR7 ligation augments hematopoiesis in Rps14 (uS11) deficiency via paradoxical suppression of inflammatory signalling

Peña, Oscar A ; Lubin, Alexandra ; Hockings, Catherine ; Rowell, Jasmine ; Jung, Youngrock ; Hoade, Yvette ; Dace, Phoebe ; Valdivia, Leonardo E ; Tuschl, Karin and Böiers, Charlotta LU , et al. (2021) In Blood Advances 5(20). p.4112-4124
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... (More)
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 and Myd88. TLR7 activation in this setting paradoxically promoted an anti-inflammatory gene signature indicating crosstalk between pro-inflammatory pathways endogenous to Rps14 loss and NFkappaB pathway via TLR7. 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. (Less)
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publishing date
type
Contribution to journal
publication status
published
subject
in
Blood Advances
volume
5
issue
20
pages
4112 - 4124
publisher
American Society of Hematology
external identifiers
  • pmid:34432872
  • scopus:85118528044
ISSN
2473-9529
DOI
10.1182/bloodadvances.2020003055
language
English
LU publication?
no
id
c7ebda10-4edd-46c2-be6b-eba26e811873
date added to LUP
2021-09-07 14:47:36
date last changed
2023-06-30 04:00:12
@article{c7ebda10-4edd-46c2-be6b-eba26e811873,
  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,<br/>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 and Myd88. TLR7 activation in this setting paradoxically promoted an anti-inflammatory gene signature indicating crosstalk between pro-inflammatory pathways endogenous to Rps14 loss and NFkappaB pathway via TLR7. 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.}},
  author       = {{Peña, Oscar A and Lubin, Alexandra and Hockings, Catherine and Rowell, Jasmine and Jung, Youngrock and Hoade, Yvette and Dace, Phoebe and Valdivia, Leonardo E and Tuschl, Karin and Böiers, Charlotta and Virgilio, Maria C and Richardson, Simon and Payne, Elspeth}},
  issn         = {{2473-9529}},
  language     = {{eng}},
  number       = {{20}},
  pages        = {{4112--4124}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood Advances}},
  title        = {{TLR7 ligation augments hematopoiesis in Rps14 (uS11) deficiency via paradoxical suppression of inflammatory signalling}},
  url          = {{http://dx.doi.org/10.1182/bloodadvances.2020003055}},
  doi          = {{10.1182/bloodadvances.2020003055}},
  volume       = {{5}},
  year         = {{2021}},
}