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- Eriksson, Mia, et al.
(författare)
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Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NFκB-dependent differentiation of AML cells
- 2017
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 1:23, s. 2046-2057
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Tidskriftsartikel (refereegranskat)abstract
- Acute myeloid leukemia (AML) is associated with poor survival, and there is a strong need to identify disease vulnerabilities that might reveal new treatment opportunities. Here, we found that Toll-like receptor 1 (TLR1) and TLR2 are upregulated on primary AML CD34+CD38-cells relative to corresponding normal bone marrow cells. Activating the TLR1/TLR2 complex by the agonist Pam3CSK4 inMLL-AF9-driven human AML resulted in induction of apoptosis by p38 MAPK-dependent activation of Caspase 3 and myeloid differentiation in a NFκB-dependent manner. By using murineTrp53 -/- MLL-AF9AML cells, we demonstrate that p53 is dispensable for Pam3CSK4-induced apoptosis and differentiation. Moreover, murineAML1-ETO9a-driven AML cells also were forced into apoptosis and differentiation on TLR1/TLR2 activation, demonstrating that the antileukemic effects observed were not confined toMLL-rearranged AML. We further evaluated whether Pam3CSK4 would exhibit selective antileukemic effects. Ex vivo Pam3CSK4 treatment inhibited murine and human leukemia-initiating cells, whereas murine normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected. Consistent with these findings, primary human AML cells across several genetic subtypes of AML were more vulnerable for TLR1/TLR2 activation relative to normal human HSPCs. In theMLL-AF9AML mouse model, treatment with Pam3CSK4 provided proof of concept for in vivo therapeutic efficacy. Our results demonstrate that TLR1 and TLR2 are upregulated on primitive AML cells and that agonistic targeting of TLR1/TLR2 forces AML cells into apoptosis by p38 MAPK-dependent activation of Caspase 3, and differentiation by activating NFκB, thus revealing a new putative strategy for therapeutically targeting AML cells.
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| 2. |
- Lichtenberg, Elinor M., et al.
(författare)
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A global synthesis of the effects of diversified farming systems on arthropod diversity within fields and across agricultural landscapes
- 2017
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Ingår i: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 23:11, s. 4946-4957
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Tidskriftsartikel (refereegranskat)abstract
- Agricultural intensification is a leading cause of global biodiversity loss, which can reduce the provisioning of ecosystem services in managed ecosystems. Organic farming and plant diversification are farm management schemes that may mitigate potential ecological harm by increasing species richness and boosting related ecosystem services to agroecosystems. What remains unclear is the extent to which farm management schemes affect biodiversity components other than species richness, and whether impacts differ across spatial scales and landscape contexts. Using a global metadataset, we quantified the effects of organic farming and plant diversification on abundance, local diversity (communities within fields), and regional diversity (communities across fields) of arthropod pollinators, predators, herbivores, and detritivores. Both organic farming and higher in-field plant diversity enhanced arthropod abundance, particularly for rare taxa. This resulted in increased richness but decreased evenness. While these responses were stronger at local relative to regional scales, richness and abundance increased at both scales, and richness on farms embedded in complex relative to simple landscapes. Overall, both organic farming and in-field plant diversification exerted the strongest effects on pollinators and predators, suggesting these management schemes can facilitate ecosystem service providers without augmenting herbivore (pest) populations. Our results suggest that organic farming and plant diversification promote diverse arthropod metacommunities that may provide temporal and spatial stability of ecosystem service provisioning. Conserving diverse plant and arthropod communities in farming systems therefore requires sustainable practices that operate both within fields and across landscapes.
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