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Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NF?B-dependent differentiation of AML cells
Department of Clinical Genetics, Lund University, Lund, Sweden.
Department of Clinical Genetics, Lund University, Lund, Sweden.
Department of Clinical Genetics, Lund University, Lund, Sweden.
Department of Clinical Genetics, Lund University, Lund, Sweden.
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2017 (Engelska)Ingår i: Blood advances, ISSN 2473-9529, Vol. 1, nr 23, s. 2046-2057Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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 NF?B-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 NF?B, thus revealing a new putative strategy for therapeutically targeting AML cells.

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American Society of Hematology , 2017. Vol. 1, nr 23, s. 2046-2057
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Hematologi
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URN: urn:nbn:se:liu:diva-146332DOI: 10.1182/bloodadvances.2017006148PubMedID: 29296851OAI: oai:DiVA.org:liu-146332DiVA, id: diva2:1195975
Tillgänglig från: 2018-04-07 Skapad: 2018-04-07 Senast uppdaterad: 2018-04-25

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