Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NFκB-dependent differentiation of AML cells

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Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NFκB-dependent differentiation of AML cells

Eriksson, Mia (författare): Lund University,Lunds universitet,Avdelningen för klinisk genetik,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Clinical Genetics,Department of Laboratory Medicine,Faculty of Medicine,Department of Clinical Genetics, Lund University, Lund, Sweden

Peña-Martínez, Pablo (författare): Lund University,Lunds universitet,Avdelningen för klinisk genetik,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Clinical Genetics,Department of Laboratory Medicine,Faculty of Medicine,Department of Clinical Genetics, Lund University, Lund, Sweden

Ramakrishnan, Ramprasad (författare): Lund University,Lunds universitet,Avdelningen för klinisk genetik,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Clinical Genetics,Department of Laboratory Medicine,Faculty of Medicine,Department of Clinical Genetics, Lund University, Lund, Sweden

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Chapellier, Marion (författare): Lund University,Lunds universitet,Avdelningen för klinisk genetik,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Clinical Genetics,Department of Laboratory Medicine,Faculty of Medicine,Department of Clinical Genetics, Lund University, Lund, Sweden

Högberg, Carl (författare): Lund University,Lunds universitet,Avdelningen för klinisk genetik,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Clinical Genetics,Department of Laboratory Medicine,Faculty of Medicine,Department of Clinical Genetics, Lund University, Lund, Sweden

Glowacki, Gabriella (författare): Department of Clinical Genetics, Lund University, Lund, Sweden

Orsmark-Pietras, Christina (författare): Lund University,Lunds universitet,Avdelningen för klinisk genetik,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Clinical Genetics,Department of Laboratory Medicine,Faculty of Medicine,Department of Clinical Genetics, Lund University, Lund, Sweden

Velasco-Hernández, Talía (författare): Lund University,Lunds universitet,Avdelningen för molekylärmedicin och genterapi,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Molecular Medicine and Gene Therapy,Department of Laboratory Medicine,Faculty of Medicine,Department of Molecular Hematology, Lund University, Lund, Sweden

Lazarević, Vladimir Lj (författare): Lund University,Lunds universitet,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine,Faculty of Medicine,Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden

Juliusson, Gunnar (författare): Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden

Cammenga, Jörg (författare): Linköpings universitet,Linköping University,Avdelningen för Kirurgi, Ortopedi och Onkologi,Medicinska fakulteten,Region Östergötland, Hematologiska kliniken US

Mulloy, James C (författare): Division of Experimental Hematology and Cancer Biology, Cincinnati Childrens Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA

Richter, Johan (författare): Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden

Fioretos, Thoas (författare): Lund University,Lunds universitet,Avdelningen för klinisk genetik,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Clinical Genetics,Department of Laboratory Medicine,Faculty of Medicine,Department of Clinical Genetics, Lund, Sweden

Ebert, Benjamin L (författare): Division of Hematology, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, USA

Järås, Marcus (författare): Lund University,Lunds universitet,Avdelningen för klinisk genetik,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Clinical Genetics,Department of Laboratory Medicine,Faculty of Medicine,Department of Clinical Genetics, Lund, Sweden

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2017-10-18
2017
Engelska 12 s.
Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 1:23, s. 2046-2057

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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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Av författaren/redakt...: Eriksson, Mia; Peña-Martínez, P ...; Ramakrishnan, Ra ...; Chapellier, Mari ...; Högberg, Carl; Glowacki, Gabrie ...; visa fler...; Orsmark-Pietras, ...; Velasco-Hernánde ...; Lazarević, Vladi ...; Juliusson, Gunna ...; Cammenga, Jörg; Mulloy, James C; Richter, Johan; Fioretos, Thoas; Ebert, Benjamin ...; Järås, Marcus; visa färre...

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Hematologi

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Av lärosätet: Lunds universitet; Linköpings universitet

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Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NFκB-dependent differentiation of AML cells

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