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Agonistic targeting...
Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NFκB-dependent differentiation of AML cells
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- Eriksson, Mia (author)
- 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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- Peña-Martínez, Pablo (author)
- 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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- Ramakrishnan, Ramprasad (author)
- 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 (author)
- 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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- Högberg, Carl (author)
- 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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- Glowacki, Gabriella (author)
- Department of Clinical Genetics, Lund University, Lund, Sweden
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- Orsmark-Pietras, Christina (author)
- 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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- Velasco-Hernández, Talía (author)
- 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
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- Lazarević, Vladimir Lj (author)
- 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
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- Juliusson, Gunnar (author)
- Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden
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- Cammenga, Jörg (author)
- Linköpings universitet,Linköping University,Avdelningen för Kirurgi, Ortopedi och Onkologi,Medicinska fakulteten,Region Östergötland, Hematologiska kliniken US
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- Mulloy, James C (author)
- Division of Experimental Hematology and Cancer Biology, Cincinnati Childrens Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA
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- Richter, Johan (author)
- Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund, Sweden
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- Fioretos, Thoas (author)
- 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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- Ebert, Benjamin L (author)
- Division of Hematology, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, USA
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- Järås, Marcus (author)
- 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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(creator_code:org_t)
- 2017-10-18
- 2017
- English 12 s.
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In: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 1:23, s. 2046-2057
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Abstract
Subject headings
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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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Eriksson, Mia
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Peña-Martínez, P ...
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Ramakrishnan, Ra ...
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Chapellier, Mari ...
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Högberg, Carl
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Glowacki, Gabrie ...
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show more...
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Orsmark-Pietras, ...
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Velasco-Hernánde ...
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Lazarević, Vladi ...
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Juliusson, Gunna ...
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Cammenga, Jörg
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Mulloy, James C
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Richter, Johan
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Fioretos, Thoas
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Ebert, Benjamin ...
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Järås, Marcus
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Hematology
- Articles in the publication
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Blood Advances
- By the university
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Lund University
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Linköping University