Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NFκB-dependent differentiation of AML cells
Autor: | Gunnar Juliusson, Carl Högberg, Gabriella Glowacki, Ramprasad Ramakrishnan, Marcus Järås, Christina Orsmark-Pietras, James C. Mulloy, Talia Velasco-Hernandez, Benjamin L. Ebert, Mia Eriksson, Thoas Fioretos, Marion Chapellier, Johan Richter, Vladimir Lazarevic, Jörg Cammenga, Pablo Peña-Martínez |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Myeloid Neoplasia Myeloid Chemistry CD34 Myeloid leukemia Caspase 3 Hematology CD38 medicine.disease 03 medical and health sciences Leukemia Haematopoiesis 030104 developmental biology medicine.anatomical_structure hemic and lymphatic diseases Immunology medicine Cancer research Hematologi Progenitor cell neoplasms |
Zdroj: | Blood Advances. 1:2046-2057 |
ISSN: | 2473-9537 2473-9529 |
Popis: | 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 in MLL-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 murine Trp53 −/− MLL-AF9 AML cells, we demonstrate that p53 is dispensable for Pam3CSK4-induced apoptosis and differentiation. Moreover, murine AML1-ETO9a -driven AML cells also were forced into apoptosis and differentiation on TLR1/TLR2 activation, demonstrating that the antileukemic effects observed were not confined to MLL -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 the MLL-AF9 AML 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. |
Databáze: | OpenAIRE |
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