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Thoas Fioretos

Thoas Fioretos

Research team manager

Thoas Fioretos

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

Author

  • Mia Eriksson
  • Pablo Peña-Martínez
  • Ramprasad Ramakrishnan
  • Marion Chapellier
  • Carl Högberg
  • Gabriella Glowacki
  • Christina Orsmark-Pietras
  • Talía Velasco-Hernández
  • Vladimir Lj Lazarević
  • Gunnar Juliusson
  • Jörg Cammenga
  • James C Mulloy
  • Johan Richter
  • Thoas Fioretos
  • Benjamin L Ebert
  • Marcus Järås
Show all

Summary, in English

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.

Department/s

  • StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
  • Division of Clinical Genetics
  • Division of Molecular Medicine and Gene Therapy
  • Stem Cell Center
  • BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation

Publishing year

2017-10-24

Language

English

Pages

2046-2057

Publication/Series

Blood Advances

Volume

1

Issue

23

Document type

Journal article

Publisher

American Society of Hematology

Topic

  • Hematology

Status

Published

Project

  • Identification and characterization of candidate therapeutic targets in acute myeloid leukemia

ISBN/ISSN/Other

  • ISSN: 2473-9529