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Thoas Fioretos

Thoas Fioretos

Research team manager

Thoas Fioretos

The complement receptor C3AR constitutes a novel therapeutic target in NPM1-mutated AML

Author

  • Sofia von Palffy
  • Hanna Thorsson
  • Pablo Peña-Martínez
  • Noelia Puente-Moncada
  • Carl Sandén
  • Anna M Blom
  • Rasmus Henningsson
  • Gunnar Juliusson
  • Ben King
  • Niklas Landberg
  • Vladimir Lj Lazarevic
  • Christina Orsmark-Pietras
  • Marianne Rissler
  • Vendela Rissler
  • Helena Ågerstam
  • Marcus Järås
  • Henrik Lilljebjörn
  • Thoas Fioretos
Show all

Summary, in English

Mutated Nucleophosmin 1 (NPM1) is the most common genetic alteration in acute myeloid leukemia (AML), found in approximately 30% of cases. Although mutations in this gene are considered favorable according to current risk stratification guidelines, a large fraction of patients will suffer from relapse, demonstrating the urgent need for new treatment options. Therefore, we aimed to identify cell surface proteins specifically expressed on NPM1)-mutated AML cells, allowing for potential targeting with antibody-based therapies. Herein, we performed an arrayed flow cytometry-based screen directed to 362 cell surface markers. Comparing the cell surface expression on NPM1-mutated AML cells to primitive (CD34+ CD38-) normal bone marrow cells, we identified the complement receptor C3AR as specifically expressed in NPM1-mutated AML. By flow cytometry and single cell RNA-sequencing, we further show that normal hematopoietic stem and progenitor cells lack detectable C3AR gene and protein expression, making it particularly suitable as a target for antibody therapy. We also demonstrate that C3AR in combination with GPR56 distinguishes the leukemic stem cells (LSCs) in NPM1-mutated AML from the normal hematopoietic stem cells, defining the LSC population, as shown by transplantation into immunodeficient mice. Mechanistically, stimulation of C3AR-expressing cells with C3a, the ligand of C3AR, leads to activation of ERK1/2 and increased survival of AML cells, suggesting that this is an important signaling axis in this subtype of AML. Finally, we show that antibodies directed against C3AR efficiently elicit NK cell-mediated killing of primary AML cells ex vivo, highlighting C3AR as a candidate therapeutic target in NPM1-mutated AML.

Department/s

  • LUCC: Lund University Cancer Centre
  • Translational Genomic and Functional Studies of Leukemia
  • Division of Clinical Genetics
  • Targeted therapies in leukemia
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Department of Translational Medicine
  • Protein Chemistry, Malmö
  • Leukemia, Genetics, Epidemiology
  • StemTherapy: National Initiative on Stem Cells for Regenerative Therapy

Publishing year

2023

Language

English

Pages

1204-1218

Publication/Series

Blood Advances

Volume

7

Issue

7

Document type

Journal article

Publisher

American Society of Hematology

Topic

  • Hematology
  • Cancer and Oncology

Status

Published

Research group

  • Translational Genomic and Functional Studies of Leukemia
  • Targeted therapies in leukemia
  • Protein Chemistry, Malmö
  • Leukemia, Genetics, Epidemiology

ISBN/ISSN/Other

  • ISSN: 2473-9529