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

von Palffy, Sofia LU ; Thorsson, Hanna LU ; Peña-Martínez, Pablo LU ; Puente-Moncada, Noelia LU ; Sandén, Carl LU ; Blom, Anna M LU orcid ; Henningsson, Rasmus LU ; Juliusson, Gunnar LU ; King, Ben LU orcid and Landberg, Niklas LU orcid , et al. (2023) In Blood Advances 7(7). p.1204-1218
Abstract

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,... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood Advances
volume
7
issue
7
pages
1204 - 1218
publisher
American Society of Hematology
external identifiers
  • pmid:36383712
  • scopus:85168221235
ISSN
2473-9529
DOI
10.1182/bloodadvances.2022007682
language
English
LU publication?
yes
additional info
Copyright © 2022 American Society of Hematology.
id
3ab53556-1759-4e76-a12f-31b0426c7b96
date added to LUP
2022-11-20 12:10:28
date last changed
2024-04-14 18:31:07
@article{3ab53556-1759-4e76-a12f-31b0426c7b96,
  abstract     = {{<p>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.</p>}},
  author       = {{von Palffy, Sofia and Thorsson, Hanna and Peña-Martínez, Pablo and Puente-Moncada, Noelia and Sandén, Carl and Blom, Anna M and Henningsson, Rasmus and Juliusson, Gunnar and King, Ben and Landberg, Niklas and Lazarevic, Vladimir Lj and Orsmark-Pietras, Christina and Rissler, Marianne and Rissler, Vendela and Ågerstam, Helena and Järås, Marcus and Lilljebjörn, Henrik and Fioretos, Thoas}},
  issn         = {{2473-9529}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{1204--1218}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood Advances}},
  title        = {{The complement receptor C3AR constitutes a novel therapeutic target in NPM1-mutated AML}},
  url          = {{http://dx.doi.org/10.1182/bloodadvances.2022007682}},
  doi          = {{10.1182/bloodadvances.2022007682}},
  volume       = {{7}},
  year         = {{2023}},
}