IL1RAP is an immunotherapeutic target for normal karyotype triple-mutated acute myeloid leukemia

IL1RAP is an immunotherapeutic target for normal karyotype triple-mutated acute myeloid leukemia

Abstract Background Surface antigens of potential clinical significance remain under-characterized in AML. The European Leukemia Network classifies normal karyotype AML (NK-AML) mutated for NPM1 (NPM1c) as a distinct entity associated with favorable outcomes if not associated with FLT3-ITD mutation....

Full description

Saved in:
Bibliographic Details
Main Authors: Arnaud Métois, Marie-Eve Bordeleau, Louis Theret, Azadeh Hajmirza, Ossama Moujaber, Jean-François Spinella, Jalila Chagraoui, Nadine Mayotte, Isabel Boivin, Éric Audemard, Léo Aubert, Véronique Lisi, Banafsheh Khakipoor, Azer Farah, Éric Bonneil, Alma Robert, Julie Lippens, Anna Moraitis, François Béliveau, Albert Feghaly, Geneviève Boucher, Richard Marcotte, Patrick Gendron, Pierre Thibault, Sébastien Lemieux, Guillaume Richard-Carpentier, Vincent-Philippe Lavallée, Josée Hébert, Philippe P. Roux, Guy Sauvageau
Format: Article
Language:English
Published: BMC 2025-04-01
Series:Biomarker Research
Subjects:
IL1RAP
Acute myeloid leukemia
Surfaceome
Immunotherapy
Cancer
Single cell
Online Access:https://doi.org/10.1186/s40364-025-00769-z
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract Background Surface antigens of potential clinical significance remain under-characterized in AML. The European Leukemia Network classifies normal karyotype AML (NK-AML) mutated for NPM1 (NPM1c) as a distinct entity associated with favorable outcomes if not associated with FLT3-ITD mutation. A subset of NPM1c NK-AML shows additional mutations in 2 genes: FLT3 (FLT3-ITD) and DNMT3 A. These leukemias, also referred to as NK triple mutated AML (NKt-AML), are particularly difficult to eradicate with current treatment options. Therefore, novel therapies are necessary that use proteins specifically expressed at the surface. Methods In order to identify surface antigens for immunotherapy in NKt-AML, an extensive multi-omic analysis was conducted on primary AML samples. Surface proteome enrichment was performed on 100 primary AML samples, twelve of which were NKt-AML. Transcriptome analysis was carried out on the 691 primary AML samples, and single-cell RNA sequencing was conducted on 23 primary AML samples. Results Herein, using multi-omics data from the Leucegene collection, we identify IL1RAP as a promising antigen for this AML subgroup. We demonstrate that IL1RAP is expressed at the surface of primitive AML cells reminiscent of leukemic stem cells in NKt-AML primary human AML specimens, while showing relatively low expression levels in normal bone marrow HSCs. Furthermore, results indicate that elevated IL1RAP expression associates with poor overall and relapse-free survival in the Leucegene cohort of AML patients and predicts nonresponse to hematopoietic stem cell transplantation. Finally, we show that IL1RAP protein is internalized following exposure to specific antibodies, suggesting that IL1RAP represents an interesting target for antibody–drug conjugate development in NKt-AML. Conclusions IL1RAP exhibits preferential expression within NKt-AML, correlating with diminished overall survival rates and diminished responsiveness to hematopoietic stem cell transplantation. Moreover, internalization of IL1RAP presents a promising avenue for immunotherapeutic intervention.
ISSN:2050-7771

Similar Items