Métois Arnaud, Bordeleau Marie-Eve, Theret Louis, Hajmirza Azadeh, Moujaber Ossama, Spinella Jean-François, Chagraoui Jalila, Mayotte Nadine, Boivin Isabel, Audemard Éric, Aubert Léo, Lisi Véronique, Khakipoor Banafsheh, Farah Azer, Bonneil Éric, Robert Alma, Lippens Julie, Moraitis Anna, Béliveau François, Feghaly Albert, Boucher Geneviève, Marcotte Richard, Gendron Patrick, Thibault Pierre, Lemieux Sébastien, Richard-Carpentier Guillaume, Lavallée Vincent-Philippe, Hébert Josée, Roux Philippe P, Sauvageau Guy
The Leucegene Project at Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Québec, H3 T 1 J4, Canada.
Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, Québec, H3 T 1 C5, Canada.
Biomark Res. 2025 Apr 14;13(1):61. doi: 10.1186/s40364-025-00769-z.
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.
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.
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.
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.
急性髓系白血病（AML）中具有潜在临床意义的表面抗原仍未得到充分表征。欧洲白血病网络将因核仁磷酸蛋白1（NPM1）发生突变（NPM1c）的正常核型AML（NK-AML）归类为一个独特的实体，如果不与FMS样酪氨酸激酶3内部串联重复（FLT3-ITD）突变相关，则预后良好。一部分NPM1c NK-AML在两个基因中显示出额外的突变：FLT3（FLT3-ITD）和DNA甲基转移酶3A（DNMT3A）。这些白血病，也被称为NK三突变AML（NKt-AML），用目前的治疗方案特别难以根除。因此，需要使用在表面特异性表达的蛋白质的新型疗法。
为了鉴定NKt-AML中用于免疫治疗的表面抗原，对原发性AML样本进行了广泛的多组学分析。对100份原发性AML样本进行了表面蛋白质组富集，其中12份为NKt-AML。对691份原发性AML样本进行了转录组分析，并对23份原发性AML样本进行了单细胞RNA测序。
在此，利用来自Leucegene数据集的多组学数据，我们确定白细胞介素1受体辅助蛋白（IL1RAP）是该AML亚组的一个有前景的抗原。我们证明，在NKt-AML原发性人类AML标本中，IL1RAP在类似于白血病干细胞的原始AML细胞表面表达，而在正常骨髓造血干细胞中表达水平相对较低。此外，结果表明，在Leucegene队列的AML患者中，IL1RAP表达升高与较差的总生存期和无复发生存期相关，并预测对造血干细胞移植无反应。最后，我们表明，暴露于特异性抗体后，IL1RAP蛋白会被内化，这表明IL1RAP是NKt-AML中抗体药物偶联物开发的一个有吸引力的靶点。
IL1RAP在NKt-AML中表现出优先表达，与总生存率降低和对造血干细胞移植的反应性降低相关。此外，IL1RAP的内化是免疫治疗干预的一个有前景的途径。
