Rücker-Braun Elke, Falk Bose, Baldauf Henning, Massalski Carolin, Schäfer Gesine, Altmann Heidi, Sauter Jürgen, Solloch Ute V, Lange Vinzenz, Egger-Heidrich Katharina, Kunadt Desiree, Stölzel Friedrich, Röllig Christoph, Middeke Jan M, von Bonin Malte, Thiede Christian, Schmidt Alexander H, Bornhäuser Martin, Schetelig Johannes, Heidenreich Falk
Department of Internal Medicine I, University Hospital TU Dresden, Dresden, Germany.
Clinical Trials Unit, DKMS Group, Dresden, Germany.
Front Immunol. 2025 Jun 10;16:1571508. doi: 10.3389/fimmu.2025.1571508. eCollection 2025.
Mutations in the nucleophosmin 1 gene (NPM1) are common and recurrent molecular abnormalities in acute myeloid leukemia (AML). NPM1 mutations are considered to be positive prognostic factors. The beneficial effect may be due to immune responses mediated by cytotoxic T cells targeting HLA-presented peptides derived from mutated NPM1 and thereby suppressing mutated NPM1-positive hematopoiesis. While the immunogenicity of these NPM1 peptides has not been demonstrated conclusively, certain HLA-types have been linked to a lower risk of NPM1-mutated AML.
In a comprehensive HLA association study at two-field resolution, we compared the proportions of HLA class I alleles between NPM1-mutated (n = 477) and/or DNMT3A-mutated (n = 216) patients with AML and a control group of healthy individuals (n = 51,890).
We found HLA-B40:01 and HLA-C03:04 to be significantly underrepresented in NPM1-mutated AML compared to the control group (4.0% vs. 10.2%, p < 0.001, and 8.2% vs, 15.9%, p < 0.001, respectively). This might suggest that neoepitopes presented by these HLA alleles trigger T-cell responses. Online epitope prediction tools predict that mutated NPM1-derived peptides bind strongly to B40:01 and C03:04.
Based on these findings, further studies should confirm the presence and functionality of neoepitope-specific T cells and characterize specific T-cell receptors (TCR). Sequence information might eventually be exploited in immunotherapeutic approaches to treat AML patients with TCR-engineered T cells or bispecific TCR T/NK cell engagers.
核磷蛋白1基因（NPM1）突变是急性髓系白血病（AML）中常见且反复出现的分子异常。NPM1突变被认为是阳性预后因素。其有益作用可能归因于细胞毒性T细胞介导的免疫反应，该反应靶向源自突变NPM1的HLA呈递肽，从而抑制突变NPM1阳性造血。虽然这些NPM1肽的免疫原性尚未得到最终证实，但某些HLA类型与NPM1突变AML的较低风险相关。
在一项双场分辨率的全面HLA关联研究中，我们比较了NPM1突变（n = 477）和/或DNMT3A突变（n = 216）的AML患者与健康个体对照组（n = 51,890）之间HLA I类等位基因的比例。
我们发现，与对照组相比，NPM1突变的AML中HLA-B40:01和HLA-C03:04明显不足（分别为4.0%对10.2%，p < 0.001，以及8.2%对15.9%，p < 0.001）。这可能表明这些HLA等位基因呈递的新表位触发了T细胞反应。在线表位预测工具预测，源自突变NPM1的肽与B40:01和C03:04强烈结合。
基于这些发现，进一步的研究应确认新表位特异性T细胞的存在和功能，并表征特定的T细胞受体（TCR）。序列信息最终可能被用于免疫治疗方法，以治疗使用TCR工程化T细胞或双特异性TCR T/NK细胞衔接器的AML患者。
