白血病相关基因的帧移位突变与接受异基因干细胞移植治疗新发急性髓性白血病患者的良好疗效相关。

IF 1.3 Q4 HEMATOLOGY Journal of hematology Pub Date : 2024-06-01 Epub Date: 2024-06-28 DOI:10.14740/jh1276
Emma Cammann, Sindha Madhav, Lloyd Hutchinson, Jan Cerny, Muthalagu Ramanathan, Jacob R Bledsoe, Vladislav Makarenko, Shyam A Patel, Xiuling Meng, Keith Tomaszewicz, Rajneesh Nath, Benjamin Chen, Bruce Woda, William Selove
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引用次数: 0

摘要

背景:异体干细胞移植(allo-SCT)是治疗急性髓性白血病(AML)的主要方法。其成功与否在很大程度上取决于供体T淋巴细胞对白血病细胞的反应,即所谓的移植物白血病(GvL)效应。GvL 的一个关键潜在驱动因素是对突变衍生的新抗原的免疫反应。以往对实体瘤的研究表明,与非同义单核苷酸变异(SNV)相比,帧移位(FS)衍生的多肽具有更强的免疫原性。因此,我们推测白血病相关基因中含有FS突变的急性髓细胞性白血病病例的免疫原性将高于仅含有其他类型突变(非FS)的病例,从而通过更强大的GvL从同种异体移植中获益更多:我们确定了在 2010 年至 2022 年间接受过 allo-SCT 的急性髓细胞性白血病患者,这些患者的诊断标本上有使用 42 个基因热点面板的下一代测序数据。我们根据FS与非FS状态,比较了诊断时存在的肿瘤突变对总生存期和无复发生存期的影响:结果:确定了 95 例急性髓细胞性白血病异体移植患者。我们观察到新发急性髓细胞性白血病患者移植后的无复发生存率(P = 0.038,危险比 (HR):0.24)和总生存率(P = 0.058,HR:0.55)分别优于非 FS 突变患者(P = 0.058,HR:0.55):我们的研究结果表明,FS 基因突变的急性髓细胞性白血病病例可能比仅有非 FS 基因突变的病例更容易从同种异体移植中获益,这可能是由于免疫原性新表位的生成增加所致。如果在更广泛的研究中得到验证,将体细胞FS突变状态纳入急性髓细胞性白血病中可能会改进骨髓移植的患者选择算法,从而获得更好的治疗效果。
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Frameshift Mutations in Leukemia-Associated Genes Correlate With Superior Outcomes in Patients Undergoing Allogeneic Stem Cell Transplant for De Novo Acute Myeloid Leukemia.

Background: Allogeneic stem cell transplant (allo-SCT) is a mainstay of treatment for acute myeloid leukemia (AML). Its success depends largely on response of donor T lymphocytes against leukemia cells, known as graft-vs-leukemia (GvL) effect. A key potential driver of GvL is immune response to mutation-derived neoantigens. Previous studies in solid tumors have demonstrated enhanced immunogenicity of frameshift (FS)-derived peptides vs. those from non-synonymous single nucleotide variants (SNVs). We therefore hypothesized that AML cases bearing FS mutations in leukemia-associated genes would be more immunogenic than those with only other types of mutations (non-FS), and thus benefit more from allo-SCT via more robust GvL.

Methods: We identified AML patients who had undergone allo-SCT between 2010 and 2022 and had next-generation sequencing data available on diagnostic specimens using a 42-gene hot spot panel. We compared the impact of tumor mutations present at diagnosis on overall survival and relapse-free survival based on FS versus non-FS status.

Results: Ninety-five AML allo-SCT patients were identified. We observed superior relapse-free survival (P = 0.038, hazard ratio (HR): 0.24) and borderline superior overall survival (P = 0.058, HR: 0.55) post-transplant in de novo AML patients, who had at least one FS mutation (other than NPM1) in one of the 42 assessed genes versus those with only non-FS mutations.

Conclusions: Our findings suggest that FS-mutated AML cases may benefit more from allo-SCT than those with only non-FS mutations, possibly due to increased generation of immunogenic neoepitopes. If validated in an expanded study, incorporation of somatic FS mutation status in AML could improve patient selection algorithms for bone marrow transplant and thereby lead to superior outcomes.

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Journal of hematology
Journal of hematology HEMATOLOGY-
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