Therapy-related myeloid neoplasms (tMNs) are severe adverse events that can occur after treatment with autologous hematopoietic stem cell transplantation (ASCT). This study aimed to investigate the development of tMNs following ASCT at the molecular level by whole-exome sequencing (WES) and targeted deep sequencing (TDS) in sequential (pre-) tMN samples. WES identified a significantly higher number of mutations in tMNs as compared with de novo myelodysplastic syndrome (MDS) (median 27 vs 12 mutations; P = .001). The mutations found in tMNs did not carry a clear aging-signature, unlike the mutations found in de novo MDS, indicating a different mutational mechanism. In some patients, tMN mutations were identified in both myeloid and T cells, suggesting that tMNs may originate from early hematopoietic stem cells (HSCs). However, the mutational spectra of tMNs and the preceding malignancies did not overlap, excluding common ancestry for these malignancies. By use of TDS, tMN mutations were identified at low variant allele frequencies (VAFs) in transplant material in 70% of the patients with tMNs. Reconstruction of clonal patterns based on VAFs revealed that premalignant clones can be present more than 7 years preceding a tMN diagnosis, a finding that was confirmed by immunohistochemistry on bone marrow biopsies. Our results indicate that tMN development after ASCT originates in HSCs bearing (pre-)tMN mutations that are present years before disease onset and that post-ASCT treatment can influence the selection of these clones. Early detection of premalignant clones and monitoring of their evolutionary trajectory may help to predict the development of tMNs and guide early intervention in the future.

中文翻译：

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自体 SCT 后治疗相关髓系肿瘤中白血病前期克隆的早期检测和演变

治疗相关的髓系肿瘤 (tMN) 是严重的不良事件，可在自体造血干细胞移植 (ASCT) 治疗后发生。本研究旨在通过全外显子组测序 (WES) 和靶向深度测序 (TDS) 在序列（前）tMN 样本中，在分子水平上研究 ASCT 后 tMN 的发展。与新发骨髓增生异常综合征 (MDS) 相比，WES 发现 tMN 中的突变数量显着更多（中位数为 27 对 12 突变；P = .001）。与从头 MDS 中发现的突变不同，在 tMN 中发现的突变没有明显的衰老特征，表明存在不同的突变机制。在一些患者中，在骨髓和 T 细胞中都发现了 tMN 突变，这表明 tMN 可能源自早期造血干细胞 (HSC)。然而，tMNs 和先前恶性肿瘤的突变谱没有重叠，排除这些恶性肿瘤的共同血统。通过使用 TDS，70% 的 tMN 患者在移植材料中以低变异等位基因频率 (VAF) 鉴定了 tMN 突变。基于 VAF 的克隆模式重建显示，在 tMN 诊断前 7 年以上可能存在癌前克隆，这一发现已通过骨髓活检的免疫组织化学证实。我们的结果表明，ASCT 后 tMN 的发展起源于带有（前）tMN 突变的 HSC，这些突变在疾病发作前几年就存在，并且 ASCT 后治疗会影响这些克隆的选择。