Brune Magdalena M, Rau Achim, Overkamp Mathis, Flaadt Tim, Bonzheim Irina, Schürch Christian M, Federmann Birgit, Dirnhofer Stefan, Fend Falko, Tzankov Alexandar
Institute of Medical Genetics and Pathology, University Hospital Basel, Schönbeinstrasse 40, CH-4031 Basel, Switzerland.
Institute of Pathology and Neuropathology, University Hospital Tübingen, 72076 Tübingen, Germany.
Cancers (Basel). 2021 Nov 9;13(22):5605. doi: 10.3390/cancers13225605.
Myeloproliferative neoplasms (MPN) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) both harbor the potential to undergo myelodysplastic progression or acceleration and can transform into blast-phase MPN or MDS/MPN, a form of secondary acute myeloid leukemia (AML). Although the initiating transforming events are yet to be determined, current concepts suggest a stepwise acquisition of (additional) somatic mutations-apart from the initial driver mutations-that trigger disease evolution. In this study we molecularly analyzed paired bone marrow samples of MPN and MDS/MPN patients with known progression and compared them to a control cohort of patients with stable disease course. Cases with progression displayed from the very beginning a higher number of mutations compared to stable ones, of which mutations in five (, , , and ) strongly correlated with progression and/or transformation, even if only one of these genes was mutated, and this particularly applied to MPN. mutations were found to have a higher allelic frequency than the putative driver mutation in three progressing cases ("-first"), whereas two stable cases displayed a -positive subclone ("-second"), supporting the hypothesis that not only the sum of mutations but also their order of appearance matters in the course of disease. Our data emphasize the importance of genetic testing in MPN and MDS/MPN patients in terms of risk stratification and identification of imminent disease progression.
骨髓增殖性肿瘤（MPN）和骨髓增生异常/骨髓增殖性肿瘤（MDS/MPN）都有发生骨髓增生异常进展或加速的可能，并可转化为急变期MPN或MDS/MPN，即继发性急性髓系白血病（AML）的一种形式。尽管起始的转化事件尚未确定，但目前的概念表明，除了初始驱动突变外，（额外的）体细胞突变是逐步获得的，这些突变触发疾病进展。在本研究中，我们对已知病情进展的MPN和MDS/MPN患者的配对骨髓样本进行了分子分析，并将其与疾病进程稳定的对照队列患者进行了比较。与病情稳定的患者相比，病情进展的患者从一开始就表现出更多的突变，其中五个基因（、、、和）的突变与病情进展和/或转化密切相关，即使这些基因中只有一个发生突变，这种情况在MPN中尤为明显。在三个病情进展的病例（“-第一”）中，发现突变的等位基因频率高于假定的驱动突变，而两个病情稳定的病例表现出一个-阳性亚克隆（“-第二”），这支持了这样一种假设，即在疾病过程中，不仅突变的总和，而且它们出现的顺序都很重要。我们的数据强调了基因检测在MPN和MDS/MPN患者的风险分层和识别即将发生的疾病进展方面的重要性。
