Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal disorders characterized by aberrant hematopoietic proliferation and an intrinsic risk of progression to blast phase. The WHO classification 2022 identifies chronic myeloid leukemia and the BCR::ABL1 negative MPNs polycythemia vera, primary myelofibrosis and essential thrombocythemia as individual entities. However, overlaps, borderline findings or transitions between MPN subtypes occur and incomplete clinical data often complicates diagnosis. By conducting a thorough genetic analysis, we’ve developed a model that relies on 12 genetic markers to accurately stratify MPN patients. The model can be simplified into a decision tree for routine use. Comparing samples at chronic and blast phase revealed, that one third of patients lost their MPN driver-gene mutation, while mutations in splicing and chromatin modifying genes were stable, indicating a shared founder clone of chronic and blast phase with different driver mutations and therefore different progressing capacities. This was further supported by gain of typical de novo AML gene mutations, accompanied by gain of complex karyotypes and RAS pathway gene mutations. Our data suggest to perform a broader genetic screening at diagnosis and also at clinical progression, as driver mutations may change and the MPN-driver mutations present at diagnosis may disappear.

骨髓增生性肿瘤（MPN）是一组异质性克隆性疾病，其特征是异常造血增殖和进展至急变期的内在风险。 2022 年 WHO 分类将慢性粒细胞白血病和BCR :: ABL1阴性 MPN 真性红细胞增多症、原发性骨髓纤维化和原发性血小板增多症视为单独的实体。然而，MPN 亚型之间会出现重叠、边界结果或转变，并且不完整的临床数据常常使诊断变得复杂。通过进行彻底的遗传分析，我们开发了一个模型，该模型依赖 12 种遗传标记来准确对 MPN 患者进行分层。该模型可以简化为决策树以供日常使用。比较慢性期和急变期的样本发现，三分之一的患者失去了 MPN 驱动基因突变，而剪接和染色质修饰基因的突变是稳定的，这表明慢性和急变期的共同创始人克隆具有不同的驱动突变，因此也不同不断进步的能力。典型的从头 AML 基因突变的获得，以及复杂核型和 RAS 途径基因突变的获得进一步支持了这一点。我们的数据建议在诊断时和临床进展时进行更广泛的基因筛查，因为驱动突变可能会发生变化，并且诊断时存在的 MPN 驱动突变可能会消失。