Fontana Diletta, Ramazzotti Daniele, Aroldi Andrea, Redaelli Sara, Magistroni Vera, Pirola Alessandra, Niro Antonio, Massimino Luca, Mastini Cristina, Brambilla Virginia, Bombelli Silvia, Bungaro Silvia, Morotti Alessandro, Rea Delphine, Stagno Fabio, Martino Bruno, Campiotti Leonardo, Caocci Giovanni, Usala Emilio, Merli Michele, Onida Francesco, Bregni Marco, Elli Elena Maria, Fumagalli Monica, Ciceri Fabio, Perego Roberto A, Pagni Fabio, Mologni Luca, Piazza Rocco, Gambacorti-Passerini Carlo
Department of Medicine and Surgery, University of Milano - Bicocca, Monza, Italy.
Hematology and Clinical Research Unit, San Gerardo Hospital, Monza, Italy.
Hemasphere. 2020 Nov 6;4(6):e497. doi: 10.1097/HS9.0000000000000497. eCollection 2020 Dec.
Atypical chronic myeloid leukemia (aCML) is a -negative clonal disorder, which belongs to the myelodysplastic/myeloproliferative group. This disease is characterized by recurrent somatic mutations in , and genes, as well as high genetic heterogeneity, thus posing a great therapeutic challenge. To provide a comprehensive genomic characterization of aCML we applied a high-throughput sequencing strategy to 43 aCML samples, including both whole-exome and RNA-sequencing data. Our dataset identifies , , and as the most frequently mutated genes with a total of 43.2%, 29.7 and 16.2%, respectively. We characterized the clonal architecture of 7 aCML patients by means of colony assays and targeted resequencing. The results indicate that variants occur early in the clonal evolution history of aCML, while mutations often represent a late event. The presence of actionable mutations conferred both ex vivo and in vivo sensitivity to specific inhibitors with evidence of strong in vitro synergism in case of multiple targeting. In one patient, a clinical response was obtained. Stratification based on RNA-sequencing identified two different populations in terms of overall survival, and differential gene expression analysis identified 38 significantly overexpressed genes in the worse outcome group. Three genes correctly classified patients for overall survival.
非典型慢性髓性白血病（aCML）是一种阴性克隆性疾病，属于骨髓增生异常/骨髓增殖性疾病组。该疾病的特征在于 、 和 基因的复发性体细胞突变，以及高度的遗传异质性，因此带来了巨大的治疗挑战。为了提供aCML的全面基因组特征，我们对43个aCML样本应用了高通量测序策略，包括全外显子组测序和RNA测序数据。我们的数据集确定 、 和 是最常发生突变的基因，分别占总数的43.2%、29.7%和16.2%。我们通过集落分析和靶向重测序对7例aCML患者的克隆结构进行了表征。结果表明， 变异发生在aCML克隆进化历史的早期，而 突变通常代表后期事件。可操作突变的存在赋予了对特定抑制剂的体外和体内敏感性，在多重靶向的情况下有强烈的体外协同作用的证据。在一名患者中获得了临床反应。基于RNA测序的分层在总生存方面确定了两个不同的群体，差异基因表达分析在预后较差的组中确定了38个显著过表达的基因。三个基因正确地对患者的总生存进行了分类。
