Division of Hematology, University Hospital Basel, CH-4031 Basel, Switzerland.
Department of Biomedicine, University Hospital Basel and University of Basel, CH-4031 Basel, Switzerland.
Curr Oncol. 2022 Feb 1;29(2):805-815. doi: 10.3390/curroncol29020068.
Chronic neutrophilic leukemia (CNL) relates to mutational CSF3R activation with membrane proximal mutations such as T618I as driver mutations, but the significance of truncating mutations is not clarified. In CNL, concomitant mutations promote disease progression, but insight into longitudinal acquisition is incomplete. In this study, we investigated the role of co-occurring germline and somatic mutations in CNL, and assessed the impact of clonal evolution on transformation to acute leukemia. We employed sequential next generation sequencing and SNP array karyotyping to assess clonal evolution in CNL of early manifestation age based on a 33-year-old patient. Germline vs. somatic mutations were differentiated using a sample from the hair follicle. To investigate a potential predisposition for CNL development and progression by germline -W791*, allelic localizations were evaluated. We detected a somatic -T618I mutation at 46% variant allele frequency (VAF) at the time of CNL diagnosis, which co-occurred with a -W791* truncation at 50% VAF in the germline. Evaluation of allelic localization revealed -T618I and W791* on the same allele. A concomitant mutation at 39% VAF increased to 48% VAF upon transformation to mixed phenotype acute leukemia (MPAL), which has both myeloid and lymphoid features. Clonal evolution further involved expansion of the double-mutant clone to 90% VAF via copy neutral loss of heterozygosity on chromosome 1p and the emergence of a mutant subclone. Allogeneic transplantation induced complete remission. This study highlights that CNL not only transforms to AML but also to MPAL. The molecular evolution is especially interesting with a -W791* mutation in the germline and acquisition of -T618I on the same allele compatible with increased susceptibility for mutation acquisition facilitating -related clonal transformation.
慢性中性粒细胞白血病（CNL）与 CSF3R 突变激活有关，其驱动突变位于膜近端，如 T618I 等，但截断突变的意义尚不清楚。在 CNL 中，同时发生的突变会促进疾病进展，但对纵向获得的认识尚不完全。在这项研究中，我们研究了 CNL 中伴发性种系和体细胞突变的作用，并评估了克隆进化对转化为急性白血病的影响。我们采用序贯下一代测序和 SNP array 核型分析，基于一名 33 岁的患者，研究了早期表现年龄的 CNL 中的克隆进化。通过从毛囊中提取样本，区分种系和体细胞突变。为了研究种系-W791突变对 CNL 发展和进展的潜在易感性，评估了等位基因定位。我们在 CNL 诊断时检测到 46%的体细胞-T618I 突变，其变体等位基因频率（VAF）为 46%，同时在种系中还存在 50%的-W791截断。等位基因定位评估显示-T618I 和 W791位于同一等位基因上。在转化为混合表型急性白血病（MPAL）时，伴随的 39%的 VAF 突变增加到 48%的 VAF，MPAL 同时具有髓系和淋系特征。克隆进化进一步涉及通过染色体 1p 上的拷贝中性杂合性丢失，使双突变克隆扩展到 90%的 VAF，并出现 突变亚克隆。异基因移植诱导完全缓解。这项研究强调了 CNL 不仅会转化为 AML，还会转化为 MPAL。分子进化尤其有趣，种系中有-W791突变，而同一等位基因上获得-T618I 突变，这增加了突变获得的易感性，促进了相关的克隆转化。
