Chronic myeloid leukemia (CML) typically occurs in late adulthood. Pediatric CML is a rare form of leukemia. In all age groups, the characteristic genetic driver of the disease is the BCR::ABL1 fusion gene. However, additional genomic events contribute to leukemic transformation, which is not yet well-characterized in pediatric CML. We investigated the mutational landscape of pediatric CML to determine whether predisposing germline variants may play a role in early-age disease development. Whole exome sequencing and targeted sequencing were performed in pediatric and adult CML samples to identify age-related germline and somatic variants in addition to the BCR::ABL1 translocation. Germline variants were detected in about 60% of pediatric patients with CML, with predominantly hematopoietic genes affected, most frequently ASXL1, NOTCH1, KDM6B, and TET2. The number of germline variants was significantly lower in adult patients with CML. If only confirmed pathogenic variants were regarded as cancer-predisposing variants, the occurrence was ~ 10% of pediatric CML, which is comparable to other hematological malignancies and most childhood cancer entities in general. We hypothesize that the interaction with the strong oncogene BCR::ABL1 may also favor the development of leukemia by weaker variants in the same genes. In pediatric patients, the germline variants of genes associated with clonal hematopoiesis may increase the likelihood that an incidental BCR::ABL1 translocation triggers the early manifestation of CML.

中文翻译：

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小儿慢性粒细胞白血病中种系变异的比例很高


慢性粒细胞白血病（CML）通常发生在成年晚期。儿童 CML 是一种罕见的白血病。在所有年龄组中，该疾病的特征遗传驱动因素是 BCR::ABL1 融合基因。然而，其他基因组事件会导致白血病转化，这在儿科 CML 中尚未得到充分表征。我们研究了儿科 CML 的突变情况，以确定易感种系变异是否可能在早期疾病发展中发挥作用。对儿童和成人 CML 样本进行全外显子组测序和靶向测序，以鉴定除 BCR::ABL1 易位之外的与年龄相关的种系和体细胞变异。约 60% 的 CML 儿科患者检测到种系变异，主要影响造血基因，最常见的是 ASXL1、NOTCH1、KDM6B 和 TET2。成年慢性粒细胞白血病患者的种系变异数量明显较低。如果仅将已确认的致病变异视为癌症易感变异，则儿科 CML 的发生率约为 10%，这与其他血液恶性肿瘤和大多数儿童癌症实体相当。我们推测，与强癌基因 BCR::ABL1 的相互作用也可能有利于同一基因中较弱的变异导致白血病的发展。在儿科患者中，与克隆造血相关的基因的种系变异可能会增加偶然的 BCR::ABL1 易位触发 CML 早期表现的可能性。