Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Blood. 2019 Mar 7;133(10):1060-1070. doi: 10.1182/blood-2018-11-844688. Epub 2019 Jan 22.
Juvenile myelomonocytic leukemia (JMML) is a unique clonal hematopoietic disorder of early childhood. It is classified as an overlap myeloproliferative/myelodysplastic neoplasm by the World Health Organization and shares some features with chronic myelomonocytic leukemia in adults. JMML pathobiology is characterized by constitutive activation of the Ras signal transduction pathway. About 90% of patients harbor molecular alterations in 1 of 5 genes (, , , , or ), which define genetically and clinically distinct subtypes. Three of these subtypes, -, -, and -mutated JMML, are characterized by heterozygous somatic gain-of-function mutations in nonsyndromic children, whereas 2 subtypes, JMML in neurofibromatosis type 1 and JMML in children with CBL syndrome, are defined by germline Ras disease and acquired biallelic inactivation of the respective genes in hematopoietic cells. The clinical course of the disease varies widely and can in part be predicted by age, level of hemoglobin F, and platelet count. The majority of children require allogeneic hematopoietic stem cell transplantation for long-term leukemia-free survival, but the disease will eventually resolve spontaneously in ∼15% of patients, rendering the prospective identification of these cases a clinical necessity. Most recently, genome-wide DNA methylation profiles identified distinct methylation signatures correlating with clinical and genetic features and highly predictive for outcome. Understanding the genomic and epigenomic basis of JMML will not only greatly improve precise decision making but also be fundamental for drug development and future collaborative trials.
幼年髓单核细胞白血病（JMML）是一种独特的儿童早期克隆性造血疾病。它被世界卫生组织归类为重叠的髓系增生/骨髓发育不良肿瘤，与成人慢性髓单核细胞白血病有一些共同特征。JMML 的病理生物学特征是 Ras 信号转导通路的组成性激活。约 90%的患者在 5 个基因之一（NRAS、KRAS、NRAS、NRAS 或）中存在分子改变，这些改变定义了具有遗传和临床特征的不同亚型。其中 3 种亚型（NRAS、KRAS 和 NRAS 突变型 JMML）在非综合征儿童中表现为杂合性体细胞获得性功能突变，而 2 种亚型（NF1 相关 JMML 和 CBL 综合征相关 JMML）则由 Ras 疾病的种系突变和造血细胞中相应基因的获得性双等位基因失活定义。疾病的临床过程差异很大，部分可根据年龄、血红蛋白 F 水平和血小板计数来预测。大多数儿童需要同种异体造血干细胞移植才能长期无白血病生存，但约 15%的患者疾病最终会自发缓解，因此前瞻性识别这些病例是临床的必要条件。最近，全基因组 DNA 甲基化谱鉴定了与临床和遗传特征相关的独特甲基化特征，对预后具有高度预测性。了解 JMML 的基因组和表观基因组基础不仅将极大地改善精确决策，而且对药物开发和未来的合作试验也至关重要。
