Allen Carl E, Parsons D Williams
Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX; Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX;
Texas Children's Cancer Center, Texas Children's Hospital, Houston, TX; Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX; and Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX.
Hematology Am Soc Hematol Educ Program. 2015;2015:559-64. doi: 10.1182/asheducation-2015.1.559.
Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), and Erdheim-Chester disease (ECD) represent histiocytic disorders with a wide range of clinical manifestations. Until recently, mechanisms of pathogenesis have been speculative and debate has focused on classification of these conditions as reactive versus neoplastic. Genomic studies have been challenged by scarce tissue specimens, as well as heterogeneous nature of the lesions with variable infiltration of pathologic histiocytes. Whole-exome sequencing recently revealed a very low frequency of somatic mutations in LCH, JXG, and ECD compared to other neoplastic disorders. However, at least in the cases of LCH and ECD, there is a very high frequency of activating mutations in MAPK pathway genes, most notably BRAF-V600E, as well as MAP2K1, in LCH and NRAS in ECD. In ECD, recurrent mutations in the PI3K pathway gene PIK3CA have also been described. The heterogeneous clinical manifestations of these disorders may therefore be the cumulative result of activation of MAPK mutations (along with modifying signals from other pathways) at distinct stages of myeloid differentiation. Implications of this model include redefinition of LCH, JXG, and ECD as a group of clinically diverse myeloid neoplastic disorders with a common mechanism of pathogenesis. This model supports refocusing therapeutic strategies for these diseases on a personalized approach based on specific mutations and the cell(s) of origin.
朗格汉斯细胞组织细胞增多症（LCH）、幼年性黄色肉芽肿（JXG）和厄尔德海姆-切斯特病（ECD）是一组临床表现多样的组织细胞疾病。直到最近，其发病机制仍只是推测，争论主要集中在将这些疾病归类为反应性还是肿瘤性。由于组织标本稀缺，以及病变具有异质性，病理组织细胞浸润程度不一，基因组研究面临挑战。与其他肿瘤性疾病相比，全外显子测序最近发现LCH、JXG和ECD中体细胞突变的频率非常低。然而，至少在LCH和ECD病例中，丝裂原活化蛋白激酶（MAPK）通路基因存在高频激活突变，在LCH中最显著的是BRAF-V600E以及MAPK1，在ECD中是NRAS。在ECD中，还发现了磷脂酰肌醇-3-激酶（PI3K）通路基因PIK3CA的复发性突变。因此，这些疾病的异质性临床表现可能是骨髓分化不同阶段MAPK突变激活（以及来自其他通路的修饰信号）的累积结果。该模型的意义包括将LCH、JXG和ECD重新定义为一组具有共同发病机制、临床表现多样的骨髓肿瘤性疾病。该模型支持将这些疾病的治疗策略重新聚焦于基于特定突变和起源细胞的个性化方法。
