Rodig Scott J, Payne Ethan G, Degar Barbara A, Rollins Barrett, Feldman Andrew L, Jaffe Elaine S, Androkites Arlene, Silverman Lewis B, Longtine Janina A, Kutok Jeffery L, Fleming Mark D, Aster Jon C
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Am J Hematol. 2008 Feb;83(2):116-21. doi: 10.1002/ajh.21044.
Langerhans cell histiocytosis (LCH) and related entities are neoplasms of unknown pathogenesis. Here, we describe studies assessing the role of NOTCH1 mutations in LCH, which were based on a case of fatal Langerhans cell tumor after T-cell acute lymphoblastic leukemia (T-ALL). Although the two types of neoplasm in this patient were temporally and pathologically distinct, molecular analyses showed that they harbored the same T-cell receptor gene rearrangements and two activating NOTCH1 mutations involving exons 27 and 34. The exon 27 mutation altered a conserved cysteine residue in the N-terminal portion of the NOTCH1 heterodimerization domain, while the mutation in exon 34 introduced a premature stop codon that results in the deletion of C-terminal negative regulatory PEST domain. Analysis of cDNA prepared from the aggressive Langerhans cell tumor showed that the NOTCH1 mutations were aligned in cis, a configuration that caused synergistic increases in NOTCH1 signal strength in reporter gene assays. Immunohistochemistry confirmed that the Langerhans cell tumor also expressed NOTCH1 protein. Although these data suggested that NOTCH1 mutations might contribute to the pathogenesis of typical sporadic LCH and related neoplasms occurring in the absence of T-ALL, an analysis of 24 cases of LCH and Rosai-Dorfman Disease occurring in patients without an antecedent history of T-ALL revealed no mutations. Thus, activating NOTCH1 mutations appear to be unique to aggressive Langerhans cell tumors occurring after T-ALL. Persistent expression of NOTCH1 in such tumors suggests that Notch pathway inhibitors could have a role in the treatment of these unusual neoplasms.
朗格汉斯细胞组织细胞增多症（LCH）及相关病变是发病机制不明的肿瘤。在此，我们描述了评估NOTCH1突变在LCH中作用的研究，这些研究基于1例T细胞急性淋巴细胞白血病（T-ALL）后发生的致命性朗格汉斯细胞肿瘤病例。尽管该患者的这两种肿瘤在时间和病理上有所不同，但分子分析显示它们具有相同的T细胞受体基因重排以及涉及外显子27和34的两个激活型NOTCH1突变。外显子27突变改变了NOTCH1异二聚化结构域N端部分的一个保守半胱氨酸残基，而外显子34中的突变引入了一个提前终止密码子，导致C端负调控PEST结构域缺失。对侵袭性朗格汉斯细胞肿瘤制备的cDNA分析表明，NOTCH1突变呈顺式排列，这种构型在报告基因检测中导致NOTCH1信号强度协同增加。免疫组织化学证实朗格汉斯细胞肿瘤也表达NOTCH1蛋白。尽管这些数据提示NOTCH1突变可能促成典型散发性LCH及在无T-ALL情况下发生的相关肿瘤的发病机制，但对24例无T-ALL既往史患者发生的LCH和罗萨伊-多夫曼病的分析未发现突变。因此，激活型NOTCH1突变似乎是T-ALL后发生的侵袭性朗格汉斯细胞肿瘤所特有的。NOTCH1在这类肿瘤中的持续表达提示Notch通路抑制剂可能在这些不寻常肿瘤的治疗中发挥作用。
