BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups.
BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups.
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DOI：
10.1084/jem.20130977
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发表时间：
2014-04-07
期刊：
影响因子：
--
通讯作者：
Allen CE
中科院分区：
文献类型：
--
作者：
Berres ML;Lim KP;Peters T;Price J;Takizawa H;Salmon H;Idoyaga J;Ruzo A;Lupo PJ;Hicks MJ;Shih A;Simko SJ;Abhyankar H;Chakraborty R;Leboeuf M;Beltrão M;Lira SA;Heym KM;Bigley V;Collin M;Manz MG;McClain K;Merad M;Allen CE
在高危LCH患者的造血祖细胞和前体髓系树突状细胞中发现了BRAF-V600E的表达，而在CD11c+细胞中BRAF-V600E的增强表达概括了高危LCH样表型。朗格汉斯细胞组织细胞增多症(LCH)是一种病因不明的克隆性疾病，其特征是CD207+树突状细胞(DC)在炎性病变中聚集。复发性BRAF-V600E突变在LCH中已有报道。在本研究中，对100例患者的皮损进行了基因分型，%的患者在浸润性CD207+DC中携带BRAF-V600E突变。BRAF-V600E在组织树突状细胞中的表达不确定特定的临床风险组，但与复发风险的增加有关。值得注意的是，我们发现活动性、高危型LCH患者外周血中CD11c+和CD14+组分以及骨髓CD34+造血祖细胞中也携带BRAF-V600E，而低危型LCH患者的突变仅限于CD207+DC。重要的是，BRAF-V600E在树突状细胞中的表达足以驱动小鼠的LCH样疾病。与我们在人类中的发现一致，BM DC祖细胞中BRAF-V600E的表达概括了人类高危LCH的许多特征，而BRAF-V600E在分化的DC中的表达更接近于低危LCH。因此，我们建议将LCH归类为髓系肿瘤，并假设高危LCH源于造血祖细胞的体细胞突变，而低危疾病源于组织限制性前体DC的体细胞突变。
BRAF-V600E expression is identified in hematopoietic progenitor and precursor myeloid dendritic cells in patients with high-risk LCH, and enforced expression of BRAF-V600E in CD11c+ cells recapitulates a high-risk LCH-like phenotype in mice. Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207+ dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207+ DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c+ and CD14+ fractions and in bone marrow (BM) CD34+ hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207+ DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs.
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DOI：
10.4049/jimmunol.0902336
发表时间：
2010-04-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Allen CE;Li L;Peters TL;Leung HC;Yu A;Man TK;Gurusiddappa S;Phillips MT;Hicks MJ;Gaikwad A;Merad M;McClain KL
通讯作者：
McClain KL
影响因子：
20.3
作者：
Sahm, Felix;Capper, David;von Deimling, Andreas
通讯作者：
von Deimling, Andreas
影响因子：
20.3
作者：
Badalian-Very, Gayane;Vergilio, Jo-Anne;Rollins, Barrett J.
通讯作者：
Rollins, Barrett J.
影响因子：
3.7
作者：
Kansal, Rina;Quintanilla-Martinez, Leticia;Nathwani, Bharat N.
通讯作者：
Nathwani, Bharat N.
影响因子：
29.4
作者：
Chang, Sun-Young;Cha, Hye-Ran;Kweon, Mi-Na
通讯作者：
Kweon, Mi-Na