Lineage switching of the cellular distribution of BRAFV600E in multisystem Langerhans cell histiocytosis.
Lineage switching of the cellular distribution of BRAFV600E in multisystem Langerhans cell histiocytosis.
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DOI：
10.1182/bloodadvances.2021006732
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发表时间：
2023-05-23
期刊：
影响因子：
7.5
通讯作者：
Collin, Matthew
中科院分区：
文献类型：
--
作者：
Milne, Paul;Bomken, Simon;Slater, Olga;Kumar, Ashish;Nelson, Adam;Roy, Somak;Velazquez, Jessica;Mankad, Kshitij;Nicholson, James;Yeomanson, Dan;Grundy, Richard;Kamal, Ahmed;Penn, Anthony;Pears, Jane;Millen, Gerard;Morland, Bruce;Hayden, James;Lam, Jason;Madkhali, Maymoon;MacDonald, Jamie;Singh, Preeti;Pagan, Sarah;Rodriguez-Galindo, Carlos;Minkov, Milen;Donadieu, Jean;Picarsic, Jennifer;Allen, Carl;Bigley, Venetia;Collin, Matthew
BRAFV 600 E等位基因在诊断多系统LCH时主要见于髓系细胞。超过2年后，T细胞占外周血单核细胞中检测到的持续BRAFV 600 E突变的85%。大多数高危朗格汉斯细胞组织细胞增生症（LCH）患儿存在BRAFV 600 E突变。诊断时，在骨髓单核细胞中可检测到BRAFV 600 E等位基因，但尚不清楚突变的细胞分布是否随时间推移而演变。在这里，分析了16例高危疾病患者的资料。2例接受常规挽救化疗，4例接受抑制剂治疗的患者每隔3 - 6年进行跟踪，10例也接受抑制剂治疗的患者在诊断后2年以上进行分析。与在6个月内完全清除BRAFV 600 E的补救化疗患者相比，接受抑制剂的儿童在血液中维持高BRAFV 600 E等位基因。诊断时，突变主要在单核细胞和髓样树突细胞中检测到。随着时间的推移，突变转移到T细胞区室，占外周血单核细胞突变负荷的大部分，从诊断开始超过2年（中位数，85.4%;范围，44.5%-100%）。最高水平的突变发生在初始CD 4 + T细胞中（中位数，51.2%;范围，3.8%-93.5%）。这项研究揭示了高危LCH中BRAFV 600 E突变的意外谱系转换，这可能影响潜在抑制剂治疗停药的监测策略，并对4例患者发生的神经退行性变的发病机制具有新的意义。
BRAFV600E alleles are mainly found in myeloid cells at diagnosis of multisystem LCH. After more than 2 years, T cells account for 85% of persistent BRAFV600E mutation detected in peripheral blood mononuclear cells. Most children with high-risk Langerhans cell histiocytosis (LCH) have BRAFV600E mutation. BRAFV600E alleles are detectable in myeloid mononuclear cells at diagnosis but it is not known if the cellular distribution of mutation evolves over time. Here, the profiles of 16 patients with high-risk disease were analyzed. Two received conventional salvage chemotherapy, 4 patients on inhibitors were tracked at intervals of 3 to 6 years, and 10 patients, also given inhibitors, were analyzed more than 2 years after diagnosis. In contrast to the patients responding to salvage chemotherapy who completely cleared BRAFV600E within 6 months, children who received inhibitors maintained high BRAFV600E alleles in their blood. At diagnosis, mutation was detected predominantly in monocytes and myeloid dendritic cells. With time, mutation switched to the T-cell compartment, which accounted for most of the mutational burden in peripheral blood mononuclear cells, more than 2 years from diagnosis (median, 85.4%; range, 44.5%-100%). The highest level of mutation occurred in naïve CD4+ T cells (median, 51.2%; range, 3.8%-93.5%). This study reveals an unexpected lineage switch of BRAFV600E mutation in high-risk LCH, which may influence monitoring strategies for the potential withdrawal of inhibitor treatment and has new implications for the pathogenesis of neurodegeneration, which occurred in 4 patients.
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DOI：
10.1084/jem.20130977
发表时间：
2014-04-07
期刊：
The Journal of experimental medicine
影响因子：
--
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
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影响因子：
3.6
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DOI：
10.1038/s41572-021-00307-9
发表时间：
2021-10-07
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Nature reviews. Disease primers
影响因子：
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影响因子：
2.1
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Maschan, Michael
影响因子：
9
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