Oncogene-induced senescence distinguishes indolent from aggressive forms of pulmonary and non-pulmonary Langerhans cell histiocytosis
Oncogene-induced senescence distinguishes indolent from aggressive forms of pulmonary and non-pulmonary Langerhans cell histiocytosis
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DOI：
10.3109/10428194.2014.887713
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发表时间：
2014-11-01
影响因子：
2.6
通讯作者：
Doglioni, Claudio
中科院分区：
文献类型：
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作者：
Chilosi, Marco;Facchetti, Fabio;Doglioni, Claudio
最近通过BRAF突变（包括肺LCH（PLCH））的高患病率证实了朗格汉斯细胞组织细胞增多症（LCH）的克隆/肿瘤性质。我们假设BRAF诱导的衰老，如痣和黑色素瘤所示，参与了LCH和PLCH的发病机制。在一系列的肺（19例）和非肺LCH（19例），包括5个侵略性的情况下，我们调查了BRAF V600 E突变的发生，分子分析和/或免疫组化使用验证抗体（VE 1）。细胞衰老标记物p16（INK 4a）和p21（CIP 1/WAF 1）的表达也进行了化学分析。我们证明，6/19例LCH和12/19例PLCH为VE 1阳性，与分子分析相匹配，并且在所有病例中，无论BRAF突变状态如何，p16（INK 4a）和p21（CIP 1/WAF 1）均表达。有趣的是，所有侵袭性病例均不表达p16（INK 4a），因此表明衰老控制的丧失可能与LCH的临床侵袭性有关，如在黑色素瘤中。
The clonal/neoplastic nature of Langerhans cell histiocytosis (LCH)has recently been demonstrated by a high prevalence of BRAF mutations, including pulmonary LCH (PLCH). We hypothesized that BRAF-induced senescence, as demonstrated in nevi and melanoma, is involved in the pathogenesis of LCH and PLCH. In a series of pulmonary (19 cases) and non-pulmonary LCH (19 cases), including five aggressive cases, we investigated occurrence of the BRAF V600E mutation by molecular analysis and/or immunohistochemistry using a validated antibody (VE1). The expression of cell-senescence markers p16(INK4a) and p21(CIP1/WAF1) was also immunohistochemically investigated. We demonstrated that 6/19 cases of LCH and 12/19 cases of PLCH were VE1 positive, matching with molecular analysis, and in all cases both p16(INK4a) and p21(CIP1/WAF1) were expressed, irrespective of BRAF mutation status. Interestingly, all the aggressive cases did not express p16(INK4a), thus suggesting that loss of senescence control could be related to clinical aggressiveness of LCH, as in melanoma.