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CSF1R Is Required for Differentiation and Migration of Langerhans Cells and Langerhans Cell Histiocytosis.
Cancer Immunology Research ( IF 10.1 ) Pub Date : 2020-06-01 , DOI: 10.1158/2326-6066.cir-19-0232
Silvia Lonardi 1 , Sara Scutera 2 , Sara Licini 1 , Luisa Lorenzi 1 , Anna Maria Cesinaro 3 , Luisa Benerini Gatta 1 , Carlotta Castagnoli 4 , Daniele Bollero 5 , Rosaria Sparti 2 , Michela Tomaselli 1 , Daniela Medicina 1 , Federica Calzetti 6 , Marco Antonio Cassatella 6 , Fabio Facchetti 1 , Tiziana Musso 2 , William Vermi 1, 5, 7
Affiliation  

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by tissue accumulation of CD1a+CD207+ LCH cells. In LCH, somatic mutations of the BRAF V600E gene have been detected in tissue LCH cells, bone marrow CD34+ hematopoietic stem cells, circulating CD14+ monocytes, and BDCA1+ myeloid dendritic cells (DC). Targeting BRAF V600E in clonal Langerhans cells (LC) and their precursors is a potential treatment option for patients whose tumors have the mutation. The development of mouse macrophages and LCs is regulated by the CSF1 receptor (CSF1R). In patients with diffuse-type tenosynovial giant cell tumors, CSF1R inhibition depletes tumor-associated macrophages (TAM) with therapeutic efficacy; however, CSF1R signaling in LCs and LCH has not been investigated. We found through IHC and flow cytometry that CSF1R is normally expressed on human CD1a+CD207+ LCs in the epidermis and stratified epithelia. LCs that were differentiated from CD14+ monocytes, BDCA1+ DCs, and CD34+ cord blood progenitors expressed CSF1R that was downregulated upon maturation. Immature LCs migrated toward CSF1, but not IL34. Administration of the c-FMS/CSF1R kinase inhibitors GW2580 and BLZ945 significantly reduced human LC migration. In LCH clinical samples, LCH cells (including BRAF V600E cells) and TAMs retained high expression of CSF1R. We also detected the presence of transcripts for its ligand, CSF1, but not IL34, in all tested LCH cases. CSF1R and CSF1 expression in LCH, and their role in LC migration and differentiation, suggests CSF1R signaling blockade as a candidate rational approach for treatment of LCH, including the BRAF V600E and wild-type forms of the disease.

中文翻译:

CSF1R是朗格汉斯细胞分化和迁移和朗格汉斯细胞组织细胞增生所必需的。

朗格汉斯细胞组织细胞增生症(LCH)是一种罕见疾病,其特征在于CD1a + CD207 + LCH细胞的组织蓄积。在LCH中,已在组织LCH细胞,骨髓CD34 +造血干细胞,循环CD14 +单核细胞和BDCA1 +髓样树突细胞(DC)中检测到BRAF V600E基因的体细胞突变。在克隆的朗格汉斯细胞(LC)及其前体中靶向BRAF V600E是肿瘤发生突变的患者的潜在治疗选择。小鼠巨噬细胞和LC的发育受CSF1受体(CSF1R)调节。在患有弥漫型腱鞘巨细胞瘤的患者中,CSF1R抑制作用可消减肿瘤相关巨噬细胞(TAM)的疗效。但是,尚未研究LC和LCH中的CSF1R信号传导。我们通过IHC和流式细胞仪发现,CSF1R通常在表皮和分层上皮的人CD1a + CD207 + LCs上表达。与CD14 +单核细胞,BDCA1 + DC和CD34 +脐带血祖细胞区别的LC表达的CSF1R在成熟后会下调。未成熟的LC向CSF1迁移,但向IL34迁移。c-FMS / CSF1R激酶抑制剂GW2580和BLZ945的使用显着减少了人类LC的迁移。在LCH临床样品中,LCH细胞(包括BRAF V600E细胞)和TAM保留了CSF1R的高表达。在所有测试的LCH病例中,我们还检测到了其配体CSF1而不是IL34的转录本的存在。LSF中CSF1R和CSF1的表达及其在LC迁移和分化中的作用表明,CSF1R信号传导阻断是治疗LCH的一种合理的候选方法,
更新日期:2020-06-01
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