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BRAF ^V600E诱导的衰老是造成朗格汉斯细胞组织细胞增多症（LCH）的病理原因，这一成果由美国西奈山伊坎医学院Miriam Merad团队经过不懈努力而取得。 2021年5月6日出版的《自然-医学》发表了这项成果。

研究人员最近发现，BRAF ^V600E突变可以影响多系统LCH疾病个体的多能造血祖细胞（HPC）。然而尚不清楚HPC中BRAF ^V600E突变如何导致LCH。

在本研究中，研究人员发现BRAF ^V600E突变在早期小鼠和人类多能HPC中的诱导表达导致HPC生长停滞、凋亡抗性和衰老相关分泌表型（SASP）的衰老程序。反过来，SASP促进HPC向MNP谱系分化，导致衰老克隆单核吞噬细胞（MNP）在组织中积聚并形成LCH病变。因此，使用INK-ATTAC转基因小鼠消除衰老细胞以及通过药物抑制SASP，改善了小鼠LCH疾病。这些结果确定了衰老细胞是治疗LCH的新靶标。

据介绍，朗格汉斯细胞组织细胞增多症是一种潜在的致命疾病，其特征是肉芽肿性病变，该病变中的MNP具有有丝裂原激活蛋白激酶（MAPK）途径激活基因的体细胞突变，最为熟知的是BRAF ^V600E。

附：英文原文

Title: BRAF V600E -induced senescence drives Langerhans cell histiocytosis pathophysiology

Author: Camille Bigenwald, Jessica Le Berichel, C. Matthias Wilk, Rikhia Chakraborty, Steven T. Chen, Alexandra Tabachnikova, Rebecca Mancusi, Harshal Abhyankar, Maria Casanova-Acebes, Ilaria Laface, Guray Akturk, Jenielle Jobson, Zoi Karoulia, Jerome C. Martin, John Grout, Anahita Rafiei, Howard Lin, Markus G. Manz, Alessia Baccarini, Poulikos I. Poulikakos, Brian D. Brown, Sacha Gnjatic, Amaia Lujambio, Kenneth L. McClain, Jennifer Picarsic, Carl E. Allen, Miriam Merad

Issue&Volume: 2021-05-06

Abstract: Langerhans cell histiocytosis (LCH) is a potentially fatal condition characterized by granulomatous lesions with characteristic clonal mononuclear phagocytes (MNPs) harboring activating somatic mutations in mitogen-activated protein kinase (MAPK) pathway genes, most notably BRAFV600E. We recently discovered that the BRAFV600E mutation can also affect multipotent hematopoietic progenitor cells (HPCs) in multisystem LCH disease. How the BRAFV600E mutation in HPCs leads to LCH is not known. Here we show that enforced expression of the BRAFV600E mutation in early mouse and human multipotent HPCs induced a senescence program that led to HPC growth arrest, apoptosis resistance and a senescence-associated secretory phenotype (SASP). SASP, in turn, promoted HPC skewing toward the MNP lineage, leading to the accumulation of senescent MNPs in tissue and the formation of LCH lesions. Accordingly, elimination of senescent cells using INK-ATTAC transgenic mice, as well as pharmacologic blockade of SASP, improved LCH disease in mice. These results identify senescent cells as a new target for the treatment of LCH. Senescence of hematopoietic progenitor cells, enforced by the BRAFV600E mutation, underlies the development of Langerhans cell histiocytosis and could be a new target for drug development and therapy of this disease in patients.

DOI: 10.1038/s41591-021-01304-x

Source: https://www.nature.com/articles/s41591-021-01304-x

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex