Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nat Med. 2021 May;27(5):851-861. doi: 10.1038/s41591-021-01304-x. Epub 2021 May 6.
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 BRAF. We recently discovered that the BRAF mutation can also affect multipotent hematopoietic progenitor cells (HPCs) in multisystem LCH disease. How the BRAF mutation in HPCs leads to LCH is not known. Here we show that enforced expression of the BRAF 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.
朗格汉斯细胞组织细胞增生症（LCH）是一种潜在致命的疾病，其特征是存在肉芽肿性病变，其中含有特征性的单克隆单核吞噬细胞（MNP），这些细胞携带有丝裂原活化蛋白激酶（MAPK）通路基因的激活体细胞突变，尤其是 BRAF。我们最近发现，BRAF 突变也可能影响多能造血祖细胞（HPC）在多系统 LCH 疾病中。HPC 中的 BRAF 突变如何导致 LCH 尚不清楚。在这里，我们显示在早期小鼠和人类多能 HPC 中强制表达 BRAF 突变会诱导衰老程序，导致 HPC 生长停滞、凋亡抵抗和衰老相关分泌表型（SASP）。反过来，SASP 促进 HPC 向 MNP 谱系倾斜，导致组织中衰老 MNPs 的积累和 LCH 病变的形成。因此，使用 INK-ATTAC 转基因小鼠消除衰老细胞，以及通过药物阻断 SASP，改善了小鼠的 LCH 疾病。这些结果表明衰老细胞是治疗 LCH 的一个新靶点。
