Tumours most often arise from progression of precursor clones within a single anatomical niche. In the bone marrow, clonal progenitors can undergo malignant transformation to acute leukaemia, or differentiate into immune cells that contribute to disease pathology in peripheral tissues^1,2,3,4. Outside the marrow, these clones are potentially exposed to a variety of tissue-specific mutational processes, although the consequences of this are unclear. Here we investigate the development of blastic plasmacytoid dendritic cell neoplasm (BPDCN)—an unusual form of acute leukaemia that often presents with malignant cells isolated to the skin⁵. Using tumour phylogenomics and single-cell transcriptomics with genotyping, we find that BPDCN arises from clonal (premalignant) haematopoietic precursors in the bone marrow. We observe that BPDCN skin tumours first develop at sun-exposed anatomical sites and are distinguished by clonally expanded mutations induced by ultraviolet (UV) radiation. A reconstruction of tumour phylogenies reveals that UV damage can precede the acquisition of alterations associated with malignant transformation, implicating sun exposure of plasmacytoid dendritic cells or committed precursors during BPDCN pathogenesis. Functionally, we find that loss-of-function mutations in Tet2, the most common premalignant alteration in BPDCN, confer resistance to UV-induced cell death in plasmacytoid, but not conventional, dendritic cells, suggesting a context-dependent tumour-suppressive role for TET2. These findings demonstrate how tissue-specific environmental exposures at distant anatomical sites can shape the evolution of premalignant clones to disseminated cancer.

肿瘤最常由单个解剖生态位内的前体克隆的进展引起。在骨髓中，克隆祖细胞可以恶性转化为急性白血病，或分化为导致外周组织疾病病理的免疫细胞^1,2,3,4。在骨髓之外，这些克隆可能会暴露于各种组织特异性突变过程，尽管其后果尚不清楚。在这里，我们研究了母细胞性浆细胞样树突状细胞肿瘤 (BPDCN) 的发展，这是一种不寻常的急性白血病，通常表现为皮肤上分离出的恶性细胞⁵。使用肿瘤系统基因组学和单细胞转录组学进行基因分型，我们发现 BPDCN 起源于骨髓中的克隆（癌前）造血前体细胞。我们观察到 BPDCN 皮肤肿瘤首先在暴露于阳光的解剖部位发生，并以紫外线 (UV) 辐射诱导的克隆扩展突变为特征。肿瘤系统发育的重建表明，紫外线损伤可能发生在与恶性转化相关的改变之前，这表明在 BPDCN 发病过程中浆细胞样树突状细胞或定型前体细胞暴露在阳光下。从功能上讲，我们发现Tet2的功能缺失突变（BPDCN 中最常见的癌前改变）赋予浆细胞样细胞（而非传统的树突状细胞）对紫外线诱导的细胞死亡的抵抗力，这表明 Tet2 具有上下文依赖性肿瘤抑制作用。 TET2。这些发现表明，远处解剖部位的组织特异性环境暴露如何影响癌前克隆向播散性癌症的进化。