Journal Article

Ultraviolet radiation shapes dendritic cell leukaemia transformation in the skin

Chung, Sun Sook, van Galen, Peter, Ssozi, Daniel, Morgan, Elizabeth A., Verga, Julia A., Lane, Andrew A., Griffin, Gabriel K., Bouyssou, Juliette M., Hornick, Jason L., Lee, Yoke Seng, Bernstein, Bradley E., Booth, Christopher A. G., Togami, Katsuhiro, LeBoeuf, Nicole R., Hovestadt, Volker, Shanmugam, Vignesh

2023

Overview

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 – 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 skin 5 . 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. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) arises from clonal (premalignant) haematopoietic precursors in the bone marrow, and BPDCN skin tumours first develop at sun-exposed anatomical sites and are distinguished by clonally expanded mutations induced by ultraviolet radiation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 45/23 / 45/91 / 631/1647/2217 / 631/532/1542 / 631/67/1990/283 / 64 / 64/60 / Bone marrow / Bone Marrow Cells - metabolism / Bone Marrow Cells - pathology / Bone Marrow Cells - radiation effects / Bone tumors / Cell death / Cell Death - radiation effects / Cell differentiation / Cell Lineage - genetics / Cell Lineage - radiation effects / Cell Transformation, Neoplastic - genetics / Cell Transformation, Neoplastic - pathology / Cell Transformation, Neoplastic - radiation effects / Chromosomes / Clone Cells - metabolism / Clone Cells - pathology / Clone Cells - radiation effects / Cloning / Dendritic cells / Dendritic Cells - metabolism / Dendritic Cells - pathology / Dendritic Cells - radiation effects / Dendritic structure / Exposure / Genetic transformation / Genotyping / Humanities and Social Sciences / Humans / Immune system / Leukemia / Leukemia, Myeloid, Acute - etiology / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - pathology / multidisciplinary / Mutation / Mutation - radiation effects / Organ Specificity / Osteoprogenitor cells / Pathogenesis / Patients / Precursors / Radiation / Radiation damage / Remission (Medicine) / Science / Science (multidisciplinary) / Single-Cell Gene Expression Analysis / Skin / Skin - pathology / Skin - radiation effects / Skin cancer / Skin Neoplasms - etiology / Skin Neoplasms - genetics / Skin Neoplasms - pathology / Transcriptomics / Transformations / Tumors / Ultraviolet radiation / Ultraviolet Rays - adverse effects