![]() Recurrent gene mutations (≥3 patients) are indicated in colour. The parentheses indicate multiple mutations in one gene. Gene labels are ordered from left to right from low to high VAF ( x axis). b, Mutated genes identified by targeted sequencing of marrow samples from 16 patients with BPDCN, including nine without marrow involvement (top limit of detection, 5%) and seven with involvement (bottom the orange bars indicate tumour cellularity). Scale bars, 200 μm (top), 100 μm (middle right and bottom right), 50 μm (middle left and bottom left). Marrow can show normal haematopoiesis (middle) or involvement by malignant cells (bottom). Thus, BPDCN presents a unique opportunity to study clonal evolution to cancer across anatomical sites, and to evaluate tissue-specific mutational processes in malignant transformation and progression.Ī, Skin tumour (top) from a representative patient with BPDCN showing infiltration by malignant cells (haematoxylin and eosin (H&E), left) expressing the pDC marker TCL1 (immunohistochemistry, right). Here we used integrated genomic and single-cell analysis to examine progression to malignancy in BPDCN, an aggressive leukaemia that often presents as isolated skin tumours without clinically apparent blood or marrow involvement 12. Whether tissue-specific mutational processes affect the clonal evolution of these immune cells is poorly understood. These cells can migrate into peripheral tissues and are increasingly recognized as mediators of organ-specific inflammation 9, 10, 11. In the bone marrow of ageing individuals, clonally expanded precursors with preleukaemic mutations give rise to a variety of differentiated immune cell populations that circulate throughout the body in the peripheral blood 1, 2, 3. Although most clones never progress, rare cells acquire additional alterations that confer a proliferative or survival advantage within the local tissue environment. These findings demonstrate how tissue-specific environmental exposures at distant anatomical sites can shape the evolution of premalignant clones to disseminated cancer.Ĭlonal expansions of cells containing somatic mutations are common in normal tissues, and often arise during ageing or in response to genotoxic stress 6, 7, 8. 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. 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. 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. Using tumour phylogenomics and single-cell transcriptomics with genotyping, we find that BPDCN arises from clonal (premalignant) haematopoietic precursors in the bone marrow. 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. Outside the marrow, these clones are potentially exposed to a variety of tissue-specific mutational processes, although the consequences of this are unclear. 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. Tumours most often arise from progression of precursor clones within a single anatomical niche.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |