Fig. 5: Tet2 loss protects pDCs from UV-induced cell death.
From: Ultraviolet radiation shapes dendritic cell leukaemia transformation in the skin
a, All detected UV-specific (CC > TT) gene mutations, including ETV6.R369W (red) in patient 14 (left). Right, XV-seq analysis of the bone marrow from patient 14 (n = 7,374 cells) showing the random-forest pDC prediction (x axis) and BPDCN signature (y axis) scores. The colours indicate cells with ETV6.R369W mutant calls (red), wild-type transcripts only (dark grey) and no variant calls (light grey). b, Ex vivo differentiation of dendritic cells from mouse bone marrow. Transduction of oestrogen-responsive HOXB8 generates progenitors capable of stable propagation and gene editing in vitro. Oestrogen withdrawal triggers differentiation over 6–8 days into pDCs and cDCs. UV exposure was performed on day 6, and cells were further differentiated until day 8. ER, estrogen receptor. c, Representative flow cytometry analysis of cDC (CD11b+B220−) and pDC (CD11b−B220+) populations in the control, Tet2-knockout and UV-exposed conditions. Gating was performed on viable CD11c+ cells, as in Extended Data Fig. 10d. d, Viable cells (y axis) in control and Tet2-knockout cells on day 8 after UV exposure on day 6. e, The proportion of viable cells (y axis) classified as pDCs or cDCs in control (purple) or Tet2-knockout (orange) conditions at the indicated UV doses. Data are normalized to the 0 UV condition. f, Proposed model for BPDCN development in UV-associated cases. Clonal (premalignant) pDCs/pDC-like precursors arise in the marrow and seed the skin. These cells are then exposed to UV, undergo clonal selection and acquire additional mutations during malignant transformation. Malignant cells then spread systemically, including through retrograde dissemination back to the bone marrow. For d and e, data are mean ± s.e.m., and include two control and two Tet2 gRNAs performed in triplicate, representative of two independent experiments. Statistical analysis in d and e was performed using two-sided Student’s t-tests; ***P < 0.001. The diagrams in b and f were created using BioRender.
