All transcripts were created with artificial intelligence software and modified with manual review by a third party. Although we make every effort to ensure accuracy with the manual review, some may contain computer-generated mistranslations resulting in inaccurate or nonsensical word combinations, or unintentional language. FASEB and the presenting speakers did not review the transcripts and are not responsible and will not be held liable for damages, financial or otherwise, that occur as a result of transcript inaccuracies.
There and Back Again: Ultraviolet Radiation Shapes Leukemia Evolution in the Skin
Andrew A. Lane 1
1 Dana-Farber Cancer Institute, Boston, MA, USA
Tumors most often arise from progression of precursor clones within a single anatomic niche. In the bone marrow, clonal progenitors can undergo progression and malignant transformation to acute leukemia, or they can differentiate into immune cells that contribute to disease pathology in peripheral tissues. Outside the marrow, these clones are potentially exposed to a variety of tissue-specific mutational processes, although the consequences of this are uncertain. We investigated the development of blastic plasmacytoid dendritic cell neoplasm (BPDCN), an unusual form of acute leukemia that often presents with malignant cells isolated to the skin. Using tumor phylogenomics and an improved method of single-cell transcriptomics with genotyping (eXpressed Variant sequencing, XV-seq), we found that BPDCN arises from clonally expanded (premalignant) hematopoietic precursors in the bone marrow, despite the marrow elements being morphologically normal. We also observed that BPDCN skin tumors first develop at sun-exposed anatomic sites and are distinguished by clonally expanded mutations induced by ultraviolet (UV) radiation. Reconstruction of tumor phylogenies including at single cell resolution revealed that UV DNA damage follows bone marrow-associated founder mutations (e.g., in TET2, ASXL1, or RNA splicing factors), but precedes the acquisition of progression mutations (e.g., in RAS or CDKN2A) associated with full malignant transformation. Together, these data implicate sun exposure of plasmacytoid dendritic cells (pDCs) or committed precursors during BPDCN pathogenesis. Functionally, we found that loss-of-function mutations in Tet2, the most common premalignant founder alteration in BPDCN, confer resistance to UV-induced cell death in plasmacytoid but not conventional DCs, suggesting a context-dependent tumor-suppressive role for TET2. These findings demonstrate how tissue-specific environmental exposures at distant anatomic sites can shape the evolution of premalignant clones to disseminated cancer. Additionally, while BPDCN is relatively rare, UV signatures have also recently been observed in normal and malignant T-cell populations and in specific genetically defined subsets of pediatric B-cell acute lymphoblastic leukemia, in the absence of overt skin lesions. Together, these data support a model for clonal selection and premalignant evolution in the blood system and in specific hematologic malignancies that may be influenced by exposure to sunlight and ultraviolet radiation. At this meeting, we will put these additional data in context with our own, and we hope to stimulate discussion and inspire future work by our community on this unexpected series of findings.