How did Ultraviolet rays affect cancer progression?

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How did Ultraviolet rays affect cancer progression?

Tumors usually arise from the clonal proliferation of precursor cells in a locus that undergoes malignant transformation leading to acute leukemia in the bone marrow, or differentiates into immune cells leading to lesions in peripheral tissues.

Outside of the bone marrow, these clones may be exposed to a variety of tissue-specific mutation-inducing factors, such as skin exposure to UV light, but whether these tissue-specific mutational processes affect the clonal evolution of these immune cells remains unclear .

Recently, a research team led by Andrew A. Lane, Peter van Galen, Volker Hovestadt, and Gabriel K. Griffin (the first author) from institutions including the Dana-Farber Cancer Institute and the Broad Institute in the United States, published an article titled “Ultraviolet radiation shapes dendritic cell leukaemia transformation in the skin” in Nature.

They discovered that blastic plasmacytoid dendritic cell neoplasm (BPDCN) originates from clonal hematopoietic precursors in the bone marrow.

BPDCN skin tumors first appear in sun-exposed areas and exhibit UV radiation-induced clonal expansion mutations. UV damage occurs before malignant transformation, and the cells undergoing malignant transformation in the skin can migrate back to the bone marrow.

Tet2 mutation enhances pDC (plasmacytoid dendritic cell) resistance to UV-induced cell death.

How did Ultraviolet rays affect cancer progression?

Blastic plasmacytoid dendritic cell neoplasm ( BPDCN ) is a rare acute leukemia that often involves the skin and bone marrow .

Therefore, some people think that BPDCN may originate from the skin, while others believe that it originates from the bone marrow.

To study the relationship between BPDCN skin tumors and premalignant bone marrow, the researchers obtained biopsy samples from 16 patients for sequencing (9 patients without bone marrow involvement, 7 patients with both skin and bone marrow involvement, and 15 patients with both males, 14 patients were older than 60 years) .

Sequencing of bone marrow samples from these patients identified pathogenic mutations in 15 of these patients (94%), including mutations in TET2 , ASXL1 , and RNA splicing factors.

They then used whole-exome sequencing, whole-genome sequencing, and targeted sequencing to find that most of the bone marrow mutations were also present in the corresponding skin tumors, while most of the BPDCN skin tumor mutations were only present in the skin, not in the skin. in the bone marrow.

Therefore, the bone marrow is the origin of premalignant clones of BPDCN, and mutation evolution at multiple tissue sites occurs during the process of cancer metastasis . Using variant allele fraction (VAF) to define initial clones and mutation progression in five patients , they found that initial clones contained recurrent mutations in TET2 , ASXL1 , and the splicing factor ZRSR2 .

Next, they constructed a single-cell transcriptional map using single-cell RNA-sequencing and genotype analysis. In order to detect the differentiation tendency of precancerous clones, they detected 16 initial mutations (the first mutation was detected in the bone marrow) of 5 patients with uninvolved bone marrow , and detected a total of 10245 wild-type cells and 1204 mutant cells.

Mutations were detected in somatic, erythroid, myeloid, and lymphoid components, suggesting that premalignant hematopoietic precursors give rise to a broad spectrum of differentiated blood cell populations, including plasmacytoid dendritic cells (pDCs), which Additional mutations were acquired during the transformation of the carcinogenesis into BPDCN .

They found significant enrichment of ultraviolet (UV) radiation-related signatures in 4 of these 5 patients, and UV-induced DNA damage was characterized by C>T transitions at the dipyrimidine level, including TC>TT, CC > CT and CC>TT, they found that these UV-associated mutations were enriched in BPDCN skin tumors, UV exposure was a feature of BPDCN recurrence, further they found that UV radiation damage occurred before BPDCN transformation, and transformed BPDCN cells in the skin spread to other locations , including retrograde spread to previously unaffected bone marrow .

UV-induced DNA damage can trigger the malignant transformation of pDC by destroying tumor suppressors or activating oncogenes.

Among the 12 CC>TT mutations they identified, one is located on a known leukemia driver gene ETV6, And only in BPDCN cells. Another hypothesis was that UV exposure might provide selective pressure for precancerous pDCs, so they used CRISPR-Cas9 to construct Tet2- mutated HOXB8 precursor cells, and then differentiated these cells into mature pDCs and cDCs, and found that in the absence of UV Under normal circumstances, Tet2 knockout will increase the proportion of pDC, and after UV irradiation, Tet2 knockout will lead to a further increase in the proportion of surviving pDC, indicating that TET2 acts as a tumor suppressor in UV-exposed pDC .

How did Ultraviolet rays affect cancer progression? UV promotes carcinogenesis of dendritic cells in the skin

Overall, this study reveals how tissue-specific environmental exposures affect the evolution and dissemination of precancerous clones.

BPDCN originates in the bone marrow, undergoes further mutation and malignant transformation after metastasizing to the skin and undergoing UV irradiation, and finally metastasizes back to the bone marrow .

It provides a new idea for the treatment of BPDCN.

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