Why can exposure to the sun much cause leukemia?

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Why can exposure to the sun much cause leukemia?

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Why can exposure to the sun much cause leukemia?

The health effects of sunlight are clear but also complex. Sun exposure can help prevent autoimmune disease, cardiovascular disease, obesity, and depression, but the sun’s ultraviolet rays can also promote skin aging and increase the risk of skin cancer. And a new study shows that it can also promote the development of a rare form of leukemia.

Recently, researchers from the Broad Institute of MIT and Harvard University, Dana-Farber Cancer Institute, and Brigham and Women’s Hospital published a paper entitled: Ultraviolet radiation shapes dendritic cell leukaemia transformation in the top international academic journal Nature Skin ‘s research paper.

Skin tumors of a rare acute leukemic blastic plasmacytoid dendritic cell neoplasm (BPDCN) first arise at sun-exposed sites and are characterized by ultraviolet radiation-induced clonal expansion mutations, the study found .

The study also found that a loss-of-function mutation of the Tet2 gene (the most common precancerous alteration in BPDCN) confers resistance to UV-induced cell death in plasmacytoid cells, suggesting an environment-dependent tumor suppressor effect of Tet2.

These findings reveal how tissue-specific environmental exposures at distal sites shape the evolution of precancerous clones to disseminated cancers.

Cells in our bodies live in very different environments depending on the tissues and organs in which they reside, the research team said, and the study shows how exposure to more than one environment shapes the evolution of precancerous cells into tumor cells .

Although the study focused on a rare cancer called blastic plasmacytoid dendritic cell neoplasm (BPDCN) , the study may shed light on how other cancers develop, particularly blood cancers and lymphomas, where cells move through the blood spread to all corners of the body.

This study also adds to our understanding of BPDCN development, helping to develop new and better treatments.

Blastoid plasmacytoid dendritic cell neoplasm (BPDCN) is a rare form of acute leukemia in which patients are usually 60 years or older and more men than women, an anomaly in leukemia.

The research team had previously found that about half of these BPDCN patients had tumors of leukemia cells in their skin when they first saw their doctor, but no abnormalities were found when their bone marrow, blood or lymph nodes were examined.

While the other half had skin tumors and leukemia cells in more traditional places. The symptoms of patients in the first group were puzzling because, according to models of leukemia development, cancer cells first appear in the bone marrow and then travel through the blood to other parts of the body, including the skin.

In fact, these patients had skin lesions, but their normal bone marrow clearly did not match the model of leukemia development.

Skin tumor in a typical BPDCN patient shows malignant cell infiltration (top panel), but bone marrow can show normal hematopoiesis (bottom panel) or malignant cell infiltration (bottom panel)

The research team attempted to answer these questions by collecting bone marrow and skin tumor samples from 16 BPDCN patients, including those whose bone marrow appeared to be normal, and analyzing the cells for genetic mutations.

The research team found that in those BPDCN patients whose skin showed only signs of the disease, the apparently normal bone marrow cells actually had mutations that matched some of the mutations in the leukemia cells in the skin.

This suggests that BPDCNs begin in the bone marrow in a state known as clonal hematopoiesis, where cells that carry mutations but behave normally appear in the skin as leukemia cells with additional mutations.

To better understand this process, the research team took an in-depth study of the genes and their expression changes in the bone marrow, blood and skin leukemia cells of these patients through single-cell sequencing and single-cell RNA sequencing.

Determine which cells in the bone marrow and blood acquired these initial mutations and which cells accumulated the mutations seen in leukemia tumors of the skin.

To achieve this goal, the research team developed a new technical approach they call eXpressed Variant sequencing (XV-seq) , which integrates two powerful forms of genetic analysis—single-cell gene expression and genotyping.

We need a high-resolution view of how these tumors evolve, so we can see which mutations arose early in the disease and which later in the disease, and in which cells, the team said. XV-seq technology allowed us to precisely identify mutation-carrying cells and pinpoint rare circulating malignant cells not seen by standard clinical methods.

The research team found that blood and bone marrow cells from all BPDCN patients had early clonal hematopoietic mutations. They then identified the culprit behind the increased mutations in skin leukemia – the sun , specifically the ultraviolet rays in sunlight .

In tumors in the skin, as well as in leukemic tissue from the blood and bone marrow, leukemia cells developed mutations caused by ultraviolet radiation, the study showed. In some patients, individual clonal hematopoietic cells in the blood had to be exposed to ultraviolet radiation and Acquire additional mutations to become leukemia cells.

Based on these findings, the research team mapped three steps in the development of BPDCN in the skin:

1. Bone marrow cells undergo mutations to clone hematopoiesis;
2. At least one of these cells enters the skin and mutates when exposed to ultraviolet light;
3. The cell then undergoes additional mutations that turn it into a mature leukemia cell.

To support the theory of the disease’s origin, the research team worked with experts in dermatology to determine where the patients’ skin lesions first formed.

They found that almost all of these occurred in sun-exposed areas, whereas in other leukemias, which can invade the skin, the lesions were distributed randomly across the skin. These findings strongly suggest that skin exposure to UV light, and the resulting genetic mutations, are part of blastic plasmacytoid dendritic cell neoplasm (BPDCN) .

Finally, the research team explored how the most common genetic mutations in BPDCN affect the development of the disease.

Mutations in the Tet2 gene are found in 80 percent of BPDCN patients , many of whom have mutations in both copies of the gene so that expression is completely switched off.

The research team further found that BPDCN cells without Tet2 gene mutations would die when exposed to ultraviolet light, while BPDCN cells with Tet2 gene mutations could survive when exposed to the same ultraviolet light.

This might explain why so many BPDCN cells are resistant to UV radiation in the skin, giving them the chance to acquire more mutations and develop leukemia.

Paper link :
https://www.nature.com/articles/s41586-023-06156-8

Why can exposure to the sun much cause leukemia?

(source:internet, reference only)

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