A change of scenery may improve one’s mood, but for some pre-cancerous cells, the move from the caverns of bone marrow to the sunken realms of the skin can lead to genetic changes that are precursors to cancer. That’s according to a new study by researchers at the Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and the Broad Institute of MIT and Harvard. The discovery, which was published in the journal Nature, is one of the first to reveal the “genetic journey” of cancer that spreads across multiple tissues.
Although the study focused on a rare type of cancer, blastic plasmacytoid dendritic cell neoplasm (BPDCN), researchers believe it may shed light on how other cancers arise, particularly those in the blood or lymph. Contains cells that go to all parts of the body through circulation. Body.
“Cells within our bodies live in very different environments depending on which organ or tissue they are in,” says co-senior author Andrew Lane, MD, PhD, of Dana-Farber and the Broad Institute. “In this study, we demonstrate how exposure to more than one of these environments can shape the development of pre-malignant cells to tumor cells. The results add to our understanding of the development of BPDCN, which is important for devising new and better treatments for the disease,” he continues.
“They may also apply to any cancer that develops in more than one site — and potentially to how cancers change after metastases to other parts of the body.” BPDCN is an aggressive malignancy of the bone marrow and blood that is diagnosed in 200–400 people in the United States each year, usually in patients 60 or older, and more often in men than women. This is also a discrepancy among leukemias.
“At the time patients first come to therapy, about half of them have tumors of leukemia cells in their skin, but when we examine their bone marrow, blood, or lymph nodes—where we find leukemia cells To expect — we don’t see anything abnormal,” says Lane, director of the BPDCN Center at Dawn Dana-Farber. “The other half have skin tumors as well as leukemia cells in more traditional locations.”
The symptoms of the first group of patients are puzzling because, according to the model of how leukemia progresses, cancer cells first appear in the bone marrow, then travel through the blood to other parts of the body, including the skin. The fact that these patients had skin lesions but apparently normal marrow ruled out that model.
Lane and his colleagues tried to solve the puzzle by collecting samples of bone marrow and skin tumors from 16 patients whose bone marrow looked normal, and analyzing the cells for genetic mutations.
In patients whose only sign of disease was in the skin, the researchers found that the normal bone marrow cells most commonly had mutations that matched some of the leukemia cells’ mutations in the skin. This suggests that BPDCN begins in the bone marrow as a condition called clonal hematopoiesis (CH) – in cells that harbor the mutation but behave normally – and as leukemia cells with additional mutations in the skin. appear in.
To better understand this process, the researchers took a deep dive into the genetics of the patients’ bone marrow, blood and skin leukemia cells — sequencing the DNA and RNA in individual cells.
“We wanted to determine which cells in the bone marrow and blood are acquiring these early mutations, and which cells are acquiring the mutations we see in skin leukemia tumors,” explains Lane.
To accomplish this, the researchers developed a new technical approach, which they termed eExpressed Variant Sequence (XV-seq), that integrates two powerful forms of genetic analysis, single-cell gene expression and genotyping.
Peter van Galen, PhD, co-senior author of the study, said, “We needed a high-resolution view of how these tumors were developing so that we could see which mutations arose early in the disease, which appeared later.” Given, and in which cells.” D., Brigham and Women’s Hospital and Broad. “XV-seq has allowed us to precisely identify cells carrying mutations and to pinpoint rare circulating malignant cells that standard diagnostic approaches cannot see.”
They found that all patients had blood and bone marrow cells with early CH mutations. He then identified the culprit for the mutations linked to skin leukemia: the sun — specifically, the ultraviolet rays in sunlight.
“We found that in tumors in the skin — and in leukemia tissue from the blood and bone marrow — leukemia cells are caused by ultraviolet [UV] radiation,” comments Lane. (Scientists have mapped the specific pattern of gene mutations produced by UV light.) “In some patients, a CH cell in the bloodstream was exposed to ultraviolet radiation—and picked up additional mutations—from it.” First it can become a leukemia cell.”
Researchers can now plan the development of BPDCN in the skin in three stages:
1) bone marrow cells develop mutations for clonal hematopoiesis;
2) at least one of the cells that penetrate the skin acquires a mutation from the UV light;
3) Later on the cell has other mutations which turn it into a full blown leukemia cell.
To corroborate this account of the disease’s origin, the investigators enlisted dermatology researchers to determine where the patients’ skin lesions first formed. “We found that almost all of them occurred in sun-exposed areas,” relates Lane. “In other types of leukemia that can invade the skin, the lesions are randomly distributed across the skin. Our findings strongly suggest that exposure of the skin to UV rays, and the resulting genetic mutations, is a factor in the development of this disease.” part of the process.”
Finally, the researchers explored how the most common gene mutation in BPDCN affects the development of the disease. Mutations in the gene Tet2 are found in 80% of patients with BPDCN, many of whom carry mutations in both copies of the gene, turning it off completely.
In a series of experiments, the researchers found that when normal counterparts of BPDCN cells are exposed to ultraviolet light, they die. When BPDCN cells carrying the Tet2 mutation are exposed to the same light, they survive. “This may explain why so many BPDCN cells encounter ultraviolet radiation exposure in the skin, giving them a chance to acquire more mutations and become leukemic,” commented Lane.