UV Radiation Linked to Rare Leukemia in the Skin

According to a new study by researchers at Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and the Broad Institute of MIT and Harvard, a journey from the caves of the bone marrow to the sunny climes of the skin can trigger genetic changes that are a harbinger of cancer for some precancerous cells such as Leukemia.

The discovery, which was published today in the journal Nature, is one of the first to reveal the “genetic travelog” of a cancer that spreads across numerous tissues. Although it focused on a rare form of cancer—blastic plasmacytoid dendritic cell neoplasm (BPDCN)—the research may shed light on how other cancers develop, particularly those involving blood or lymph cells that travel the bloodstream to all corners of the body, investigators say.

“The cells within our body live in very different environments depending on which organ or tissue they’re in,” says study co-senior author Andrew Lane, MD, Ph.D., of Dana-Farber and the Broad Institute. “In this study, we demonstrate how exposure to more than one of these environments can shape the evolution of premalignant cells to tumor cells.”

“The results add to our understanding of the development of BPDCN, which is critical to devising new and better treatments for the disease,” he continues. “They may also be applicable to any cancer that evolves in more than one site—and potentially to how cancers change after they’ve metastasized to other parts of the body.”

BPDCN is an aggressive bone marrow and blood cancer that affects 200-400 persons in the United States each year, usually in patients 60 or older and more often in males than in women. It is also unusual among leukemias.

“At the time patients first come to medical attention, 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’d expect to find leukemia cells—we don’t see anything abnormal,” says Lane, director of the BPDCN Center at Dana-Farber. “The other half have skin tumors as well as leukemia cells in the more traditional places.”

The symptoms of the first group of patients are perplexing since, according to the leukemia progression model, malignant cells first form in the bone marrow and then migrate through the blood to various regions of the body, including the skin. The fact that these patients had cutaneous lesions but normal marrow contradicted that concept.

Lane and his colleagues attempted to answer the conundrum by collecting bone marrow and skin tumor samples from 16 patients, including those with normal bone marrow, and studying the cells for genetic alterations.

Researchers discovered that the purportedly normal bone marrow cells of individuals whose only sign of disease was in the skin had mutations that matched several of the mutations of the leukemia cells in the skin. This suggests that BPDCN begins in the bone marrow as a condition known as clonal hematopoiesis (CH), in which cells have mutations but act normally, and then manifests in the skin as leukemia cells with further mutations.

To further comprehend this process, researchers sequenced the DNA and RNA in individual cells from patients’ bone marrow, blood, and skin leukemia cells.

“We wanted to determine which cells in the bone marrow and blood are acquiring these initial mutations, and which cells are accruing the mutations we see in the skin leukemia tumors,” Lane explains.

To do this, the researchers created eXpressed Variant Sequencing (XV-seq), a new technological approach that combines two strong modes of genetic analysis, single-cell gene expression and genotyping.

“We needed a high-resolution view into how these tumors were evolving, so that we could see which mutations arose early in disease, which ones appeared later, and in which cells,” said study co-senior author Peter van Galen, Ph.D., of Brigham and Women’s Hospital and the Broad. “XV-seq allowed us to precisely identify mutation-carrying cells and pinpoint rare circulating malignant cells that standard clinical approaches couldn’t see.”

They discovered that all of the patients’ blood and bone marrow cells had early CH mutations. The sun—specifically, UV radiation in sunlight—was eventually identified as the source of the additional mutations in the skin leukemias.

“We found that in the tumors in the skin—and in leukemia tissue from blood and bone marrow—the leukemia cells had mutations caused by ultraviolet [UV] radiation,” Lane remarks. (Scientists have mapped the specific patterns of gene mutations produced by UV light.) “In some patients, a single CH cell in the bloodstream had to have been exposed to ultraviolet radiation—and picked up additional mutations—before it could become a leukemia cell.”

Researchers can now trace the progression of BPDCN in the skin in three steps: 1) Bone marrow cells receive mutations for clonal hematopoiesis; 2) At least one of those cells, going into the skin, acquires mutations from UV rays; and 3) The cell later acquires additional mutations that transform it into a full-fledged leukemia cell.

To buttress this account of the disease’s origins, the investigators enlisted dermatological researchers to determine where patients’ skin lesions first formed. “We found that almost all of them occurred in sun-exposed areas,” Lane relates. “In other types of leukemia that can invade the skin, the lesions are randomly distributed across the skin. Our findings strongly suggest that skin exposure to UV rays, and the resulting genetic mutations, are part of the process of this disease.”

Finally, researchers investigated how the most prevalent gene mutation in BPDCN influences illness progression. The mutation in the gene Tet2 is present in 80% of BPDCN patients, with many having changes in both copies of the gene, effectively shutting it down.

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