News Releases

Ludwig Harvard study uncovers role of ultraviolet radiation in the development of a rare leukemia in the skin

JUNE 7, 2023, NEW YORK – A study led by Ludwig Harvard researchers Andrew Lane and Peter van Galen and their Harvard colleague Volker Hovestadt is one of the first to uncover the “genetic travelogue” of a rare cancer—blastic plasmacytoid dendritic cell neoplasm (BPDCN)—that evolves across multiple tissues. The study, which could have implications for our understanding of how other blood cancers develop, appears online in Nature today.

“The cells within our body live in very different environments depending on which organ or tissue they’re in,” said Lane, who is an associate professor of medicine at Harvard Medical School and an investigator at the Dana-Farber Cancer Institute 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.”

An aggressive malignancy of the bone marrow and blood diagnosed in 200-400 people in the U.S. each year, BPDCN is something of an anomaly among leukemias. Half of BPDCN patients have tumors of leukemia cells in their skin, but have no apparent abnormalities in their bone marrow, blood or lymph nodes—where leukemia cells are typically found.

To find out why, the researchers analyzed mutations in bone marrow and skin tumor samples from 16 patients, including those whose marrow looked normal. In patients with signs of disease only in the skin, the ostensibly normal bone marrow cells had mutations that matched some of the mutations in leukemic skin tumors. This suggested that BPDCN begins in the bone marrow as a condition called clonal hematopoiesis (CH)—in cells that harbor mutations but behave normally—and shows up in the skin as a leukemia with the accumulation of additional mutations.

To better understand this process, the researchers conducted genetic analysis using a method they developed, eXpressed Variant sequencing (XV-seq), that integrates two powerful forms 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 van Galen, who is an assistant professor at Brigham and Women’s Hospital, Harvard Medical School, and an investigator at the Broad Institute.

The researchers found that all patients had blood and bone marrow cells with early CH mutations. They then identified the likely cause of the additional mutations in the skin leukemias: ultraviolet light from the sun, which leaves a discernable mutational signature.

Based on their findings, the researchers present the following model of BPDCN development: 1) Bone marrow cells develop mutations for clonal hematopoiesis; 2) at least one of those cells, venturing into the skin, acquires mutations from UV light; 3) this cell later incurs other mutations that turn it into a full-fledged leukemia cell.

Dermatological studies of patients supported this model. The researchers also explored how mutations in the gene Tet2, found in 80% of BPDCN patients, drive the cancer. They show that mutations to Tet2 support cell survival following exposure to UV light.

The full Dana-Farber press release from which this summary is derived is available here.


You are now leaving Ludwig Cancer Research's website and are going to a website that is not operated by the association. We are not responsible for the content or availability of linked sites. Do you wish to continue?