For some precancerous cells, traveling from the bone marrow to the skin can trigger genetic transformations that can result in leukemia, according to a novel study published by Griffin et al in Nature. The new findings may have shed light on what researchers have termed the “genetic travelogue” of blastic plasmacytoid dendritic cell neoplasms (BPDCN) as well as how other cancer types develop—particularly those involving blood or lymph cells that travel across the body through the bloodstream.
Background
“The cells within our body live in very different environments, depending on which organ or tissue they're in. In this study, we demonstrate how exposure to more than one of these environments can shape the evolution of [precancerous] cells to tumor cells,” explained co–senior study author Andrew Lane, MD, PhD, Associate Professor of Medicine at Harvard Medical School and Director of the Blastic Plasmacytoid Dendritic Cell Neoplasm Center at the Dana-Farber Cancer Institute. “[Our findings] add to our understanding of the development of BPDCN, which is critical to devising new and better treatments for the disease. 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,” he added.
BPDCN, an aggressive malignancy of the bone marrow and blood, is newly diagnosed in 200 to 400 U.S. patients each year—more often in male patients aged 60 years or older. The disease is also an anomaly 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 … we don't see anything abnormal. The other half have skin tumors as well as leukemia cells in the more traditional places,” Dr. Lane noted.
For patients who had leukemia cells in their skin, the symptoms can be puzzling because, according to the model of how leukemia progresses, cancerous cells first appear in the bone marrow and travel via the bloodstream to other parts of the body. The fact that these patients had skin lesions but normal bone marrow defied that model.
Study Methods and Results
In the new study, Dr. Lane and his colleagues sought to solve this conundrum by collecting samples of bone marrow and skin tumors from 16 patients, including from those whose bone marrow appeared normal, and analyzing the cells for genetic mutations. The researchers discovered that among patients whose only sign of disease was in the skin, their normal bone marrow cells had mutations that matched some of the leukemia cell mutations in the skin. They suggested that BPDCN may arise in the bone marrow as a condition called clonal hematopoiesis—where cells that harbor mutations behave normally—and may present in the skin as leukemia cells with additional mutations.
To better understand this process, the researchers examined the genetics of the patients' bone marrow, blood, and skin leukemia cells by sequencing the DNA and RNA in each cell. “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,” Dr. Lane explained. To accomplish this, the researchers developed a new approach they called eXpressed Variant sequencing that integrated 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,” emphasized co–senior study author Peter van Galen, PhD, MSc, Assistant Professor of Medicine at Harvard Medical School and Assistant Professor of Hematology at the Brigham and Women’s Hospital. “[Expressed Variant sequencing] allowed us to precisely identify mutation-carrying cells and pinpoint rare circulating malignant cells that standard clinical approaches couldn't see,” he highlighted.
The researchers discovered that all of the patients involved in the study had blood and bone marrow cells with early clonal hematopoiesis mutations. They then identified ultraviolet radiation as the culprit for the added 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 radiation,” Dr. Lane said. “In some patients, a single [clonal hematopoiesis] cell in the bloodstream had to have been exposed to ultraviolet radiation and picked up additional mutations before it could become a leukemia cell,” he stressed.
Conclusions
With these findings, the researchers were able to plot the development of BPDCN in the skin in three steps: (1) bone marrow cells develop mutations for clonal hematopoiesis; (2) at least one of those cells, venturing into the skin, acquires mutations from ultraviolet radiation; (3) the cell later incurs other mutations that turn it into a leukemia cell.
To validate this account of the BPDCN’s origins, the researchers enlisted dermatologists to determine where the patients' skin lesions first formed.
“We found that almost all of them occurred in sun-exposed areas. 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 [ultraviolet radiation], and the resulting genetic mutations, are part of the process of this disease,” Dr. Lane underscored.
Lastly, Dr. Lane and his colleagues explored how the Tet2 mutation—the most common genetic mutation in BPDCN found in 80% of patients—could affect the development of the disease. Many of these patients were found to have mutations in both copies of the Tet2 gene, completely shutting it down.
In a series of experiments, the researchers found that when the normal counterparts of BPDCN cells were exposed to ultraviolet radiation, they died; however, when BPDCN cells carrying Tet2 mutations were placed under the same light, they survived.
"This may explain why so many BPDCN cells withstand ultraviolet radiation exposure in the skin, which gives them the opportunity to acquire more mutations and become leukemic," Dr. Lane concluded.
Disclosure: The research in this study was supported by the Damon Runyon Cancer Research Foundation, Charles H. Hood Foundation, Children's Cancer Research Fund, the V Foundation, the National Cancer Institute, the Starr Cancer Consortium, the Gilead Sciences Research Scholars Program in Hem/Onc, the Harvard Medical School Epigenetics & Gene Dynamics Initiative, the Leukemia & Lymphoma Society, the Glenn Foundation for Medical Research, the American Federation for Aging Research, the William Guy Forbeck Research Foundation, the U.S. Department of Defense, the Mark Foundation for Cancer Research, the Ludwig Center at Harvard, and the Bertarelli Rare Cancers Fund. For full disclosures of the study authors, visit nature.com.
