Research Sheds More Light on Mechanisms Causing Rare Leukemia BPDCN

Medically Reviewed By: Andrew A. Lane, MD, PhD

A rare leukemia called BPDCN (blastic plasmacytoid dendritic cell neoplasm) is three to four times more common in people with one X chromosome, for reasons that hadn’t been clear.

Now, however, research led by Dana-Farber Cancer Institute scientists has identified a genetic factor that appears to explain a large part of the discrepancy, and also sheds new light on the mechanisms causing the blood cancer.

Reporting in Cancer Discovery, investigators led by Andrew Lane, MD, PhD, say that patients with BPDCN often have mutations in a gene called ZRSR2, and nearly all of those mutations occur in males. ZRSR2 codes for a tumor-suppressor protein that helps protect against the development of cancers, and it is located on the X chromosome. Some people only have one X chromosome, so it only takes one mutation to knock out the protective gene; others have two X chromosomes — and therefore, two copies of the ZRZR2 gene, so two mutations would have to occur in that gene to cause the cancer.

Mutations in the ZRSR2 gene account for at least half of the one-X-chromosome-predominant pattern of BPDCN, says Lane, who is director of the BPDCN Center at Dana-Farber. The explanation for the remaining half may be due to other mutations in ZRSR2 that weren’t detected in the study, they say, or to mutations in another gene.

Examining the qualities of BPDCN

BPDCN is a form of leukemia that affects the blood and bone marrow, but also frequently causes lesions in the skin — especially on the arms, legs, face, and neck — and many other organs including the liver, spleen, and central nervous system. BPDCN is estimated to affect only 1,000 to 1,400 people annually in the United States and Europe combined. The cancer first develops in precursors of plasmacytoid dendritic cells (pDCs), immune cells that produce type 1 interferons in response to bacterial and viral stimuli.

Using whole-exome sequencing to identify genes that were frequently mutated in BPDCN, the investigators homed in on the ZRSR2 gene. This gene carries the formula for a protein known as a splicing factor, which removes certain segments of strings of messenger RNA — a necessary step in converting the DNA instructions in a gene into a protein the cell needs to function.

“We found that when ZRSR2 is mutated, many genes are ‘mis-spliced,’” says Lane, “and these include genes important to how the immune system responds to infection or inflammation.”

One consequence of “mis-splicing” is that the pDC immune cells, which are supposed to sense inflammation and then self-destruct, fail at their designated task and also don’t die as they are programmed to do.

“They hang around longer than normal and there are too many of them,” says Lane. “We think this makes them more likely to acquire additional mutations that can turn them into a leukemia cell.”

Because BPDCN is caused in part by mutations in ZRSR2 that lead to erroneous splicing of RNA, the scientists say that it would be worth evaluating drugs that are being tested for modulating RNA splicing in other blood cancers. Another strategy, they say, is restoring the ability of BPDCN cells to die.

“We could do this by blocking pathways that inhibit cell death, like with BCL inhibitors such as venetoclax that we previously found were active in BPDCN — but we didn’t know why. We have a clinical trial open currently testing venetoclax in combination with other drugs for patients with BPDCN.”

About the Medical Reviewer

Andrew A. Lane, MD, PhD

Dr. Lane received his MD and PhD degrees from Washington University. He completed his residency in internal medicine at Brigham and Women's Hospital, and his fellowships in hematology and medical oncology at DFCI. His research focuses on developing new treatments for leukemia by studying the genetic changes that occur in cancer and how they alter the normal development of blood cells.