Gene Mutation Behind Pelger-Huët Anomalies Discovered

Cancer biologists have discovered the genetic mutation behind Pelger-Huët anomalies, which are marked by nuclei squeezed in the middle. First discovered in 1928, the anomaly is currently used by clinical labs to diagnose leukemias and myelodysplastic syndrome, a disease of blood-forming cells in the bone marrow.

Although this structural change inside blood cells indicates possible cancer, until a recent study led by University of Washington (UW), no one knew what caused it to happen.  “The primary diagnosis of many cancers, even in the era of genomic medicine, remains centered on the appearance of cells under a microscope,” says Dr. Sergei Doulatov, an associate professor of medicine in the Division of Hematology at the University of Washington (UW) School of Medicine in Seattle.

One of Doulatov’s own research interest is in malignancies of infection-fighting white blood cells called neutrophils. He and his team assumed something was lurking in the genome of the more primitive progenitor, or stem cells, that go on to create blood cell lineages. Called myeloid cells when still in their multipotent state, progenitor cells can give rise to any one of a variety of blood cell categories, including neutrophils, red blood cells and platelets.

But myeloid cells themselves can sometimes show abnormal, precancerous changes. The researchers on UW study were able to cast suspicion on the loss of nuclear lamin B1, encoded on chromosome 5q. It is frequently deleted in cells examined from abnormally growing myeloid tissue. Evidence from this study suggests this loss is at fault in the misshapen nuclei in Pelger-Huët anomalies.

 “Lamins are proteins that line the inside of the nucleus, and are mutated in inherited disorders—famously progeria, the disorder of accelerated aging,” says Doulatov. “We showed that loss of nuclear Lamin B1 induces defects in the nuclear morphology and in human hematopoietic [blood-forming] stem cells associated with malignancy.”

His group went on to detail that lamin B1 deficiency alters genome organization. This in turn caused expansion of the blood-forming stem cells, a bias towards their becoming myeloids, genome instability due to defective DNA damage repair and other problems that set the stage for cancer. They also showed that the abnormal nuclei in the cells of myeloid pre-cancerous growths in patients were associated with deletions in chromosome 5q that spanned the lamin1 B1 region.

“We show that lamin B1 deletion causes changes in stem cell function, nuclear shape, and leukemia progression,” says Doulatov said.  “Our research discovers lamin mutations in cancer and demonstrates that these mutations are responsible for the oddly shaped nuclei that have puzzled and helped pathologists recognize cancers over the past century.”

The findings were published recently in Cell Stem Cell.