For more than 100 years, pathologists have recognized that cancer cells look different under a microscope. In fact, this is still how many cancers are diagnosed. Doctors use procedures, such as Pap tests, to look for enlarged nuclei in a patient’s cells – an indication that something might be wrong.
In blood cancers, like leukemia and myelodysplastic syndromes (MDS), this unusual cell morphology is known as Pelger-Huet Anomaly (PHA), a genetic disorder that is characterized by abnormally-shaped nuclei and chromatin. While PHA was first identified in 1928, it remains unclear how exactly the condition, which can be benign, is related to cancer.
That question is at the heart of a new study, published in the journal Cell Stem Cell, from the lab of ISCRM faculty member Sergei Doulatov, PhD, an Associate Professor of Medicine/Hematology. Doulatov and his team use induced pluripotent stem cells (iPSCs) to study how blood diseases impact stem cell biology. The lead author of the new paper is Andreea Reilly, a Postdoctoral fellow in the lab. Other authors include ISCRM faculty member Zhijun Duan and Janis L. Abkowitz, MD Head of the Division of Hematology.
“A lot of what we do is basic science, which is an important driver of translational discoveries,” says Doulatov. “What is really exciting in this study is the connection between cell morphology and cell function. Establishing a clearer connection between the hallmarks of PHA and certain blood cancers fills in a missing piece of the story and points to the field toward new diagnostic tools and therapies.”
According to the researchers, the crux of the connection between misshapen nuclei and blood cancers is a gene called lamin B1. Lamins are proteins that line the inside of the nucleus. Mutations in this gene are linked to certain inherited disorders, including progeria, a disease of accelerated aging.
In the investigation that led them to lamin B1, Doulatov and his team were focused on a piece of chromosome 5 that is commonly deleted in leukemia and blood cancers. There was good reason to suspect that lamin B1 might be involved in the nuclear deformities observed in blood cancers. After all, lamin B1 help gives cell their shape. It stands to reason loss of lamin B1 would lead to changes in structure.
Using gene-editing tools to decrease expression of lamin B1 in two stem cell models (including cells from a patient who was missing the crucial section of chromosome 5), the researchers were able to show conclusively that deletion of lamin B1 does in fact causes change in stem cell function and nuclear shape – and contributes to leukemia progression.
Are the changes a cause of cancer or a side-effect of cancer?
That is the million dollar question, says Doulatov. “The best answer is that PHA deformities and cancer are related. When the gene is deleted, we observe changes in how stem cells are behaving, which is consistent with cancer. And we find abnormalities in the shape of the nucleus. Based on what we’re seeing, we believe the deletions cause the misshapen nuclei and promote cancer.”
The discovery of lamin mutations in cancer that are responsible for the oddly shaped nuclei help explain a phenomenon that has baffled scientists for decades. The finding has significance for the future, too, if these nuclear changes can be used as a biomarker for earlier diagnosis of leukemia and other blood cancers.
Doulatov adds that stem cell technologies his lab uses could also help them develop a model of leukemia with deletions on chromosome 5. These deletions are often paired with a mutation in a gene (P53) which is the most frequently mutated gene in cancer. Combining the deletions on chromosome 5 with the P53 mutations give rise to an aggressive leukemia. Establishing a lab model of this condition would help researchers better understand how it develops and how to target it for treatment.
“It may not be realistic to do routine genetic testing to catch these disorders in patients,” says Doulatov. “But we are exploring now whether automatic blood screening can pick up the signs of PHA in patients who might not even suspect they are at risk for cancers like MDS and leukemia. And, if these deletions do promote cancer, we are also asking if we can take advantage of that therapeutically.”