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Jorge Di Paola, MD, Medical Director of Pediatric Hematology at the Center for Cancer and Blood Disorders at Children’s Hospital Colorado, and his colleagues have discovered a gene variant not previously described in humans. The rare familial gene defect causes low platelet counts and makes carriers more susceptible to acute lymphoblastic leukemia (ALL).
Dr. Di Paola’s research laboratory found the gene defect, a mutation in the gene ETV6, when they began gathering DNA from families from all over the world to try to better understand how people can have low platelets and a predisposition to ALL. For example, in Detroit, the team sequenced 11 members of one family with the disease. Two first cousins in the family had the disease; since first cousins share approximately 6% of their DNA, this allowed Dr. Di Paola’s team to narrow the search area for the mutated gene. Leila Noetzli, a graduate student from the Human Medical Genetics and Genomic Program at the University of Colorado and a member of the Di Paola lab, led the study.
“We focused on the parts of the genome they had in common to find this potential platelet/leukemia gene.”
– Dr. Di Paola
Of the many families Dr. Di Paola and his colleagues have studied, they found just one variant, one single change in the DNA sequence of the gene ETV6, that was common to those affected with leukemia who also had low platelets.
A mutation in ETV6 does not appear to be sufficient to cause leukemia, but puts those who have it at higher risk of developing the disease. Identifying the gene mutation could lead to a better understanding of the disease and perhaps improve early detection and prevention.
An expert in hematology and genetics, Dr. Di Paola leaned on collaborators Ken Jones, PhD, a bioinformatics researcher at the Center for Cancer and Blood Disorders, and Chris Porter, MD, now at Emory University, and Alisa Lee-Sherick, MD, physician-scientist at the University of Colorado, for their expertise in leukemia. They are also working in collaboration with scientists at University of Toronto and the University of Utah.
“You cannot do science alone,” Dr. Di Paola says. “If it wasn’t for our collaboration with the Porter and Lee-Sherick labs, and other scientists in the world, including laboratories in Utah, Michigan, Canada and Italy, we would not have been able to find these mutations.”
“Their work demonstrates how a multidisciplinary approach can strengthen our knowledge and expand the field,” says Lia Gore, MD, Chief of Pediatric Oncology. “It also helps explain a previously unidentified genetic disorder that has allowed us to better watch patients who might be at risk.”
Dr. Di Paola and his colleagues published their findings in Nature Genetics in 2015. Other studies with similar findings were published at the same time. A more recent study showed that ETV6 germline mutations are common in up to 1% of individuals with ALL.
Today, Dr. Di Paola and collaborators at Emory University, and in Colorado and Utah, are working to understand the molecular mechanisms of this disease through a newly generated mouse model to further study the gene mutation and its effects on blood.
Dr. Di Paola has been asking himself this question for the last 20 years. He studies von Willebrand disease (VWD), the most common bleeding disorder among adults and children, characterized by highly variable symptoms, even within members of the same family. Scientists have long understood the genetic basis of VWD. But, according to Dr. Di Paola, they still don’t understand why, among those who have moderate to mild disease, some bleed more severely than others.
Dr. Di Paola and his team are conducting one of the largest studies in the world to understand the complexities of the genetics and biology of the disease. Their study included an Amish family with 2,000 members, from which he collected 900 samples over the last decade.
Using modern genomic techniques, his team made a multi-gene array that they plan to use in collaboration with groups in Milwaukee, Ireland and Canada.“It appears there might be a combination of gene variants that might make you more susceptible to bleeding,” Dr. Di Paola says.
Identifying those genes could help target treatment for patients with VWD, adjusting as necessary to prevent bleeding complications.
“When it comes to most common forms of VWD, we were all still in the dark ages,” says Dr. Di Paola. “With this genetic array we made, we hope we are starting to understand the genetic underpinnings that make this disease so variable.”