What researchers are learning about clonal hematopoiesis
As the body ages, it is normal for cells to undergo changes. “Cells divide and mutations occur every day.” “We’re thrilled to be able to help patients with this disease,” said Emma M. Groark, M.D., chief hematologist and research scientist in NHLBI’s Hematopoietic and Bone Marrow Failure Institute. “Most of the time, it has no effect.”
However, for some people, mutations in blood-forming cells can multiply and cause something called clonal hematopoiesis. For a small subgroup of people who suffer from it, the risk of developing heart disease, blood cancer, and other diseases can be significantly increased.
Clonal hematopoiesis mainly affects the elderly. Approximately 10-20% of adults over 70 years of age are affected by clonal hematopoiesis, whereas younger adults are rarely affected. These mutations are often not detected during a traditional physical exam, and many people who carry them do not experience complications. “Many of these mutations are low risk,” Groark says. “It often occurs naturally with age, and most people remain healthy.”
So how do doctors identify people with high-risk mutations? And how can they develop personalized treatments to modify their risk and track conditions related to clonal hematopoiesis? These are the questions that NIH-supported researchers are studying and seeking answers to.
Here’s what they know so far:
Very few people carry high-risk mutations, but those who have the mutations are at particularly high risk.
People can have different types of clonal hematopoiesis. When a leukemia-like mutation occurs in at least 2% of hematopoietic cells and there is no underlying blood disease, it is called clonal hematopoiesis of indefinite potential (CHIP). When an unexplained blood condition or abnormal blood cell count is present, it is called clonal cytopenia of undetermined significance (CCUS).
Researchers found that only a small proportion of adults with CHIP or CCUS face increased risk when it comes to heart disease and blood cancers. But for high-risk adults, the risks are alarmingly high.
Using data from the Atherosclerosis Risk in Communities (ARIC) study, researchers found that most adults over age 70 with clonal hematopoiesis (approximately 60%) have low-risk mutations and are at risk for cardiovascular disease. found that there was no additional risk of These findings show that JAMA network open. But importantly, the 6% of adults with the high-risk variant had a nearly three-fold increased risk of developing a fatal heart attack or stroke.
Tools help you calculate risk
in order to help Identifying adults at high risk of developing cardiovascular disease and cancer, researchers are using a clonal hematopoietic risk calculator. To determine an individual’s risk, multiple factors can be entered, including the type of mutation a person has, the number of mutations, the percentage of cells with the mutation, and other variables such as age and blood cell count.
Adults who have high-risk mutations and are at increased risk for heart disease should work with their doctors to take steps to prevent the disease from developing or consider secondary approaches such as statin therapy. You can offset those risks by doing things like:
but, Pradeep Natarajan, M.D., chief of preventive cardiology at Massachusetts General Hospital and associate professor at Harvard Medical School, said: Even with these measures in place, inflammation that poses cardiovascular risks is still present, he noted. This is why he and others have been researching ways to inhibit or quell the inflammatory pathways associated with specific mutations. This approach is similar to personalizing cancer treatment.
“We’re all trying to be oncologists,” he said. Natarajan. “If we have great examples that cause disease, we try to target those causes.”
Clinical trials have begun for treatment
Researchers are deepening our understanding of clonal hematopoiesis while supporting clinical trials to identify new treatments.
Two new studies, including a Phase 1 and a Phase 2 trial, show that altering inflammatory pathways may improve outcomes in adults with heart disease who carry TET2 CHIP mutations (often associated with heart disease) It is being investigated whether there is A phase 1 study is testing the benefits of inhibiting the NLRP3 pathway, and a phase 2 study is evaluating the consequences of altering the IL-6 and IL-18 pathways in adults with DNMT3A and TET2 CHIP mutations.
A sub-analysis of the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) found that an antibody used to block the inflammatory pathway IL-1β was associated with an increased risk of cardiovascular events, including heart attack and stroke, in adults with TET2 CHIP mutations. It was previously found to significantly reduce He had heart disease. However, further research is needed to validate these findings. Researchers are also investigating ways to update treatments that target JAK2 mutations to offset cardiovascular risks.
“We’ve gone from not even knowing this disease existed 10 years ago to trying treatments,” said Alexander G. Bick, MD, assistant professor of medicine at Vanderbilt University Medical Center. “This is an example of how rapidly precision medicine is advancing.”
Clonal hematopoiesis research advances new scientific frontiers
As treatment research progresses, a team of experts, including geneticists, hematologists, cardiologists, and oncologists, has established a clonal hematopoietic clinic to help treat adults with high-risk mutations. “We don’t want to tell people that they have a disease that isn’t actually a disease,” Groark said. “Rather, we would like to select patients at risk and follow them more closely.”
Groarke is leading a 10-year natural history study to assess how clonal hematopoiesis affects other aspects of health and disease. This includes studying the association between metabolic conditions, infections, vitamin levels, and chronic lung and liver disease. Researchers are also studying cases in which these mutations can be propagated, such as telomere disorders.
Additionally, other researchers have begun trials to study how clonal hematopoiesis coexists with or increases the risk of conditions such as heart failure, pulmonary embolism, and lupus. Surprisingly, researchers found that CHIP was associated with a lower incidence of Alzheimer’s disease.
“CHIP causes inflammation, which causes coronary artery disease and heart failure, and contributes to stroke, but the case with Alzheimer’s disease is completely different,” Bick said. He explained that in Alzheimer’s disease, mutated cells appear to be cleared out rather than promoting the growth of inflammatory plaques. “This is an example of how these somatic mutations open windows into biology that we didn’t even know existed.”
“Clonal hematopoiesis is just the tip of the iceberg,” Natarajan says. Researchers are working to improve detection and prevention of other diseases through the NIH Consortium and are studying additional types of acquired mutations throughout the body.
“This represents a new frontier in understanding not only the genome we are born with, but also the genome that every cell in our body has (and which can develop over time). “It will be,” Bick added.
resource
For more information about the CHIP/CCUS natural history study, please visit https://www.clinicaltrials.gov/study/NCT04102423.
To learn more about NIH’s Somatic Mosaicism across Human Tissues (SMaHT) network, visit https://commonfund.nih.gov/smaht#.
