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Molecular Aging Initiative to Profile Clonal Hematopoiesis Consequences in Patient Populations

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NEW YORK – At Weill Cornell Medicine's Englander Institute for Precision Medicine (EIPM), investigators are making clonal hematopoiesis the centerpiece of a new study on molecular aging — exploring its ties to disease risk and potential interventions.

"It's not just looking at molecular aging, it's trying to mitigate the molecular effects of aging," explained Olivier Elemento, EIPM's director.

For the Molecular Aging Initiative, the team plans to do gene panel sequencing and exome sequencing on blood and other samples from several hundred or possibly up to 1,000 individuals. By following germline and somatic mutations found in genes related to cancer, heart disease, and other conditions over time, the group hopes to learn why some clonal hematopoiesis cases progress to life-threatening diseases and others do not.

Because participants are being drawn from populations of patients already visiting Weill Cornell and collaborating centers for routine care, the researchers explained, the effort will also provide opportunities to find treatments that protect against the ill effects of clonal hematopoiesis — interventions that may be explored more fully through clonal hematopoiesis-focused trials in the future.

"What we're aiming to do is understand very closely, and define molecularly, how it is that these clones are impacting the aging phenotype — and potentially to find modes of intervention," explained project co-leader Duane Hassane, director of the EIPM leukemia genetics program.

Based on what is already known about genes that tend to be mutated during clonal hematopoiesis — including genes involved in epigenetic regulation or RNA splicing — there are some tantalizing strategies for targeting clonal hematopoiesis, though findings from the new study and others like it may also reveal previously unappreciated treatment, said Michael Rauh, a pathology and molecular medicine researcher at Queens University, who studies clonal hematopoiesis, but is not part of the Molecular Aging Initiative.

The project evolved from earlier the group's earlier work on clonal hematopoiesis, Hassane said, pointing to research published in Nature Medicine last year that revealed somatic mutations that arose in the decade or more before acute myeloid leukemia patients developed the disease.

Over the 10 or 20 years that individuals live with clonal hematopoiesis before diagnoses, he explained, the clones are not inert. Rather, they seem to have pro-inflammatory and other effects that may contribute to the broader aging phenotype.

In addition, a growing body of research suggests that clonal hematopoiesis might significantly increase an individual's risk of still other, non-cancer-related conditions such as cardiovascular disease. 

In a study appearing in the New England Journal of Medicine in 2014, for example, researchers from Brigham and Women's Hospital, Harvard Medical School, and elsewhere linked the presence of clonal hematopoiesis to increased incidence of not only blood cancers, but also all-cause mortality — in part due to a rise in cardiovascular disease in those carrying the somatic mutations. Such potential ties were spelled out further in a review article appearing in the journal JAMA Cardiology earlier this year.

At Queens University, Rauh led a team that found evidence suggesting the cardiovascular effects of clonal hematopoiesis may reflect hyper-inflammation instigated by monocyte and macrophage immune cells that are prone to developing somatic mutations in related genes.

"The question is: if they affect heart disease, could they affect other diseases as well, because inflammation, aging, monocytes, and macrophages are also implicated in other inflammatory diseases of aging," he said. "We've been looking at that in my lab as well and finding associations with lung disease, and potentially diseases of the [gastrointestinal] tract. And others are wondering if this is just the tip of the iceberg."

Such realizations have prompted several teams to take a keen interest in clonal hematopoiesis and its potential cause or effect connections to aging and disease. Along with the Molecular Aging Initiative, Rauh pointed to studies underway at Memorial Sloan-Kettering and in Toronto through the University Health Network Princess Margaret Hospital and Ted Rogers Heart Research Centre.

"It's new territory, but it's tremendously exciting," Rauh said. "There's some potential here to make major impacts in the treatment of leukemia and diseases associated with aging. So this is the starting point."

For example, he noted that while clonal hematopoiesis can progress to blood cancers such as AML, that progression happens in a small fraction of individuals, making it difficult to know if or how patients with clonal hematopoiesis should be managed.

That's just one of several questions the Molecular Aging Initiative researchers want to answer.

The team expects to assess clonal hematopoiesis using the center's PreCISE-1 test, a next-generation sequencing-based panel test focused on more than 100 genes related to clonal hematopoiesis, cancer, cardiovascular disease, or other conditions that may contain risky germline variants or mutations acquired somatically with age.

"Instead of just focusing on the genes that are known to contribute to hematologic cancers, we've decided to use this as an opportunity to create a comprehensive risk portrait that not only includes the genes that progress to hematologic cancers, but also genes known to be implicated in cardiovascular risk outside the context of clonal hematopoiesis," Hassane said. 

Results from that panel will be considered alongside exome sequence data produced with EIPM's ExACT-1 exome test, which was approved for clinical use in oncology by New York State's Department of Health in 2015, to get an integrated look at the interplay between inherited and acquired mutations.

The EIPM effort is primarily concerned with molecular aging in general, and team members will collect blood samples and independent sources of germline DNA such as spit, when possible, But when cancer patients do participate, the profiling approaches used should provide a molecular look at tumors found in patients with or without accompanying clonal hematopoiesis.

"We are trying to get a very comprehensive picture of the aging process, but also the connection with the malignant process," Elemento said, noting that "not everyone gets the same mutations [with age]."

When such somatic mutations lead to AML, for example, the combined panel and exome sequence data generated for the project should also offer a window into the kind of AML involved and it molecular make up.

Longer term, the researchers may also incorporate additional epigenetic and metabolic data from methylation assays, blood biomarker profiling, telomere testing, and so on.

The team has already started using the PreCISE-1 test to assess patients who visit Weill Cornell's hospital and is gearing up to recruit many more participants in the study — from geriatric individuals to those seeking treatment for cancer, heart disease, or conditions with no known ties to clonal hematopoiesis.

Because these patients are already receiving various treatments, or even participating in clinical trials, Elemento explained, "we're hoping to be able to find therapies that can kill [clonal hematopoiesis-derived] clones."

"There's an interventional component that we're also trying to explore that, I think, makes this initiative pretty unique," he said. "Is there a therapy that people get … that we would see in practice that would actually kill those clones? We'd like to be able to detect those."

If such targets do come out of the initial stages of the initiative, the researchers and their collaborators may eventually run their own clinical trials on interventions that show promise for mitigating clonal hematopoiesis-related disease risk and other negative effects of aging, though Elemento said they need to boost their therapeutic hypotheses before pursuing such trials.

At the moment, researchers expect to get samples from study participants roughly once a year, though additional samples will likely be collected from cancer patients or individuals known to be at increased risk of certain hematologic cancers.

"We want to sample as many people as possible for as long as possible," Hassane said.

Because the Molecular Aging Initiative testing is being done in a research setting, outside of a CLIA lab, the investigators will not be able to return results to participants. Nor will physicians receive patient results for use in clinical care, Elemento said.

Depending on what the study reveals, though, the effort may eventually evolve into a more clinical undertaking.

"We're not talking yet about results that are very compelling to return, because there is no way to do anything about those results. But that may change in the future, and we would like to position this initiative as something that would be able to report results to physicians," Elemento explained.

Rauh expressed enthusiasm about the insights that can be gained from carefully implemented studies such as the Molecular Aging Initiative. But, he too cautioned that clonal hematopoiesis is fairly common with aging, with only a fraction of affected individuals going on to develop blood cancer.

"Gathering more information and studying more patients and their natural history, their health history, will enable us to better understand who is at greatest risk of disease and of which diseases," Rauh said.

In the meantime, broad searches for clonal hematopoiesis are not recommended in the clinical setting, though he and other investigators are working on low-cost clonal hematopoiesis tests for large patient populations participating in research, which might eventually make the leap to the clinic.

In the case of the PreCISE-1 assay developed at EIPM, for example, Elemento predicted that the "jump to a CLIA assay, I think, will be pretty smooth once we decide to do so, but we're not there yet."

"What we've done is to design a … test that is really meant to be very easy to deploy and cost effective, because if we want to test 1,000 participants, we need the test to be reasonably cost-effective," he said.

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