Rare Inherited Mutation Appears to Protect Against Age-Linked Blood Cancers

Most stories about cancer genes start with bad news: an inherited mutation that silently raises the odds of disease. A new study in Science turns that script around, describing a rare genetic variant that appears to make some people’s blood stem cells more resistant to the march toward leukemia.

In research published Jan. 1, an international team analyzing genetic and blood data from more than 640,000 people identified an inherited DNA change that lowers the risk of an age-related condition called clonal hematopoiesis—and the blood cancers that can follow. The variant acts by dialing down a stem cell protein known as Musashi-2, or MSI2, long suspected to be a driver of aggressive leukemia.

“We’ve discovered the mechanism by which a change within the MUSASHI2 gene region appears to protect people from blood cancers related to clonal hematopoiesis,” said Michael Kharas, a cancer biologist at Memorial Sloan Kettering Cancer Center and one of the senior authors. “It’s remarkable that a single letter change in DNA can have such a large effect on cancer risk.”

The work offers a clear example of “genetic resilience” to cancer and points directly to a protein that drug developers are already trying to target.

A brake on a common pre-cancer state

The researchers focused on clonal hematopoiesis, a surprisingly common phenomenon: as people age, some of their blood-forming stem cells acquire mutations in genes often seen in leukemia, such as DNMT3A, TET2, ASXL1 and JAK2. If a mutated stem cell gains a growth advantage, its descendants can begin to dominate the blood, forming what scientists call a clone.

This condition—sometimes labeled clonal hematopoiesis of indeterminate potential, or CHIP—usually causes no symptoms and is often picked up only when people undergo detailed DNA sequencing for other reasons. But it is not benign. Studies have shown that people with CHIP face a markedly higher risk of developing myeloid malignancies such as myelodysplastic syndromes and acute myeloid leukemia. They also have elevated risks of heart attack, stroke and overall mortality, even after accounting for traditional cardiovascular risk factors.

By some estimates, 10% to 20% of people over age 70 have CHIP. That made it a compelling target for researchers seeking inherited factors that might influence who develops these pre-cancerous clones and how fast they grow.

In the new study, scientists from the Broad Institute of MIT and Harvard, Boston Children’s Hospital, Memorial Sloan Kettering and other centers pooled data from three large cohorts: the UK Biobank, the Geisinger Health Study in Pennsylvania and the National Institutes of Health’s All of Us Research Program. They identified about 43,000 people with clonal hematopoiesis and compared their inherited genomes to those of nearly 600,000 people without detectable clones.

Among the signals that emerged from the genome-wide association analysis, one stood out for its unusual direction: a variant known as rs17834140, located in a regulatory region near the MSI2 gene on chromosome 17. People carrying the T form of this variant were substantially less likely to have clonal hematopoiesis.

According to the researchers, individuals with one copy of the protective allele had about a 16% lower risk of developing clonal hematopoiesis and roughly a 20% lower risk of myeloid malignancies compared with noncarriers. Those with two copies saw about a 30% reduction in clonal hematopoiesis risk.

“This inherited variant can actually be good,” Kharas said in an institutional statement, contrasting it with better-known risk-raising mutations such as those in BRCA1 and BRCA2.

The protective version of the gene change is uncommon but not extremely rare. The study estimates that about 4% of people worldwide carry at least one copy, with higher frequencies in some Northern European populations and lower frequencies in groups such as the Amish and certain Middle Eastern and East Asian communities.

Turning down Musashi-2

The association alone did not explain how the DNA change might work. To answer that, the team turned to detailed molecular and animal experiments.

The rs17834140 variant sits in an enhancer—a stretch of noncoding DNA that regulates when neighboring genes are switched on—near the MSI2 gene. MSI2 encodes Musashi-2, an RNA-binding protein that helps control which messenger RNAs are translated into proteins in stem cells. Previous work had shown that MSI2 is highly expressed in primitive blood stem and progenitor cells and is often overactive in aggressive leukemias, where high levels correlate with worse survival.

In laboratory studies of human stem and progenitor cells, the researchers found that the protective T allele disrupts a binding site for the transcription factor GATA2, weakening the enhancer’s activity. As a result, cells from carriers produce less MSI2.

That modest reduction appears to have significant effects on how stem cells behave. By using CRISPR gene editing to manipulate MSI2 levels in human hematopoietic stem and progenitor cells, and to introduce common clonal hematopoiesis driver mutations such as those in ASXL1, the team showed that lowering MSI2 blunted the growth advantage of mutant clones. Mutant cells were less able to outcompete normal stem cells and dominate the culture.

In mouse models engineered to overexpress MSI2 and carry alterations in Asxl1, animals developed blood and bone marrow abnormalities resembling myelodysplastic syndromes, including an expansion of immature stem and progenitor cells. When MSI2 activity was reduced, many of those disease features were attenuated, the authors reported.

“When this variant is present, it dramatically lowers levels of the MUSASHI2 protein in blood stem cells,” Kharas said. “It essentially flips a light switch and turns off potentially harmful growth.”

Slower-growing clones in real people

The team also examined how the protective variant affected clonal behavior over time in people. In a subset of participants who had two blood samples taken roughly six years apart, carriers of rs17834140-T showed slower growth in the fraction of blood cells belonging to a given clone, a measure known as variant allele fraction. Their clones were more likely to shrink or fall below the threshold used to define clonal hematopoiesis, rather than continue expanding.

“Instead of these mutant clones steadily taking over the blood, in carriers of the variant they seem to grow more slowly and, in some cases, fade away,” said Vijay Sankaran, a pediatric hematologist and geneticist at Boston Children’s Hospital and the Broad Institute, and a senior author of the study.

Sankaran noted that the discovery depended on large-scale data sharing and public resources such as the UK Biobank and All of Us. “Our ability to find a single protective variant with this kind of effect really comes from having access to genetic and sequencing data on hundreds of thousands of individuals,” he said.

A Perspective article accompanying the Science paper, written by hematologists Francisco Caiado and Markus Manz of University Hospital Zurich, said the work supports targeting MSI2 as a potential “pan-cancer” therapeutic approach, noting that small-molecule MSI2 inhibitors are already under development in preclinical models.

Toward prevention, with unanswered questions

Although the findings do not translate into an immediate test or therapy, researchers say they strengthen the case for trying to mimic the effects of the protective variant in people at high risk.

One possibility is to use MSI2 inhibitors, originally envisioned as drugs to treat established leukemia, as preventive treatments for individuals with high-risk clonal hematopoiesis—for example, older adults whose blood carries multiple driver mutations or large clones, or cancer survivors who developed clonal hematopoiesis after chemotherapy or radiation. Another is to use RNA-based medicines or gene-editing tools to partially dampen MSI2 expression in blood stem cells.

The human genetic data offer a measure of reassurance: people who are naturally born with lower MSI2 activity due to rs17834140-T do not show obvious signs of bone marrow failure in population cohorts. But scientists caution that pharmacologic inhibition could be stronger or act in additional tissues, and MSI2 plays a role in normal stem cell function.

“MSI2 is clearly important for maintaining blood stem cells, so the challenge will be finding the right level of inhibition that reduces cancer risk without compromising normal blood production,” Sankaran said.

The study also raises broader questions about equity in genomic medicine. Because the protective allele is more frequent in some ancestries than others, its benefits—in the absence of a drug—are unevenly distributed. Experts say the finding underscores the need to include diverse populations in large genetic studies, to identify other protective variants that may be more common in underrepresented groups.

For now, clonal hematopoiesis remains largely a research diagnosis. There is no consensus on routine screening in the general population, and no approved interventions aimed specifically at shrinking or slowing clones. But as more hospitals build programs to monitor clonal hematopoiesis and assess leukemia risk, discoveries like the MSI2 variant are likely to influence how clinicians think about who is at risk—and who might be inherently more protected.

The new work suggests that, in at least a small fraction of people, evolution has already run a subtle experiment in cancer prevention: softening the activity of a powerful stem cell gene so that pre-cancerous clones have a harder time taking over with age. The challenge ahead for researchers is to see whether medicine can safely learn, and eventually apply, the same trick more broadly.