Scientists have known for decades that there are gene mutations that increase your risk of developing cancer. But there is also a genetic variant that could reduce the risk of developing certain blood cancers, according to new research co-led by scientists from Memorial Sloan Kettering Cancer Center (MSK). The findings are reported January 1, 2026, in Science.
“We’ve discovered the mechanism by which a change within the MUSASHI2 (MSI2) gene region appears to protect people from blood cancers related to clonal hematopoiesis,” says cancer biologist Michael Kharas, PhD, a member of the Molecular Pharmacology Program in the Sloan Kettering Institute and co-corresponding author of the paper. “The findings suggest ways that we eventually may be able to reduce the risk of blood cancers in some people.”
What Is Clonal Hematopoiesis and Why Does It Increase Cancer Risk?
The researchers made the discovery while studying the genes involved in a condition called clonal hematopoiesis (CH), in which some of the stem cells responsible for creating blood cells acquire a genetic change that enables them to outpace the growth of normal blood cells and infiltrate the blood stream.
Clonal hematopoiesis becomes more common with age, affecting about 10% of people over 65. There are no warning signs of CH, and most people with the condition never have any symptoms.
CH is not cancer, but it increases the risk of developing certain blood cancers, especially myeloid diseases, including leukemia. For people with solid tumors, CH is an indicator that their cancer is likely to be more aggressive and difficult to treat. CH also has been linked to an increased risk of death from cardiovascular disease and other conditions of aging.
“Since CH was discovered, there’s been a lot of interest in studying it,” Dr. Kharas says. “If you could find a way to target clonal hematopoiesis, theoretically you could prevent people from developing CH-related myeloid cancers or having these other negative effects.”
Learn more about clonal hematopoiesis and MSK’s CH clinic.
Looking for Gene Variants Linked to Clonal Hematopoiesis
Small differences in nucleotides — the individual “bases” that make up our DNA code — are scattered across our genomes. These changes are called variants. They don’t change the gene or protein itself, but they do impact how much of the protein is made. To identify gene variants related to CH, scientists analyzed the genomes of many people through what’s called a genome-wide association study (GWAS).
By combining datasets from three large genomic studies, the researchers were able to compare the gene sequences of 43,000 people with CH against the gene sequences of 600,000 people without the condition. This work was done by scientists at the Harvard Stem Cell Institute and led by Science paper co-corresponding author Vijay Sankaran, MD, PhD.
When a variant of the MSI2 gene came up as the most likely to protect against CH, Dr. Sankaran reached out to Dr. Kharas, whose lab studies that gene. Serendipitously, they had already gotten to know each other when Dr. Kharas was a postdoctoral fellow at Brigham and Women’s Hospital in Boston and Dr. Sankaran was a graduate student at Harvard.
How a Single Variant in the MSI2 Gene Can Decrease the Risk of CH
The MSI2 gene (which stands for MUSASHI RNA-BINDING PROTEIN-2) and its protein, called MUSASHI2, help regulate adult stem cells.
The variant the team focused on — called “rs17834140-T” — appears to play an important role in preventing someone from developing clonal hematopoiesis and myeloid cancers.
- People who had the variant in one copy of the MSI2 gene had a 16% decreased risk of developing CH and 20% protection against getting myeloid diseases.
- People with the variant in both copies of the MSI2 gene were even less likely to develop CH — with a 30% decreased risk.
Finding out that this single genetic alteration can prevent cancer is an important discovery by Dr. Kharas, a leading expert on the MSI2 gene, the MUSASHI2 protein, and the role they play in blood cancers.
“The variant that may protect someone from developing clonal hematopoiesis involves a change in a single DNA base — the building blocks responsible for building the DNA code,” Dr. Kharas says. “It’s remarkable that such a small change can have such a large effect.”
Understanding the Mechanism of the MSI2 Variant rs17834140-T
Dr. Kharas’ lab used mouse models and human blood cells to learn more about the rs17834140-T variant. “Many labs are now doing GWAS to link variants to diseases — ranging from diabetes to heart disease to Alzheimer’s,” he says. “But it’s usually very hard to figure out why or which specific genetic variation causes the disease.”
In this new research, the team was able to determine the mechanism by which the MSI2 variant acts on the MUSASHI2 protein: When the rs17834140-T variant is present, it dramatically lowers levels of the MUSASHI2 protein in blood stem cells, which in turn reduces the risk that a harmful subset of cells will grow out of control and lead to CH.
“This MSI2 variant is, in effect, flipping a light switch and turning off potentially harmful growth,” Dr. Kharas says.
Understanding this mechanism may make it possible to develop a drug or other treatment, such as a gene therapy, to reduce the risk of cancer in those with CH, or even to prevent CH from developing at all, Dr. Kharas says.
MSI2 Variants Are Passed Down in Families
So how do people acquire this variant that can protect them from developing certain blood cancers?
It turns out the rs17834140-T variant in MSI2 is inherited through the germline (the hereditary genes that you get from your parents).
“We know that other inherited mutations, like BRCA1 and BRCA2, raise your risk of cancer, but our research shows that this inherited variant can actually be good,” Dr. Kharas says.
The analysis revealed that about 4% of human beings have inherited this protective gene variant, but its incidence varies greatly in people of different genetic ancestries. For example, people with European ancestry, especially those from Finland, are most likely to have the MSI2 variant; it is least common in Amish populations, followed by those with Middle Eastern and East Asian ancestry.
“Just as we’ve learned some genes increase your risk of cancer, now we are learning some can reduce your risk. And it can all depend on your genetic ancestry,” says Dr. Kharas. “This discovery illustrates the importance of including people with diverse backgrounds in genetic research.”
Dr. Kharas is part of an ongoing project sponsored by Break Through Cancer and Blood Cancer United (formerly the Leukemia and Lymphoma Society) to further study clonal hematopoiesis and cancer risk. “The possibilities of where this project might lead are very exciting to think about,” he says.
Additional Authors, Funding, and Disclosures
Additional MSK authors on the study are Xueqin Xie, Tzu-Chieh Ho, Trevor Barlowe, Arthur Chow, Alexandra Schurer, James Taggart, and Omar Abdel-Wahab.
Dr. Kharas’s research in this paper was supported by Blood Cancer United; the American Society of Hematology; and National Institutes of Health grants R01 DK101989, R01 CA193842, R01 HL135564, R01 CA274249, R01 CA186702, R01 CA283578, R01 CA225231, and P30 CA008748. Additional funding sources are listed in the paper.
Key Takeaways
- Research co-led by scientists at MSK finds that a gene variant may reduce someone’s risk of developing certain blood cancers.
- The variant, in a gene called MSI2, appears to turn off potentially harmful cell growth.
- The discovery was made when scientists were looking at genes related to a blood condition called clonal hematopoiesis.
- The finding may lead to ways to prevent blood cancers in people with clonal hematopoiesis.
