A multi-institutional research team that included genomic scientists from Vanderbilt Health has identified a potential target for blood cancer prevention and treatment.
Their report, published Jan. 1 in the journal Science, could lead to new treatments for blood cancers, which kill an estimated 23,540 people in the United States every year.
The research team, led by scientists from Boston Children’s Hospital, Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard, and Memorial Sloan Kettering Cancer Center, found that the protein Musashi-2 (MSI2) is essential for the function of blood-forming stem cells.
High levels of MSI2 can support the unchecked growth of abnormal stem cells, a precancerous condition known as clonal hematopoiesis of indeterminate potential, or CHIP.
The researchers used a genome-wide association study (GWAS) meta-analysis to identify a haplotype, or inherited grouping of genomic variants, which reduces MSI2 expression, thereby protecting against CHIP.
To validate these findings in humans, Alexander Bick, MD, PhD, Yash Pershad, and colleagues leveraged Vanderbilt Health’s DNA biobank, BioVU, the world’s largest repository of genetic material linked to de-identified electronic health records based at a single academic center.
By analyzing a unique longitudinal cohort of 3,000 patients with genetic sequencing performed approximately six years apart, the Vanderbilt Health team tested whether a variant which reduced the expression of MSI2 protected against the expansion of precancerous mutations.
Patients who carried the protective variant had precancerous clones that grew significantly more slowly than those without the variant. In many of these patients, the abnormal cells were transient; that is, they disappeared entirely over the study period rather than expanding into cancer.
“Most genetic studies only provide information from a snapshot in time, but the longitudinal samples in BioVU allowed us to study the mutations over six years,” noted Pershad, an MD/PhD student in the Bick lab, who with Bick is among the paper’s co-authors.
“We could clearly see that in people with the protective variant, precancerous clones behaved fundamentally differently than we expected — they shrunk or disappeared rather than expanding and becoming cancer,” Pershad said.
While CHIP results from somatic (acquired) blood stem cell mutations, this protection against it is inherited. This human genetic evidence suggests a potential way to prevent blood cancer by targeting MSI2 through small molecule inhibition or genome editing.
“More broadly,” the researchers concluded, “we provide an example of how resilience to cancer can arise through inherited genetic variation, motivating the search for other natural pathways that could be leveraged to prevent or treat malignancy.”
Bick, the Edward Claiborne Stahlman Professor, associate professor of Medicine, and director of the Division of Genetic Medicine and Clinical Pharmacology at Vanderbilt Health, is internationally known for his research on the genetics of blood disorders.
His research is supported in part by National Institutes of Health grants DP5OD029586, R01AG088657 and R01AG083736, a Burroughs Wellcome Fund Career Award, a Pew-Stewart Scholar for Cancer Research award, and a Hevolution/AFAR New Investigator Award in Aging Biology and Geroscience Research.
