A cellular wrong turn in blood cancer

Despite major advances in understanding the genetics of myelodysplastic syndrome (MDS), effective targeted therapies remain limited.  A new study from researchers at the Herbert Irving Comprehensive Cancer Center (HICCC) uncovers a key mechanism behind how mutations in a gene called STAG2 disrupt normal blood cell formation, offering new insight into how MDS develops and a framework for potential targeted therapies. 

Published in the journal Blood, the study, led by HICCC member Aaron Viny, MD, and MD/MS candidate Varun Sudunagunta, shows that STAG2 mutations alter chromatin, the three-dimensional structure of DNA and its associated proteins, in ways that misdirect the genetic instructions that guide red blood cell formation. The findings help explain why many patients with STAG2-mutant MDS develop severe anemia and point toward potential future strategies for chromatin-targeted therapies. 

MDS is a group of rare cancers that occur when blood-forming cells in the bone marrow become abnormal, failing to produce enough healthy blood cells. About one-third of cases eventually progress to acute myeloid leukemia (AML), an aggressive blood cancer. Mutations in STAG2 occur in roughly 10–12% of MDS cases and are associated with particularly severe anemia and resistance to erythropoietin, a hormone that stimulates red blood cell production. 

How altered chromatin reshapes blood cell fate 

Prior research from Viny’s lab found that loss of STAG2, a component of the cohesin complex, dramatically alters chromatin architecture, changing which regions of DNA are accessible to proteins that control gene activity. In the new study, the researchers wanted to understand how those structural changes disrupt red blood cell maturation. 

The team zeroed in on GATA1, a transcription factor essential for both red blood cell and platelet development. Normally, chromatin structure helps guide transcription factors like  GATA1 to their correct target genes, directing developing cells toward a mature red blood cell fate. But when STAG2 is lost, that chromatin organization breaks down. 

Instead of efficiently focusing on red blood cell genes, GATA1 becomes partially redirected toward genetic programs of other cell types. As a result, developing red blood cells fail to fully mature and instead retain characteristics of platelet-producing cells, suggesting the cells are no longer fully committed to the correct developmental pathway.

“It’s a localization problem, not an expression problem,” says Viny, who is an assistant professor of medicine at Columbia Vagelos College of Physicians and Surgeons and a member of the Columbia Stem Cell Initiative. “The transcription factor itself isn’t mutated. It’s that the chromatin landscape changes where it can go.”

A GPS for gene regulation 

Viny describes the process as a kind of molecular misdirection, where changes in chromatin structure send GATA1 toward the wrong genetic targets. 

He compares the process to navigating through a city without GPS. Normally, chromatin architecture helps guide transcription factors to the correct genetic targets. But when STAG2 is lost, those directions become less precise, allowing GATA1 to activate genes that should normally remain inaccessible in developing red blood cells. 

To validate the findings in patients, the researchers used CellaVision, a high-resolution digital microscopy platform at Columbia that scans blood smears and identifies individual cell types. In all the STAG2-mutant MDS cases examined, the team identified immature red blood cell precursors circulating in the blood — cells that normally should remain confined to the bone marrow until maturation is complete. 

The work also helps explain a longstanding clinical observation: patients with STAG2-mutant MDS often respond poorly to erythropoietin-based therapies designed to stimulate red blood cell production. Because GATA1 activity becomes dispersed across competing genetic programs, the normal signal to produce red blood cells becomes less effective. 

Toward chromatin-targeted therapies

Beyond MDS, the findings may have implications across cancer biology. STAG2 mutations occur in at least 17 different cancer types, including bladder cancer, glioblastoma, and Ewing sarcoma, suggesting that similar mechanisms of chromatin-driven transcriptional misdirection may contribute to disease in other tissues as well. The researchers are now exploring whether targeting downstream pathways involved in this process could help restore normal red blood cell development. 

Ultimately, Viny says, the work provides a new framework for understanding how changes in chromatin accessibility can reshape cell identity and drive cancer development. 

“We’re beginning to understand that chromatin accessibility is not just a bystander in cancer biology. It can actively shape cell fate,” says Viny. “As the next step, we are figuring out how to therapeutically manipulate those programs to restore normal blood development in patients.”