Scientists Uncover Nuclear Droplets Uniting Leukemias
A hidden cellular structure is reshaping our understanding of leukemia. Beneath the microscope, what appeared chaotic follows a simple physical rule, connecting various mutations driving the disease. Researchers at Baylor College of Medicine have discovered that different genetic drivers of leukemia utilize the same secret compartments within the cell nucleus to sustain cancer growth. This finding points to a shared physical target, offering inspiration for novel treatments.
The study challenges the long-held view of how common leukemia originates and presents a fresh approach to designing therapies that target a single weakness shared across distinct genetic forms of the disease. Leukemia begins when mutations in blood-forming cells disrupt the equilibrium between growth and differentiation. Patients with diverse genetic changes exhibit remarkably similar gene activity patterns and respond to the same drugs.
What invisible thread could make so many mutations behave identically? The Riback and Goodell labs at Baylor joined forces to uncover the answer. Dr. Joshua Riback, an assistant professor and CPRIT Scholar who studies protein droplet formation through phase separation, collaborated with Dr. Margaret "Peggy" Goodell, Baylor's chair of the Department of Molecular and Cellular Biology and a pioneer in understanding blood stem cell leukemia. Together, they embarked on a journey to explore the physics hidden within cancer's chemistry.
The breakthrough moment arrived when graduate student Gandhar Datar, co-mentored by Riback and Goodell, examined Riback's high-resolution microscope. He discovered something unexpected: leukemia cell nuclei shimmered with a dozen bright dots, absent in healthy cells.
These dots weren't random. They contained large amounts of mutant leukemia proteins and attracted numerous normal cell proteins to activate the leukemia program. The dots were novel nuclear compartments formed by phase separation, akin to oil droplets in water. The team named this new compartment "coordinating bodies," or C-bodies.
Within the nucleus, C-bodies function as miniature control rooms, gathering molecules that keep leukemia genes active. Like oil drops on soup, they emerge when the cell's molecular composition reaches the right balance.
Even more remarkably, cells with different leukemia mutations formed droplets with identical behavior. Despite their chemical differences, the resulting nuclear condensates performed the same function, employing the same physical principles.
A novel quantitative assay developed in the Riback lab confirmed this. These droplets are biophysically indistinguishable, akin to soups made from different ingredients but resulting in the same consistency. Regardless of the initiating mutation, each leukemia formed the same type of C-body.
"It was astonishing," Riback stated. "All these diverse leukemia drivers, each with its unique recipe, ultimately created the same droplet or condensate. This is what unites these leukemias and provides a common target. By understanding the biophysics of the C-body, its general recipe, we can dissolve it and reveal new insights for targeting multiple leukemias."
The team validated the finding across human cell lines, mouse models, and patient samples. When they altered the proteins to prevent droplet formation or dissolved them with drugs, the leukemia cells ceased dividing and began maturing into healthy blood cells.
"Observing C-bodies in patient samples made the connection crystal clear," co-author Elmira Khabusheva, a postdoctoral associate in the Goodell lab, remarked. "By contextualizing existing drugs within the C-body framework, we can comprehend why they work across different leukemias and initiate the design of new drugs targeting the condensate itself. It's akin to finally witnessing the entire forest rather than just the trees."
"By identifying a shared nuclear structure that all these mutations depend on, we connect basic biophysics to clinical leukemia," Goodell added. "This means we can target the structure itself, a novel approach to therapy."
"Across every model we studied, the pattern was consistent," Datar said. "Once we observed those bright dots, we knew we were examining something fundamental."
The discovery of C-bodies provides leukemia with a physical address, a structure scientists can now see, touch, and target. It offers a simple physical explanation for how diverse mutations converge on the same disease and points to treatments aimed at dissolving the droplets that cancer relies on, akin to removing fat from soup to restore balance.
This finding establishes a new paradigm for linking droplet-forming disease drivers into shared, generalizable therapeutic targets. It suggests that just as distinct mutations in leukemia converge on the same condensate, other diseases, such as ALS, may each assemble their own biophysically indistinguishable droplets governed by the same physical rules.
The study's success was made possible through collaboration between the Riback and Goodell labs at Baylor College of Medicine and international partners, including the Associazione Italiana per la Ricerca sul Cancro (AIRC), the Trond Mohn Foundation, and the Norwegian Cancer Society.
The research, led by Gandhar Datar and Elmira Khabusheva, is published in the journal Cell.
