Leukemia Renewal and Propagation Blocked by Inhibition of Surface Molecule
A new study by researchers at the University of California, San Diego, School of Medicine, reveals a protein’s critical—and previously unknown—role in the development and progression of acute myeloid leukemia (AML). The finding offers a novel target for better treating AML, and possibly other cancers, by cutting off the ability of tumors to access nearby cellular players that feed its growth. The study was published by Kwon et al in Cell Stem Cell.
“The work really focuses on trying to understand the dependence of cancer cells on the microenvironment that surrounds them,” said Tannishtha Reya, PhD, Professor in the Department of Pharmacology. The microenvironment refers to the normal cells, molecules, and blood vessels around the cancer that may support and fuel its expansion.
The latest findings build on earlier work by Dr. Reya and colleagues, which identified Musashi (Msi) as a critical stem cell signal that is hijacked in several blood cancers. “We had this idea that analysis of the molecular programs controlled by Msi may identify new genes important for these leukemias,” she said.
The researchers conducted a genome-wide expression analysis of Msi-deficient cancer stem cells from two kinds of aggressive leukemia, blast crisis chronic myelogenous leukemia (bcCML) and AML. “We identified genes commonly regulated by Msi in both leukemias,” said Dr. Reya, also a member of the Sanford Consortium for Regenerative Medicine and Moores Cancer Center.
Tspan3
Unexpectedly, the analysis identified tetraspin3 (Tspan3) as one of the core genes controlled by Msi in leukemia. The protein is part of a large family of membrane proteins active in diverse cellular processes, including cell adhesion, proliferation, hematopoietic stem cell function, and blood formation. “We are particularly excited about this work because, to our knowledge, this is the first demonstration of a requirement for Tspan3 in any primary cancer,” said Dr. Reya.
In the study, the researchers showed that Tspan3, a cell surface molecule, serves as a key link for cancer cells to interact with supportive parts of the microenvironment that help them replicate and flourish. “We found that blocking this molecule leads to a very profound inhibition of leukemia growth,” said Dr. Reya.
The researchers demonstrated their results in both AML mouse models and patient cancer samples.
Dr. Reya said these findings are particularly important because AML is a cancer that often doesn’t respond to current therapies. In addition, Tspan3 is a surface molecule, making it of greater translational interest as a target for antibody-mediated therapy. “There’s been great progress in pediatric leukemia research and treatment over the last few years,” said Dr. Reya. “But unfortunately, children with AML are often poor responders to current treatments. Identifying new approaches to target this disease remains critically important.”
To explore the connection further, the researchers took a “leap of faith” and generated the scientific community’s first Tspan3 “knockout” mouse, bred to be deficient in Tspan3. In testing, the researchers found that Tspan3 deletion impaired leukemia stem cell self-renewal and disease propagation, and markedly improved survival in animal models of AML. In patient samples, Tspan3 inhibition blocked growth of AML, suggesting Tspan3 is also important in human disease.
The research was funded by a Lymphoma and Leukemia Society Scholar Award, the UC San Diego Moores Cancer Center NCI Core Grant, and the National Institutes of Health.
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