Cell Surface Protein Deletion Blocks AML Growth in Mouse Model

Cancer researchers have found that the cell surface protein tetraspanin3 (Tspan3) is required for the development and propagation of the fast-growing and extremely difficult-to-treat blood cancer, acute myelogenous leukemia (AML).

AML is an aggressive cancer that strikes both adults and children and is frequently resistant to therapy. Thus, identifying signals needed for AML propagation is a critical step toward developing new approaches for treating this disease.

Towards this end, investigators at the University of California, San Diego (USA; www.ucsd.edu) examined the role of Tspan3 by genetically engineering a line of mice to lack the gene required for production of this protein.

The investigators reported in the July 23, 2015, online edition of the journal Cell Stem Cell that Tspan3 "knockout" mice were born without overt defects. However, Tspan3 deletion impaired leukemia stem cell self-renewal and disease propagation and markedly improved survival in mouse models of AML. Additionally, Tspan3 inhibition blocked growth of AML patient samples, suggesting that Tspan3 was also important in human disease.

Results also showed that at the molecular level Tspan3 was a target of the RNA binding protein Musashi 2, which plays a key role in AML, and that the chemokine response of AML cancer cells was impaired by Tspan3 deletion.

“There has been great progress in pediatric leukemia research and treatment over the last few years,” said senior author Dr. Tannishtha Reya, professor of pharmacology at the University of California, San Diego. “But unfortunately, children with acute myeloid leukemia are often poor responders to current treatments. So identifying new approaches to target this disease remains critically important.”

“Tetraspanin3 (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,” said Dr. Reya. “We found that blocking this molecule leads to a very profound inhibition of leukemia growth. The work really focuses on trying to understand the dependence of cancer cells on the microenvironment that surrounds them. The microenvironment refers to the normal cells, molecules, and blood vessels around the cancer that may support and fuel its expansion.

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