Researchers at the University of California, San Diego School of Medicine (CA, USA), have discovered a protein’s critical function in the development and progression of acute myeloid leukemia (AML). The study was recently published in the journal Cell Stem Cell and the discovery presents a new target for the treatment of AML by restricting tumor access to vital nutrient sources.
“The work really focuses on trying to understand the dependence of cancer cells on the microenvironment that surrounds them,” commented senior author Tannishtha Reya (University of California, San Diego School of Medicine) .
The researchers demonstrated that a cell surface molecule, tetraspanin3 (Tspan3), provides a key link for cancer cells to interact with the cell microenvironment, aiding tumor replication. The authors found that the blocking of Tspan3 led to extensive reductions of AML growth. This inhibition was demonstrated in mouse models and patient samples.
The importance of these findings is that at present AML does not respond favorably to current therapies. Furthermore, due to the cell-surface nature of Tspan3, there is greater interest from a translational medicine perspective for antibody-mediated therapy. “There’s been great progress in pediatric leukemia research and treatment over the last few years,” said Reya. “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.”
These findings add to previous discoveries by the Reya lab, including that of 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 Musashi may identify new genes important for these leukemias,” explained Reya.
The researchers subsequently conducted a genome-wide expression analysis of Msi-deficient cancer stem cells from two kinds of aggressive leukemia, blast crisis chronic myelogenous leukemia and AML, and genes were identified that are commonly regulated by Msi in both leukemias.
The analysis identified Tspan3 as a core gene controlled by Msi in leukemia. “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,” continued Reya.
In testing this conclusion, the researchers created the first Tspan3 knockout mouse. It was demonstrated that Tspan3 deletion negatively affected leukemia stem cell selfrenewal and disease propagation and improved survival in animal models of AML. Similar results were shown in patient samples of AML, suggesting an important role in human disease.