The protein tetraspanin3 (Tspan3) plays a critical role in the development and progression of acute myeloid leukemia (AML), according to research published in Cell Stem Cell.
Investigators found that Tspan3, a cell surface molecule, is expressed in hematopoietic stem and progenitor cells as well as in leukemic cells.
Deleting Tspan3 did not affect normal hematopoiesis, but it prevented AML self-renewal and propagation in vitro and in vivo.
Inhibiting Tspan3 in patient samples led to decreased colony formation in vitro and hindered leukemic growth in primary patient-derived xenografts.
“We found that blocking this molecule leads to a very profound inhibition of leukemia growth,” said study author Tannishtha Reya, PhD, of the University of California San Diego in La Jolla.
These findings build on earlier work by Dr Reya and her colleagues, in which they identified the RNA binding protein Musashi 2 (Msi2) as a critical stem cell signal that is hijacked in several hematologic malignancies.
“We had this idea that analysis of the molecular programs controlled by Musashi 2 may identify new genes important for these leukemias,” Dr Reya said.
So the investigators conducted a genome-wide expression analysis of Msi2-deficient cancer stem cells from blast-crisis chronic myelogenous leukemia and AML. This revealed genes commonly regulated by Msi2 in both leukemias.
Tspan3 was one of the core genes controlled by Msi2. The Tspan3 protein is part of a large family of membrane proteins (the tetraspanin family) that are active in diverse cellular processes, including cell adhesion and 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,” Dr Reya said.
To explore the connection further, the investigators generated the first Tspan3 knockout mouse. In testing, the team found that Tspan3 deletion impaired leukemia stem cell self-renewal and disease propagation and markedly improved survival in the mice.
In patient samples, Tspan3 inhibition blocked the growth of AML, which suggests Tspan3 is also important in human disease.
Dr Reya said these findings are particularly important because AML often doesn’t respond to current therapies. And because Tspan3 is a surface molecule, it is of great 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,” Dr Reya said. “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.”
