New research has identified a novel nutrient-uptake process that maintains the activity of murine chronic myelogenous leukemia (CML) stem cells. The study in Nature Communications (doi:10.1038/ncomms9039) by a team of Japanese and Korean researchers found that certain nutrients support CML stem cell activity in vivo, thus suggesting a potential target for therapy.

Figure. Diagram shows the researchers' proposed role of dipeptide uptake in long-term CML stem cell maintenance. According to the theory, because the mechanism is not important for normal hematopoietic stem cells, interfering with dipeptide uptake nutrient signaling may be a new therapeutic approach for CML patients.

"Although tyrosine kinase inhibitors [TKIs] such as the first-generation TKI imatinib mesylate and the second-generation TKIs dasatinib and nilotinib have markedly improved the prognosis of patients with chronic-phase CML, a cure remains elusive. To completely eradicate CML stem cells and CML, TKIs may have to be coupled with novel therapeutics targeting alternative mechanisms," the lead researcher, Kazuhito Naka, PhD, Associate Professor at Hiroshima University, explained in a news release.

CML stem cells were found to accumulate significantly higher levels of certain dipeptide species than normal hematopoietic stem cells do. Once internalized, these dipeptide species act as nutrients for the CML stem cells and play a role in the maintenance of CML stem cells. Importantly, an inhibitor of the dipeptide uptake blocks CML stem cell activity in mice.

"Our proposed approach of using inhibitors to shut down a key nutrient-uptake process specific to CML stem cells, in combination with TKI therapy, may thus provide concrete therapeutic benefits to patients with CML," Naka said. "It will open up a novel avenue for curative CML therapy.

A First

"To our knowledge, our study is the first to demonstrate that CML stem cell activity depends on nutrient signaling that regulates post-translational phosphorylation of Smad3 at Ser208. Furthermore, we have shown that dipeptide-induced p38MAPK activation is responsible for this Smad3-Ser208 phosphorylation, and that Foxo3a binds specifically to Smad3 in LT-CML stem cells."

The research also showed that the antibiotic cefadroxil attenuates dipeptide uptake by CML stem cells and so may be an option to use in combination with TKIs.

"However, we still do not understand how dipeptides act as a nutrient source for specific cell types, or how systemic dipeptide distribution contributes to normal health," the team wrote in their conclusion.

"Indeed, administration of cefadroxil in the absence of a TKI appeared to accelerate disease development in CML-affected mice. ... Our proposed approach of using cefadroxil to shut down a key nutrient source specific to CML stem cells, in combination with TKI therapy, may thus bring concrete therapeutic benefits to CML patients."