Forcing quiescent leukemia cells to proliferate holds promise for acute myeloid leukemia (AML) chemotherapies
Some cancers, such as acute myeloid leukemia (AML), are particularly difficult to eradicate. Patients with AML often relapse and do not survive more than a year after chemotherapy treatment. Findings by a team of researchers from Japan, along with Jackson Laboratory Professor Lenny Shultz, Ph.D., could improve that survival rate (Saito et al., 2010).
The team generated humanized AML mouse models by engrafting irradiated newborn mice from JAX® Mice strain NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (005557) — abbreviated “NSG” for NOD scid gamma — with purified human AML stem cells. Populations of engrafted human AML cells had been shown to home to the endosteal region of the bone marrow and be chemotherapy resistant (Ishikawa et al., 2007). Hypothesizing that the cells are chemotherapy resistant because they are quiescent and non-dividing, the team tracked which populations of AML cells survive in engrafted mice treated with cytosine arabinoside (Ara-C), a standard chemotherapeutic AML treatment (Mikkola, Radu, and Witte, 2010). They found that Ara-C preferentially targets dividing AML cells, leaving behind the quiescent ones. They next hypothesized that if these quiescent cells could be induced to re-enter the cell cycle, they would be more Ara-C susceptible. The team therefore treated groups of AML-engrafted NSG mice with either Ara-C alone or Ara-C and a cell-cycle inducer, human cytokine granulocyte colony-stimulating factor (G-CSF). They found that the combined treatment eliminates significantly more AML stem cells, through a chemotherapy-initiated apoptotic cascade, than Ara-C alone.
These findings strongly imply that cell cycle inducers, such as G-CSF, might significantly increase the efficacy of chemotherapy in AML patients. In fact, multiple clinical trials continue to examine the positive effects of G-CSF, alongside standard chemotherapy, as treatment for AML patients.
Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S, Nakamura R, Tanaka T, Tomiyama H, Saito N, Fukata M, Miyamoto T, Lyons B, Ohshima K, Uchida N, Taniguchi S, Ohara O, Akashi K, Harada M, Shultz LD. 2007. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 25:1315-21.
Mikkola HK, Radu CG, Witte ON. 2010. Targeting leukemia stem cells. Nat Biotechnol 28:237-8.
Saito Y, Uchida N, Tanaka S, Suzuki N, Tomizawa-Murasawa M, Sone A, Najima Y, Takagi S, Aoki Y, Wake A, Taniguchi S, Shultz LD, Ishikawa F. 2010. Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat Biotechnol 28:275-80.