Both oncogenic mutations identified by Lowe's team in AML patients have been well studied. The oncogene AML1/ETO previously has been associated with a favorable therapeutic outcome in people, while fusion oncogenes involving the MLL gene have been associated with an adverse outcome. To design an animal model that predicts these outcomes, the team introduced each mutation individually into stem and progenitor cells along with another oncogene, called Nras, which also appears frequently in human AML and is commonly found in concert with AML1/ETO and MLL fusion genes.
These altered stem cells were transplanted into mice that were first treated with radiation to destroy existing bone marrow cells. The altered stem cells then took over the "host" bone marrow and promoted the development of leukemia. To track leukemia onset and response to therapy, the scientists tagged all leukemia cells with a gene from fireflies that encodes an enzyme called luciferase, which makes leukemia cells glow and detectable by a ultrasensitive camera. Within weeks, the mice developed leukemias that showed the same genetic and pathological features as human AML.
"We were therefore certain," says Lowe, "that these animals were good models for studying the impact of cancer's genetic heterogeneity on therapy response and getting a correct read-out in terms of outcome prediction."
Sensitivity vs. resistance to chemotherapy
Experiments in which the team treated the mice with the same chemotherapy regimen administered to AML patients have proved Lowe to be correct. Just as in humans, leukemias in mice that received the AML1/ETO oncogene were also sensitive to chemotherapy and soon regressed, whereas ML
|Contact: Hema Bashyam|
Cold Spring Harbor Laboratory