Targeting a More Deadly Form of Leukemia
Researchers at Cincinnati Children's Hospital Medical Center have found that the unique conditions that exist inside a person’s body may play a significant role in whether that person will develop one type of leukemia over another. The findings, published in the June 9 issue of Cancer Cell, focused on a particularly deadly form of leukemia caused by a gene mutation called a “mixed lineage leukemia translocation.” The researchers also discovered that certain compounds, called Rac inhibitors, specifically target leukemias caused by this MLL translocation and might be promising as a treatment.
MLL translocations happen when a fragment of chromosome 11 detaches and re-attaches to another chromosome. MLL translocations don’t always lead to the same type of leukemia: they cause about seven percent of all acute lymphoid leukemia cases, and about nine percent of all acute myeloid leukemia cases. In the past, researchers suspected that the type of leukemia that developed from MLL translocations just depended on where in the chromosome the translocation re-attached. “But in this paper, we use the translocation partner that usually causes myeloid leukemia in people, yet we can get exclusively lymphoid [leukemia] or exclusively myeloid leukemia, depending on what environment we expose the cells to,” said Cincinnati Children’s researcher James Mulloy, PhD.
For the study, Mulloy’s team inserted the cancer-causing MLL translocated genes into human cells and grafted these cells into a mouse. “You cannot make lymphoid leukemia in the mouse cells with these same gene fusions. But in this human cell background we can do it, and actually it’s much more biased toward lymphoid, which is interesting,” he said. Mulloy thinks that timing, and where the cell is in the normal cycle of blood cell formation, may play a larger role than previously thought. “Now we will be able to come to an understanding of how important the maturation of the cell is during the formation of MLL-related leukemia,” said Mulloy, “and if that’s playing a major role, it could impact therapy.” Targeting cells at crucial stages during leukemia cell maturation could make chemotherapy more successful and less toxic.
Mulloy’s team also used their mouse model grafted with human cells to test a type of drug called a “Rac inhibitor.” Rac is a protein that sends survival signals to cells, and it seems to play a crucial role in MLL-related leukemia. “MLL fusion proteins use a whole different signalling pathway to get to their end result of leukemia,” said Mulloy. “And the MLL’s really depend on Rac, they are really addicted to these signals.”
Rac signals are also important for normal cell functions, but Mulloy says that non-cancerous cells can often work around certain signals, while cancer cells cannot. “It’s strange, and we don’t know exactly why that is,” said Mulloy. “Probably, the cancer cells become really hardwired, really addicted to these signals and normal cells have much more flexibility. They can get around this stuff and use other pathways, but the cancer cells are stuck.” Rac inhibitors dramatically killed the cancer cells in a culture dish but had little effect on normal blood stem cells. The group is now testing the compound in the mouse model.
The Rac inhibitor looks promising, but Mulloy says he is most excited about the new human-grafted mouse model used in this study, because it will teach him more about what happens when certain genes mutate in humans. “Data that we have in the paper shows we are pretty close to the patient samples in terms of faithfulness to gene signalling pathways and gene signatures,” he said. “We are in the cell that is probably really targeted in people by this chromosomal translocation. So you have some exposure to a chemical, or whatever causes these translocations to happen, and we can duplicate that in the lab and learn about the precise signalling pathways. The model really works.”
