The human gene MLL is named for the mixed lineage leukemia it creates. Specifically, the gene may break apart and fuse with parts from one of a number of other genes on other chromosomes to create cancer–causing translocations. These translocations make new proteins that have never been seen by the cell and can cause cancerous growth. In addition to mixed lineage leukemia which occurs in children, MLL translocations cause about 15 percent of adult acute myeloid leukemia (AML).

Thus MLL has been a major focus of drug development aimed at stopping the cancers caused by these translocations. However, despite their promise, these drugs have struggled to show clinical benefit.

A University of Colorado Cancer Center paper published in the journal Cancer Cell challenges existing understanding of potential therapeutic targets in MLL–translocation leukemia. Specifically, the study shows that within the family of MLL–related proteins, MLL2 and not MLL is the most appropriate target for drugs challenging the disease. In other words, drug developers aiming at MLL may have been missing slightly to one side of the real target.

When the researchers knocked out MLL, there was no change in the course of leukemia. But when they knocked out MLL2, it resulted in about 40 percent less leukemia. And when they knocked out both MLL and MLL2, they saw about 90 percent reduction in leukemia. Finding that MLL2 may be a target in MLL–translocation leukemia was an important result. But the question of MLL involvement that the group thought it had put to rest (namely the finding that there was no involvement) had now acquired an important nuance: “How can a thing that does nothing on its own – namely MLL knockout – have such a dramatic effect when combined with this other thing, namely MLL2 knockout?” Chen asks.

“It’s a classic synergism,” Ernst says. “Like in a car: if you mess with the brakes a little, maybe nothing happens. But if you mess with the brakes a little and also mess with the accelerator so that it sticks, now you’ve got a problem.”

Chen took MLL2 knockout leukemia cells to the CU Cancer Center Genomics and Microarray Core Facility to see if she could figure out why the gene collaborated with MLL translocations (and with wildtype MLL) to cause leukemia. Basically, RNA sequencing could tell her how MLL2 was connected to other genes – what did it turn up or down, and what general pathways did MLL2 influence? It turned out that 177 genes were deregulated by MLL2 alone and that 444 genes were deregulated when both MLL and MLL2 were removed. When viewed together, it turned out that groups of these genes had very significant meaning in the context of leukemia, including members of three leukemia pathways that are already considered significant drug targets in AML.

“These are all very important leukemia pathways,” Ernst says. “If you had a drug for MLL2, you could hit these really big targets.”

Additionally, while MLL is essential to the function of healthy bone marrow stem cells, MLL2 seems to have little function in the adult body. This means that targeting MLL2 may come with fewer side effects.

Of course, the group’s continuing work is making the case for the development of exactly this kind of drug. Chen is working with cells from human cancer patient samples provided by CU Cancer Center investigator Daniel Pollyea, MD and Children’s Colorado investigator Kelly Maloney, MD, to show that the effect of MLL2 inhibition is not specific to mouse biology. And Ernst is working to show how broadly relevant MLL2 as a drug target may be in other blood cancers.