In cancer research, everything is relative. For instance, the rare blood cancer multiple myeloma is a great success story, as survival rates have nearly doubled over the last decade. Yet the grim reality is that most patients in the United States don’t live beyond five years of diagnosis. The issue is not a dearth of therapies. Rather, it is defining how they might be best used to extend lives even further.

The hunt for these “needles in the haystack” is getting easier, thanks to a new mouse model of multiple myeloma developed by a team of Mayo Clinic researchers. Mice that develop, or model, a human disease are nearly always an early step in identifying the best agents to move forward toward clinical application.

A good mouse model of multiple myeloma hadn’t existed before, but now, cancer geneticist P. Leif Bergsagel, M.D., can use the mice he and his colleagues developed to identify drugs with the most promise and uncover new clues to myeloma’s origins. This particular model is remarkable in that it is the only one that consistently responds to multiple myeloma in the same way patients do, while not responding in ways not seen in patients.

The First Clue

You might say that multiple myeloma is in Dr. Bergsagel’s blood. His father, a world-renowned oncologist, developed the first effective therapy for the disease. The younger Bergsagel grew up knowing he wanted to do cancer research himself, but his ultimate decision to study myeloma was purely intellectual.

“The fact that myeloma is a tumor of the bone marrow cells — or plasma cells — that produce antibodies held the clue to discovering the genetic causes of the disease,” says Dr. Bergsagel, one of the lead investigators in Mayo Clinic’s Multiple Myeloma Research Program. “I knew that I should start by looking for acquired changes in antibody genes. If I had been studying lung cancer instead, I wouldn’t have had a clue where to look.”

Segments of antibody genes are rearranged — essentially cut and pasted together — by the immune system to create billions of different antibodies to ward off infection. In the process, mistakes can be made, with segments shuffled into abnormal patterns. These abnormal rearrangements result in a condition called monoclonal gammopathy of undetermined significance (MGUS), which always precedes multiple myeloma. However, MGUS — which affects 3 percent of adults, rarely turns into cancer. Exactly what other cellular events arise to set off full-blown malignancy has been the recent focus of Dr. Bergsagel’s research.

“Most people with the premalignant condition are fine. It never progresses, it never even bothers them,” says the Canadian-educated Dr. Bergsagel. “If we could identify the trigger that turns these cells cancerous, we could revert patients back to the chronic, relatively benign disease or prevent the transformation from happening altogether.”

Another clue brought him closer to this cancer-causing trigger. Previous studies had detected one type of abnormal rearrangement — called a chromosomal translocation — in other plasma cell cancers (also called B cell cancers). So the team searched for translocations in antibody genes — also called immunoglobulin genes — in cells derived from myeloma patient tumors. They spotted dozens of such translocations, which they then mapped to their exact locations on the chromosomal DNA. A number of genes, among them FGFR3, MMSET, c-maf, cyclin D1, and MYC, were altered by the DNA-breaking translocations.

Tricks of the Trade

But what role, if any, these genes had in causing myeloma still wasn’t clear. So the researchers systematically mutated each of the genes in mice, hoping that one of them would result in a true mouse model of the disease. Such a model has long been sought by myeloma researchers, whose many attempts have failed to produce a model that closely resembles the human disease. In the case of MYC, a known cancer-causing oncogene, previous transgenic models did actually develop cancer. It just arose earlier in life, in a form of leukemia. The Mayo Clinic researchers devised a trick to “turn on” the MYC gene later in the mouse by exploiting the cellular machinery underlying the disease.

This cellular machinery comes into play when the immune system encounters something foreign – specifically, an antigen. The B cells begin to grow and divide rapidly, and within them the immunoglobulin genes are deliberately bombarded with mutations. The mutations that make the antibody a better fit for the offending antigen are selected for; those that do not die out. Dr. Bergsagel and his colleagues took this mutation-accumulating propensity of B cells into account when designing the MYC mouse model.

Within the transgenic vector, which contains the DNA instructions to produce the MYC protein, the researchers plunked a stop codon — a molecular stop sign of sorts. As the B cells within the mice began to grow and develop, this stop codon kept the MYC protein from being made. But later, when the mutation machinery kicked in to produce a new cadre of antibodies, the mutations started accumulating and, eventually, one landed in the stop sign, morphing it from “stop” to “go.”

“It really is a neat trick, and it mimics what we think is happening when these chromosomal translocations occur,” says Dr. Bergsagel. “The gene just has to get turned on in one cell — one single B cell — and it leads to cancer.”

Normally, the blood contains a wide spectrum of antibodies. But in myeloma, one of those antibody-producing cells has become abnormal and multiplies out of control. The researchers can track the development of the disease and the ability of different therapies to stymie its progress by measuring levels of these abnormal antibodies — designated monoclonal spikes or M spikes — in the blood. Dr. Bergsagel’s team found that the transgenic mice began to develop myeloma when they are around 1-year old, or middle-aged in human years.

“This mouse suggests that one of the mechanisms by which cells convert from the benign state to the malignant one is by activating the MYC gene,” says Dr. Bergsagel. “It is really critical that we understand that and see if we can specifically block the effects of MYC to turn the cancer back into a more chronic disease.”

The researchers have already tested a number of drugs and have discovered that the same drugs that work in the transgenic mice also work in patients. Dr. Bergsagel is using what he learns in the mouse to help him prioritize which treatment he should try next in his own patients. The mouse is not just informing current treatments, it is also yielding new insights that could drive entirely new therapies.

“It has shown us things that we didn’t know about in humans,” says Dr. Bergsagel. “For instance, we discovered that a gene called UTX was inactivated or “turned off” in about a third of mouse tumors. Turns out that same gene is inactivated in some patient cells. So it is a very faithful model, in terms not only of the way it behaves but also in terms of its genetic progression.”

The Way Forward

Multiple myeloma is probably not triggered by one single cellular event, but rather one in a list of four or five possibilities. Whatever the initiating event might be, it sets off a cascade of genetic changes in the myeloma cells that in turn determine how quickly the disease progresses. Dr. Bergsagel’s team is now adding some of these secondary changes, including mutated forms of the cancer-causing genes NF-kappaB and p53, into the mouse model to gauge the effect on the disease and its treatment. As the picture of the disease becomes more complex, Dr. Bergsagel is thankful to have colleagues at the Mayo Clinic Cancer Center in Arizona to turn to, particularly Rafael Fonseca, M.D., and Keith Stewart, M.B., Ch.B.

Still, he can’t help but take his work home with him. His wife, Marta Chesi, Ph.D., happens to be a key figure in his laboratory. She was instrumental in creating the MYC mouse model. They often find themselves bouncing ideas off each other at the dinner table, much to their children’s chagrin. Dr. Bergsagel recalls the younger of their two sons complaining, “All you guys ever do is Myeloma, Myeloma, Myeloma.” If this 7-year-old decides to follow in their footsteps, he will be doing the same thing one day.

— Marla Broadfoot, Ph.D., March 2010