On the trail of a potential killer

The quest to target the causes and characteristics of strange, elusive disease — myelodysplastic syndrome
Dr. Joachim Deeg and Dr. Anneclaire De Roos
Dr. Joachim Deeg, Clinical Research Division, and Dr. Anneclaire De Roos, Public Health Sciences Division, are closing in on the characteristics, treatment options and ways of preventing myelodysplastic syndrome — a disease that predominantly affects an aging population. Photo by Lillian Furlong

Trying to treat myelodysplastic syndrome is like trying to seize a suspected criminal with few leads and only a few iffy descriptions, on which some of the witnesses disagree. MDS, also known as myelodysplasia, is an umbrella term for several different diseases, so pinpointing the syndrome as a whole is a challenge. The common denominator among MDS diseases is that the bone marrow doesn't function normally; although it generates many cells, the cells tend to die before leaving the marrow, so MDS patients have low blood cell counts. The course may be one of mild or moderate anemia as a progression to leukemia. In the past, MDS was often referred to as "preleukemia," but in actuality, only one-third of patients develop full-blown leukemia.

And therein lies the important question: Why do some patients develop leukemia while others don't?

Part of the mystery is in the simple fact that not much is known about MDS as a whole — but that's changing. "MDS has really become interesting over the last decade or so," said Dr. Joachim Deeg of the Clinical Research Division. "It's a very exciting area of research in a disease that has been somewhere on the sidelines, but not much was being done and people didn't understand it. Part of the interest has been generated by the fact that MDS is predominantly a disease of older patients, and as the population ages, an increasing number of people are being diagnosed with MDS."

Switched signals

As a result, MDS research has expanded at the Hutchinson Center and around the country over the past few years. Deeg, who has devoted the past 10 years to understanding abnormal cell signals that are operative in MDS, is one of several researchers at the Center trying to zero in on the disease and develop treatment that is based on the disease mechanisms.

"It is not clear what triggers the switch from a disease where the most prominent finding is actually an excessive rate of cell death — apoptosis — to a disease where the most prominent finding is an exaggerated proliferation of cells," Deeg said. "That is a very intriguing question, and that is really where my work is centered."

While there are likely many factors involved, the question Deeg is focused on is the switch from sensitivity to signals that result in programmed cell death, to a situation where cells are resistant to death. Many tumors are resistant to apoptosis, so Deeg and his colleagues are dissecting molecules involved in the regulation of cell death. One interesting lead concerns the molecule, FLIP. Increasing FLIP levels counteract cellular death signals and provide a growth advantage to the cell.

Deeg wants to find a way to eliminate the abnormal cells but allow the normal cells to grow. "One molecule we are studying is TRAIL, which provides one of the death signals, but interestingly, has the ability to preferentially kill abnormal cells. Such an ability would make it a very attractive agent to treat cancer," Deeg said. He pointed out that it's not black and white, there is still much work to be done, but the research looks promising.

Proving cause and effect

Dr. Beverly Torok-Storb is taking another angle on studying MDS. Her work focuses on interactions of cells that control the development of blood cells in the bone-marrow microenvironment. "MDS is a strange disease; clearly the microenvironment is not working well because there are normal stem cells there, but for whatever reason, those stem cells are not proliferating and differentiating properly," said Torok-Storb, an investigator in the Clinical Research Division. "If we understood why that is, we might have an effective way to treat the disease and reduce symptoms, even if we can't cure the disease." She added that because MDS is a chronic disease in older patients, relieving some of the most severe symptoms could provide tremendous benefit during the life of the patient.

In previous years, it had been assumed the structural elements of the microenvironment were defective. Torok-Storb found that the fixed structural elements are not part of the disease, but they behave abnormally because of instructions from other cells, known as monocytes, which are a part of MDS. Monocytes travel in the blood and go into the tissue, where they turn into incredible factories that are known as macrophages. Macrophages produce a number of important proteins. Abnormal macrophages in MDS patients appear to make inappropriate proteins that can change the function of the microenvironment.

"Although we have demonstrated that MDS macrophages are abnormal, it is imperative for us to prove cause and effect," Torok-Storb said. "To do this, Dr. Manoj Pillai, an investigator in the lab, has created a transgenic mouse that will enable us to control these factories in a reversible manner. He will be able to turn them on or off and see how controlling the macrophage will change the microenvironment."

Understanding MDS at the cellular level is also important to characterizing the disease. "Part of the work we are doing is an effort to better characterize subgroups of patients so that when the diagnosis is being made, one can test for certain features and on the basis of those findings, make a recommendation for therapy rather than throwing the same treatment at everybody, which is still being done among some colleagues," Deeg said. "Many of them tell us, 'I know how to treat MDS.' I say, 'Well, I don't.'"

Pinpointing the disease is a challenge. "Believe it or not, not a single good MDS epidemiological study has been done in North America," Deeg said.

One of the Center epidemiologists tackling that challenge is Dr. Anneclaire De Roos of the Public Health Sciences Division. De Roos is working on two MDS studies, one of which is funded by Surveillance Epidemiology and End Results, or SEER, which is a program of the National Cancer Institute to provide information on cancer incidence and survival across the country. SEER did not start recording MDS as a reportable cancer until 2001.

Data on the disease

"Before that time, it was not in their databases. Now we have four years of data, so we'll look at that to get some idea of the incidence of the disease and descriptive statistics. That's never been done before," De Roos said.

She's also combing through Group Health Cooperative's databases for information about MDS. "We'll be doing descriptive epidemiology by looking at incidence, prevalence and survival. We'll have a lot more information on those people than we will in the SEER study," De Roos said. "Group Health has all kinds of information about their treatments, medications and what kinds of health conditions people have that might lead to MDS."

Uncovering the characteristics of the disease, finding ways to treat it and knowing how to prevent it could lead to closing in on the disease and nabbing the criminal once and for all.

Much of the funding for the Center's MDS studies comes from the National Institutes of Health and the NCI.

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