What is inflammation and its relationship to MDS?
Inflammation is a complex biological response to an injury or an irritant. Inflammatory responses protect the body and cells from specific insults, with the purpose to rapidly neutralize the injury or insult the body has experienced. This could be a pathogen like bacteria, or even result of cell death, where intracellular components are released into the environment. These immediate cellular effectors of inflammatory responses involve white blood cells, immune cells, blood vessels and additional molecular factors. This process reflects what we refer to as the ‘innate immune system’ at work, and which specifically appears to be activated in MDS.
What are MDSCs?
The main cells that seem to be involved in operationalizing the inflammatory response are something called myeloid-derived suppressor cells (MDSCs). We found that these cells are markedly expanded in the bone marrow of MDS patients and their role appears to be to suppress blood formation. They will suppress and kill neighboring cells in the bone marrow and are genetically distinct or separate from the MDS clone. This findings suggests that MDSCs –may have preceded, and drive the emergence of the MDS clone.
We have also learned that MDSC’s are expanded and activated by a specific inflammatory protein, called S100A9, which together with its binding partner, S100A8, can drive the expansion of these cells. MDSCs and S100A9 also trigger a specific type of cell death. Targeted cells die by a unique process called pyroptosis – this is an inflammatory form of cell death. In the process of cell death, the cells swell and get larger. These are known as macrocytic cells, that are often seen in MDS -- and it also drives their proliferation. They appear to have a very important role in the disease biology and this signaling occurs through a protein complex called the inflammasome.
What are some inflammatory symptoms?
We have known for years that there are increased inflammatory complications in MDS. There was a large Swedish registry study showing that people who sustained chronic inflammation, whether it is asthma, rheumatoid arthritis, or some sort of autoimmune disorder, had a much higher risk of developing MDS. MDS patients can develop rashes, profound fatigue, vasculitis or inflamed blood vessels, and Sweet’s Syndrome which are painful flares in the skin associated with fever and inflamed, swollen joints. There are number of inflammatory symptoms that are all related to activation of innate immunity.
For people who have MDS and experience inflammatory disorders, I think we are on the cusp of having some new therapies that will help suppress this process. I have many patients where their hemoglobin is not low enough to have symptoms, but they have profound fatigue and aches with inflammatory symptoms. These novel kinds of treatment that are coming may have a role in treating all of the symptoms and initiating biological events, and represent an unprecedented opportunity for the future, not just for treatment but also for prevention.
We have heard about gene mutations that can be detected a very low level in the peripheral blood of people who are otherwise hematologically normal, These individuals have about an eleven fold increase in risk for developing MDS later on. If the inflammatory process drives it, it could eventually be as simple as taking a pill to prevent this from occurring. I think there’s enormous opportunity in the future for this.
What are some possible directions for future research?
I think the most important take home message is that understanding this biology which is very new, allows us to target the MDS clone therapeutically in a very specific way that we never could before. The convergence points in this process are the inflammasome, as well as S100A9, the key soluble mediator of expansion of MDSCs or activation of the cell death pathway we call pyroptosis.
We can target this in the laboratory now, by creating a soluble receptor that will neutralize S100A9, and using an inflammasome inhibitor which could be taken as a pill. These agents have been licensed to Celgene for clinical development in the years ahead. In the laboratory they work beautifully to enhance the survival of the cells and the effective production of blood cells.
For future research, the real question is what the mechanism of activation is for this pathway within the cells. If we can find the specific internal activators, we can make more specific inhibitors to help arrest the process. This needs to be a key priority of research in in the next few years.
Dr. Alan List is the President and Chief Executive Officer of Moffitt Cancer Center in Tampa, FL.
Dr. List is internationally recognized for his many contributions in the development of novel, more effective treatment strategies for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). His pioneering work led to the development of lenalidomide (Revlimid®) from the laboratory to clinical trials, which went on to receive fast-track designation from the
U.S. Food and Drug Administration and approval for the treatment of patients with MDS and multiple myeloma. This work transformed the natural history of MDS from a premalignant condition that progressed to malignancy requiring aggressive treatment to a condition managed in the outpatient setting with oral agents.
Prior to his current position, Dr. List served as Executive Vice President and Physician-in- Chief, the Vice Deputy Physician-in-Chief, and the Chief of the Malignant Hematology Division at Moffitt, where he holds the Morsani Endowed Chair.
Before coming to Moffitt in 2003, Dr. List was a Professor of Medicine at the University of Arizona, Tucson, where he also served concurrently as the Director of the Leukemia and Blood and Marrow Transplant Program and Director of the Division of Translational/Clinical Research Program.
After earning a medical degree in 1980 from the University of Pennsylvania, Philadelphia, Dr. List completed an internship and residency in internal medicine at the Good Samaritan Medical Center in Phoenix, Arizona. He then completed fellowships in hematology and medical oncology at Vanderbilt University Medical Center in Nashville, Tennessee.
Dr. List receives peer-reviewed NIH support for his work and publishes extensively in the areas of MDS and acute leukemia. He lectures nationally and internationally and has received several awards in recognition of his seminal contributions such as induction into The Joshua Lederberg Society; the Emil J. Freireich Award for Clinical Research, M.D. Anderson (2006); the J.P. McCarthy International Prize for Advancing the Body of Scientific Knowledge in Myelodysplastic Syndrome (2004); and the General Motors Cancer Research Foundation Merit Award (1991).
He is the author of more than 280 peer-reviewed articles and the Clinician’s Manual on Myelodysplastic Syndromes (2008). He serves as a member of the Myelodysplastic Syndrome Foundation Board of Directors. He also is an active member of the American Society of Clinical Oncology; American Society of Hematology; American Association for Cancer Research; International Society for Experimental Hematology; JP McCarthy Foundation Medical Advisory Committee; and the Southwestern Oncology Group.