Monica Bessler, M.D., Ph.D., founder and director of CHOP’s Pediatric & Adult Comprehensive Bone Marrow Failure Center, spoke about her research at the 2011 annual meeting of the American Society of Hematology in December 2011. One of that meeting’s major scientific events, the Presidential Symposium, had a special focus on bone marrow failure (BMF) this year, and Dr. Bessler was invited to describe her studies of how chromosome structures called telomeres influence BMF.
Located at the ends of all chromosomes, telomeres are complex structures made of DNA and proteins that protect the chromosomes from sticking together or being degraded. Because telomeres are essential to cell normal growth and survival, they play crucial roles in human health, roles that continue to be investigated by scientists.
Dr. Bessler and other scientists have investigated how telomeres may give rise to bone marrow failure (BMF), the inability to produce sufficient numbers of circulating blood cells. BMF is not a single disease; it encompasses more than 80 known syndromes. Thus, distinguishing among different types of BMF allows physicians to provide more effective care to patients.
Recent discoveries are leading to reevaluation of current medical thinking about BMF. BMF was previously regarded primarily as being acquired during life, or as idiopathic — meaning caused by unknown factors. But Dr. Bessler’s investigations have revealed that many forms of BMF have a genetic origin; genetic changes can be inherited or newly acquired even though environmental factors such as smoking or exposure to chemicals also contribute to BMF. Additionally, types of inherited BMF formerly considered largely as childhood diseases are frequently being diagnosed in adults.
One important example of BMF is dyskeratosis congenita (DC), a rare, inherited multisystem disorder. In addition to the bone marrow where blood cells are produced, this disease affects multiple parts of the body including the immune system, the skin, oral cavity and tongue, the lungs, liver, brain, bone, the gastrointestinal system, nails and teeth. DC also increases a patient’s risk of preleukemia, leukemia and some forms of cancer. The disease is highly variable, presenting differently according to the age of onset of symptoms, the gene involved and the type of genetic mutation. Genetic mutations in DC impair telomere maintenance, causing the telomeres to shorten prematurely which results in the premature aging of cells in particularly those that undergo a high rate of cell divisions, such as the bone marrow cells, the skin cells and the lining of the oral cavity.
Telomeres have been compared to the plastic or metal tips at the end of shoelaces that keep them from fraying. In a basic way, telomeres keep chromosomes from sticking to each other and otherwise engaging in processes that make them unstable or lead to their degradation. Because telomeres shorten after every cell division, their protective function gradually decreases, and they leave aging cells vulnerable to DNA damage, unable to divide and destined to die.
Not all patients with BMF have abnormal telomeres, and not all patients with short telomeres have DC. However when telomeres are short in a patient with bone marrow failure genetic testing should be performed to rule out DC. DC may not always show with BMF but the initial manifestations change with age, are different between different individuals and sometimes even within an individual family. Sometimes there is genetic anticipation: over succeeding generations in a family, telomeres get progressively shorter, with disease symptoms becoming more severe and occurring at younger ages in the second and third generations compared to the first generation.
In patients with BMF in particular in children but also in the young adult having specific disorders such as aplastic anemia or myelodysplastic syndrome (a form of preleukemia), it is essential for physicians to order testing to determine whether the underlying problem could be a telomere defect, because that makes a difference for a patient’s prognosis, drug response and late complications.
For instance, doctors often treat BMF with a bone marrow transplant, preferably from a patient’s matched unaffected sibling. However, this is not appropriate if the potential donor, while unaffected, carries the disease-causing gene variant. Further research, said Dr. Bessler, will allow physicians to make a more accurate diagnosis and develop better, more effective protocols for personalizing BMF treatments to individual patients.