This is not an invasion of parasitic aliens wishing to control your brain, or of zombies desiring to make a snack of it, but rather of your own cells gone rogue. It turns out that most of us are probably safe from invasion by rogue cells (I make no claim about zombies or aliens). But for a small part of the population, primarily children, the brain is not safe from leukemic invasion.
This small part of the population has a type of leukemia that effects T-cells (a type of white blood cell that monitors the body for pathogens) called T-cell acute lymphoblastic leukemia (T-ALL). ALL (encompassing both T-cell type and B-cell type) is the most common form of cancer in children age 1-7. For patients with this type of leukemia prognosis is usually good, however about 30% of patients will relapse within two years. Silvia Buonamici and her colleagues1 investigate one cause of relapse in which leukemic cells enter the brain. It has long been known that in some patients with T-ALL the brain is invaded by leukemic cells, leading to the current broad therapy. In addition to chemotherapy which a patient receives against leukemia cells, they also receive radiation therapy to the head as a preventative measure. For the patients who are cured of the leukemia, this head radiation therapy often reduces the quality of life by causing new cancers, growth defects, developmental and learning difficulties, and other negative side effects. This is especially devastating to children for whom growth and development is essential.
Buonamici and her colleagues at New York University Cancer Institute investigate the molecular basis for leukemia invading the brain in order to develop better therapies. By using mice that develop T-ALL, Buonamici and her colleagues investigated how the leukemic cells invade into the brain. They looked at thin slices of the brain to identify T-cells (which look different from normal brain tissue) under the microscope. T-cells do not normally accumulate in the brain, so the ability to visualize them in normal brain structures allowed Buonamici and her colleagues to assess if the leukemic cells had invaded. With this ability to assess the invasion, they investigated the difference between leukemic cells that invade the brain, leukemic cells that do not invade the brain, and normal T-cells. They found a specific molecule on the surface of the leukemic cells, called CCR7, which allows the leukemic cells to enter the brain. Buonamici and her colleagues also identified a molecule expressed on the surface of brain cells, called CCL19, which is required for invasion of leukemia cells into the brain. These two molecules are like a lock and key to the door of a house. CCR7 is the key on the surface of the leukemic cells, CCL19 is the lock on the surface of brain cells, and entering the brain is like entering the door of the house. If you do not have the correct lock and key pair, you cannot get into the house. By identifying this lock and key pair, Buonamici and her colleagues have opened the door for future scientists to design a therapeutic drug that prevents the key from turning in the lock, therefore blocking leukemic cells from entering the doorway to the brain.
Buonamici and her colleagues focus in this paper on a specific type of T-ALL that is induced by an activated form of Notch1, a molecule that normally participates in growth and differentiation decisions (such as whether to become a T-cell or a B-cell). The amount of CCR7 (our key) on the surface of a leukemic cell is increased by Notch1 (like a locksmith making many copies of your key). Notch1 is activated in 80% of T-ALL patients, leading to the question: What causes leukemic invasion in the other 20% of patients? This question could be especially important to therapeutics because it is unclear what proportion of the 30% of relapse patients overlap with the 20% of patients without activated Notch1.
Paper Referenced
Buonamici, S. et al. (2009). Ccr7 signalling as an essential regulator of CNS infiltration in t-cell leukaemia.Nature, 459. Retrieved from http://www.nature.com/nature/journal/v459/n7249/full/nature08020.html doi: doi:10.1038
Post authored by Sally Trabucco
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