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    The final frontier

    For some, space may be the final frontier. But strange new worlds can also be found on a molecular level.

    The battle of battles has begun. Starship Neutrophil pulls alongside starship Macrophage. The first in a galaxy of defenders, each ship is poised to defend the universe against attack. After successfully fulfilling their quest, the starships self-destruct, leaving tranquility in their wake.

    White blood cells called neutrophils and macrophages are the first responders of the immune system. They serve as the initial line of defense against invading microbes—identifying, engulfing and eliminating the enemy. When these protective cells have obliterated their attackers, they must quickly destroy themselves so the immune system can return to normal and the body can dispose of the toxic microbial waste and damaged cells.

    Scientists at St. Jude Children’s Research Hospital have discovered a regulator for this process that might yield insights into diseases like sepsis and some leukemias.


    To explore strange, new worlds

    St. Jude researchers recently found that a gene called MCL-1 produces a protein that protects neutrophils from self-destructing as these white blood cells mature in the bone marrow. The MCL-1 protein also helps macrophages survive while they do their job of eliminating extracellular microbes.

    “The fine-tuned balance mediated by MCL-1 is critical because you want to protect the macrophages when they encounter a pathogen and allow them to do their job,” says Joseph Opferman, PhD, of St. Jude Biochemistry. “After clearance of the microbe, the body needs to rapidly downregulate the immune response by eliminating the cells that have been recruited to the infection site and return the immune system to normal. Otherwise, an accumulation of active inflammatory cells can lead to tissue destruction.”

    The researchers’ basic findings of MCL-1’s function could yield insights into its role in such disorders as sepsis, an often lethal inflammation in which the immune system goes out of control. Also, the finding could give insight into leukemias in which MCL-1 levels are known to increase, contributing to the abnormally prolonged life of the malignant cells.

    “Myeloid cells are very important to the body,” Opferman says. “We are trying to understand what regulates their development, survival and function. The most important finding of this research was an unexpected difference in the molecules used for promoting the survival of the neutrophils versus macrophages.

    “This is a molecule that is essential for a variety of different cell types’ survival. What we are trying to do is assess whether it is playing another role in a very important type of blood cell that is in essence the first line of defense in the immune system.”


    To seek new information

    Trying to understand that role is significant because it can teach researchers about when these blood cells are deregulated and how that might lead to cancer.

    “MCL-1 happens to be a molecule that promotes cell survival,” Opferman says. “Therefore, it needs to be tightly regulated. We are trying to understand how to take advantage of its normal regulation in order to foster the elimination of unwanted, damaged or obsolete cells.”

    MCL-1 had been shown to be important in a variety of other blood cell lineages. Previously, Opferman showed that the molecule was necessary for the survival of lymphocytes, blood stem cells and a variety of different early blood cell progenitor populations in the bone marrow. 

    “Starting this study, there was a common implication that this pro-survival molecule was essential for all blood cell lineages,” he says. “And, some people in the field suggested that no matter what lineage you knock MCL-1 out in, it’s going to be lethal. That was not what we found in this study.”

    In studies with macrophages, the researchers found that while MCL-1 was not necessary for development and basic function, its loss rendered the macrophages sensitive to elimination when they ingested microbes.

    “This is one of the most striking findings,” Opferman says. “In all other blood cell lineages, if you delete MCL-1, those cells are basically gone. But macrophages survive, and we want to find out why they survive, and why losing MCL-1 only makes them more susceptible to apoptosis.”


    To boldly go

    Besides yielding insights into inflammation, a deeper understanding of MCL-1’s normal role might also help in developing treatment strategies for myeloid leukemia.

    “MCL-1 is highly expressed in several different leukemias and lymphomas, and many groups are developing treatments to antagonize MCL-1 function in order to eliminate cancer cells,” Opferman says. “As we come to understand the primary, normal functions of MCL-1, we appreciate that simply eliminating its function might have significant detrimental side effects. Our findings suggest that treatment strategies should aim at modulating MCL-1 protein levels without completely blocking its function.”

    The other important finding was that the macrophages, which normally express this protein, were not eliminated but instead had some functionality. That was also not previously observed in the literature.

    “The real question I am interested in is how MCL-1 affects cell survival and function in vivo,” Opferman says. “We are trying to find what role MCL-1 plays in normal cell development and understand how it is regulated. One of the lessons that can be learned from these studies is that, if we can understand its normal regulation, we might be able to take advantage of these normal regulatory pathways. Instead of causing a full elimination of the protein, which would have dramatic side effects, we might be able to turn it down in situations where you want to promote blood cell elimination. In other cases, you might be able to turn up MCL-1 expression when you want to prevent elimination of blood cells. That is the way I see our role.”

    For children who might one day benefit from this research, the exploration is far more exciting than mapping stars or studying nebula. For them, the possibilities are as wide as the universe.

    Reprinted from Promise Summer 2009

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