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    Life-and-death protein regulates immune system’s “emergency team”

    Joseph T. Opferman, PhD

    White blood cells called neutrophils and macrophages are the first responders of the immune system. They serve as the first line of defense against invading microbes—identifying them, engulfing them and eliminating them. However, once these protective cells have obliterated their quarry, they must quickly commit suicide, so the immune system can return to normal and the body can dispose of the toxic microbial waste and damaged cells.

    St. Jude researchers have now established a central regulator of this knife-edge balance between life and death of myeloid lineages. They have found that a gene called MCL-1 produces a protein that protects neutrophils against cell suicide, or apoptosis, as they mature in the bone marrow. However in macrophages, the MCL-1 protein appears to be dispensable for maturation, but instead governs the macrophages’ life-and-death balance, promoting survival while the macrophage works to eliminate 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,” said Joseph Opferman, PhD, Biochemistry. “But after the clearance of the microbe, you need 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 homeostasis. Otherwise, an accumulation of active inflammatory cells can lead to tissue destruction.”

    Opferman is the senior author of a report on this work published in the December 8, 2008, advanced online issue of the journal Blood.

    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 yield insight into leukemias in which MCL-1 levels are known to increase, contributing to the abnormally prolonged life of the malignant cells, Opferman said.

    Previous studies in the Opferman lab indicated that MCL-1 was protective during the birth stages of white blood cells in the bone marrow. In the scientists’ new experiments, they sought to understand whether MCL-1 was also important later, as neutrophils and macrophages differentiate into mature cells and carry out their function.

    To study MCL-1’s role in myeloid function, the researchers used a conditional knockout technique that allowed them to switch off the MCL-1 gene specifically in the neutrophil and macrophage lineages. They needed to use a conditional knockout technique because MCL-1 is so critical throughout development that simply deleting it in fertilized mouse eggs results in death at an extremely early embryonic stage.

    These knockout experiments establish that in neutrophils MCL-1 is critical to their differentiation into mature cells. The researchers’ experiments yield clues about how MCL-1 functions with other known components of the cell death machinery in neutrophils.

    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 death when they ingested microbes.

    “This is one of the most striking findings of our study,” Opferman said. “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 cell death.”

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

    MCL-1 is highly expressed in a lot of different leukemias and lymphomas, and many groups are developing treatments to antagonize MCL-1 function in order to kill cancer cells,” he said. “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. So, our data suggest that treatment strategies should aim at modulating MCL-1 protein levels, without completely getting rid of its function.”

    In further studies, Opferman and his colleagues will trace how MCL-1 is regulated in the immune cells to aid development of strategies to precisely adjust levels of the protein.

    Other authors of this paper include Kelli Boyd, DVM, PhD, Veterinary Pathology Core; Gerard Zambetti, PhD, Biochemistry; and Desiree Steimer, formerly of St. Jude.

    This research was supported in part by the Pew Scholars Program in the Biomedical Sciences, the National Cancer Institute and ALSAC.

    March 2009