Signalling the way to new therapies Changes in cell signalling are thought to be an important factor in the development of chronic lymphocytic leukemia (CLL), which is among the most common forms of cancer affecting adults. Research into the underlying mechanisms behind these changes could lead to both a deeper understanding of the disease and improved treatment, as Professor Hassan Jumaa explains The
molecular mechanisms that regulate the development of lymphocytes are an area of great interest in medical research, in particular B-lymphocytes, which generate the antibodies which protect us against infectious diseases. Alongside investigating the underlying mechanisms behind this process, Professor Hassan Jumaa and his colleagues at Ulm University are also interested in abnormalities in lymphocyte development. “If this development is not working well then cells can become transformed or malignant, and grow in an uncontrolled way,” he explains. “This leads to new questions – what are the signals that lead to this transformation? Which genes or gene products are involved? How can we interfere with their growth so that we can identify targets for therapy or diagnosis? These are the general questions that we are investigating.” Chronic lymphocytic leukemia This research holds particular relevance to our understanding of chronic lymphocytic leukemia (CLL), one of the most common types of cancer among adults. In CLL, a transformed B-lymphocyte expands in an uncontrolled manner and makes too many of the clonal B-lymphocytes, which have given up their physiological function and, instead, can hamper the ability of residual untransformed B-lymphocytes to protect against disease. “By secreting antibodies, the B-lymphocytes normally label pathogens, which become visible to phagocytes, which in turn respond and eat up the pathogen,” explains Professor Jumaa. The B-lymphocytes have an intrinsic machinery for mutation, so they can improve their affinity for a specific pathogen by mutating their genome; while this is important to generating high affinity antibodies, it can lead to other changes. “When the B-lymphocytes mutate their genome to generate these high-affinity antibodies, they might induce mutations that might lead to other transformations,” says Professor Jumaa.
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Figure 1 Activation of BCR-dependent signaling in CLL B cells. (A) Signaling of conventional BCRs is activated by binding of self- or foreign antigen (Ag) to neighboring BCRs. (B) In CLL B cells, BCR signals are generated by an inter-molecular interaction between the variable regions of neighboring BCRs independent of external antigens. Therefore, this BCR activation modus is referred to as antigen-independent or cell-autonomous signaling. The development of CLL and other forms of leukemia are associated with these kinds of changes in the basic mechanisms of cells. While the B-lymphocytes need to mutate to generate efficient antibody responses, there is a price. “Sometimes mistakes happen, which are usually removed by control mechanisms. But if these mechanisms fail, then the cells might become malignant and not secrete antibodies in the case of CLL. So, the malignant cells give up their original function, meaning that people with CLL are immune deficient,” outlines Professor Jumaa. A prime focus now is investigating the mechanisms behind the survival or transformation of the cells that cause CLL, building on earlier basic research. “We suggest that these cells have acquired cell autonomous mechanisms for
proliferation and survival, so mechanisms independent of the outside environment,” continues Professor Jumaa. These changes allow the cells to activate their signalling machinery without requiring an outside ligand to initiate the process, now researchers aim to learn more about the underlying factors behind this. A key area that Professor Jumaa and his colleagues are investigating is acquired changes in the B-cell antigen receptor, which lead to the autonomous activation of signalling. “We think it is most likely that these changes occur during immune responses. We have identified a sub-group of patients, in which a mutation in the receptor is essential for self-aggregation of receptors, for the induction of cellautonomous signalling,” he explains. “If we can learn more about the molecular details, we might be able to interfere with this mechanism and develop a specific therapy against the disease, as this autonomous signalling appears to be specific to CLL. Our investigations might improve the otherwise poor prognosis of this sub-group.” This goal forms an important part of the wider agenda, with Professor Jumaa keen to explore the clinical implications of this research. Alongside exploring fundamental mechanisms at the B-cell antigen receptor, Professor Jumaa also
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