Autonomous CLL BCRs

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. 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

aims to develop effective therapies against CLL, building on a deeper understanding of these underlying mechanisms. “The idea is to develop antibodies with which we could precisely target and remove the cells with the specific changes that we’ve identified. This would be the first really CLL-specific therapy,” he outlines. “It would not be effective for all patients, as every CLL sub-group has its own specific change, which needs to be characterized in order to develop a specific therapy. For the sub-group with poor prognosis mentioned above, we are in the process of developing and characterising such specific reagents, to recognise the mutated site, and to hopefully remove the malignant cells.”

There is also the possibility of using this approach in prevention of CLL among groups at higher risk of developing the disease. CLL affects mainly older people, who could be screened for the presence of such cells once the reagents for detecting the malignant cells of the sub-group with poor prognosis are available. If necessary these cells could be removed before the disease develops. “We are primarily focused on developing a therapy specifically for this sub-group of patients that we’ve identified, but this research could also hold implications for the treatment of other groups in future,” says Professor Jumaa. The primary focus at the moment however is this specific subgroup, because the change that has been identified is clear, and it’s known to be associated with the key mechanism. “If we could develop an antibody or a reagent that recognises this change, then we will have achieved our aim,” continues Professor Jumaa.

This applied research is central to improving treatment, yet Professor Jumaa plans to also pursue more basic work that can reveal fundamental insights into the behaviour of cells and the underlying causes of CLL. While it is important to maintain close links with clinicians if the disease is to be more fully understood,

If this development is not working well then cells can become transformed or malignant, and grow in an uncontrolled way. 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?

Professor Jumaa believes this needs to be balanced by more fundamental research. “If you focus just on the patients, you might miss the key mechanisms,” he points out. “So if you understand the biology, and look at the cases that might be related to the biology, then this is an unbiased way of understanding diseases. I would say, for me, that this is the right way to go. So our focus will remain on basic research and connecting to our partners in the clinic, to see what problems are, and where can our improved understanding be applied in the cases that we see?”

Full Project Title

Role of autonomous B cell receptor signalling and external antigen in the pathogenesis of chronic lymphocytic leukaemia [CLL] (Autonomous CLL BCRs)

Project Objectives

Chronic Lymphocytic Leukaemia (CLL) is a common type of blood cancer. It is characterized by uncontrolled growth of B-lymphocytes that normally produce antibodies to fight infections. The European Research Council Advanced Grant Autonomous CLL BCRs aims at characterizing the mechanisms that cause immune cells to convert into malignant cancer cells.

Project Funding

Funded by an ERC-ADG - Advanced Grant. EU contribution: EUR 2 256 250

Project Partners

• Nicholas Chiorazzi, MD, The Feinstein Institute for Medical Research, Head, Karches Center for Oncology Research, Hofstra Northwell School of Medicine, 350 Community Drive, Manhasset, NY 11030 / • Massimo Degano, PhD, Biocrystallography Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy / • Paolo Ghia, PhD, Università Vita-Salute San Raffaele, Milan, Italy / • Kostas Stamatopoulos, PhD, Institute of Applied Biosciences, Center for Research and Technology, Thessaloniki, Greece / • Stephan Stilgenbauer, MD, Department of Internal Medicine III, Ulm University hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany

Contact Details

Project Coordinator Professor Hassan Jumaa Ulm University Albert-Einstein-Allee 11 89081 Ulm Germany T: +49 (0)731500-65200 E: hassan.jumaa@uni-ulm.de W: http://cordis.europa.eu/project/ rcn/204856_en.html

Professor Hassan Jumaa

Professor Hassan Jumaa is a Full Professor (W3) and Chair, Institute of Immunology, University Hospital Ulm. He received the Georges-Kohler-Award of the German Society of Immunology (DgfI) in 2004 and has held his current position since 2013.