There was an introductory talk by Professor John Cawley, who gave an overview of clinical work and research. This was followed by a talk by Dr Richard Clark whose main interest is in CML. However, the main event was the tour of the laboratories, detailed in section III below

It was clear to me that some innovative work is being carried out, but that it is very hard, if not impossible, to predict how quickly the research will be translated into improved clinical practice. Some of the work is clearly at an early stage of development. It was also clear that CLL is a complicated disease, arguably even more complicated than many other haematological malignancies. Nevertheless I am personally fairly hopeful that further exciting progress will be made in the next ten years, but the open day illustrated that there are still important gaps in scientists understanding of CLL (let alone in mine!). As we know, CLL is currently classed "incurable". This is because CLL has been (and to some extent still is) less well understood than other leukaemias. As Professor Daniel Catovsky said at a different meeting last year, CLL has been 'the Cinderella of haematological malignancies' I hope he was also correct when he said it is now in the front line of research.

It seems true, however, that more attention is being devoted to CLL research than before. GrannyBarb has already mentioned money directed at CLL research in the United States. The current research into CLL of Prof. Cawley has been awarded 205,000 by the LRF (Sorry, I don't have the current pound-dollar exchange rate). I am sure this is not the total amount that is devoted to CLL research in the UK. On the other hand, I could find only one other centre in the UK currently directed at CLL research. This is located at the Institute of Cancer Research , London, and looks at the possibility that some people may inherit a susceptibility to CLL. So I believe it is rather a mixed picture, and we still need to find a way of publicising our case for more funds to be directed at CLL research. The LRF does a great job and they support many other worthy projects, so our aim should be to increase their overall funding as well as the proportion devoted to CLL. (Their total research commitments for the five years from March 1997 amounted to 35 million, according to the " LRF Year Book").

I have largely written this report in non-technical language. This is the advantage of not having any medical training! Obviously, technical terms do need to be used but I try to explain each of these. As I mention in my disclaimer (V below), this presents my own understanding of what I learned during the day; I am not claiming that I understand everything.

The main areas of leukaemia research at Liverpool focus on CLL as well as CML (Chronic Myelogenous Leukaemia) and HCL (Hairy Cell Leukaemia).

It is worth noting that this represents research carried out at one institution and does not necessarily represent the focus of research at other institutions.

A. The role of GM-CSF in mature malignant B-Cell survival

Each cell has receptors, commonly found on the cell surface. It is thought that these receptors, classed as cytokines or integron (ligands) play a key role in cell survival and migration (I believe the correct term is cell motility). The research has examined both HCL and CLL. In HCL, malignant cells travel to and accumulate in the spleen but not in bone marrow or lymph nodes, whereas in the CLL they accumulate primarily in the lymph nodes and marrow (and sometimes also in the spleen). One reason for this could be to do with the way that cells are blocked from one site and not another (but I did not get a clear idea as to why although even the experts do not seem to understand fully. (See b) below for more about this process).

They found that GM-CSF (Granulocyte Macrophage-Colony-Stimulating Factor) was present on the cell surface in both CLL and HCL. Macrophages are found in nearly all parts of the body, and GMCSF plays a factor in stimulation of macrophages. Monocytes develop into macrophages after leaving the bone marrow, while macrophages play a key role in the immune system as they ingest antigens and help leukocytes recognise foreign matter. (macrophage comes from the Greek, meaning 'big eater'.)

However, in CLL, it seems that GM-CSF also plays a key role in preserving immature white cells. The cells have receptors (E.g. cytokines) that secrete the GM-CSF which in turn send back a signal to the cell to survive. Cytokines are basically small proteins on the cell surface involved in cell signalling. To explain in more detail, B-Cell receptors will secrete antibodies that bind to antigens (it is far more complicated, and I am still learning about this, but the basic idea is correct; note, antibodies is another term for IMMUNOGLOBULIN - second nature to the experts, but I only just discovered this!) As I understand it, receptors do more than just act as sites for binding to antigens. There are different types of receptors and their structure determines how foreign matter is recognised. Researchers believe that GM-CSF (which as you will recall, is produced by certain cell receptors) is also playing a role in survival of malignant cells. So although cell receptors have an important role to play in the immune system through the destruction of antigens, researchers are focusing their effort to get a better understanding of these receptors. It was significant that they did find the presence of GM-CSF in both CLL and HCL. They are looking at ways of blocking GM-CSF, or preventing the signal to the malignant cell to survive. An anti- GM-CSF antibody (a monoclonal antibody) was introduced to the cell, and they found that this inhibited the production of malignant cells. But the problem is that it is not only GM-CSF that can send such signals of cell survival. There are six other types of "CSF" involved, which adds considerably to the complexity of the problem.

B. Role of VEGF and MMP in the tissue migration of malignant B-Cells ");?>

The process of whether a cell can migrate was compared to having an open or closed door. In some cells, a signal is sent which effectively closes the door or prevents the cell from migrating to one location or another. This, put simply, determines whether an immature lymphocyte can migrate to a particular site in the body. It is thought that once such a cell finds its way to a lymph node, for example, it finds a very favourable environment for its long-term survival. This is partly due to the density of cells in such locations. For example, cells in the bone marrow are much more tightly packed than elsewhere. This helps keep the cell alive (prevents cell apoptosis). If a way can be found of blocking this migration (sending a cell signal to 'close the door'), then malignant cells will no longer have a favourable environment for their survival. (Please find the way NOW I kept thinking to myself!)

It was found that only tumour cells produce VEGF (Vascular Endothelial Growth Factor). VEGF is thought to play a role in inducing the migration of monocytes (as mentioned, monocytes are a type of white blood cell capable on ingesting infectious agents, they account for about 7 per cent of the total leukocytes). The spontaneous expression of VEGF by leuakaemic cells was investigated. VEGF was found to be present in both HCL and CLL. VEGF produce proteins called MMP (Matrix Metalloproteinases) which is thought to signal cells to pass through EC (Endothelial cell). Note that the EC cells are normally the cells that would push a cell away (i.e. prevent it migrating) This is a normal process that is happening millions of times in the human body. When this process of cell blocking fails, then you have cell accumulation in sites not found in non-CLL people. Researchers wanted to know why this process fails.

Thus, it is not so much the structure of the protein but the function of it that they are investigating. (Although I would guess that the structure was also important).

It is possible that the material cells have to pass through to migrate contains a special type of collagen (Type 4) which is rare. The MMP, which is an enzyme, is thought to digest this type-4 collagen, and thus allow the cell to migrate. However, this itself was an over-simplification. In fact, there were 20 types of MMP, only two of which can digest collagen. The researchers found that CLL and HCL cells secrete one of these enzymes called MMP-9. Once a way can be found of preventing the failure of the blocking process, then new therapies could be possible for combating CLL (but they are obviously not there yet, but believe they are "barking up the right tree!")

C. Role of hyaluronan and IL-8 in tissue localisation of mature lympocytes

Basically, cells cannot move if they do not have receptors (as was explained above). IL-8 is another example of a factor promoting cell movement. Research focuses on cell surfaces (where most of the action is). When IL-8 is added to cells, they develop such receptors and are found to move (they showed a video of cells moving). Once this was established, the researchers examined CLL (and HCL) cases and, sure enough, they saw that IL-8 was present in the spleen and bone marrow. Once again, they are looking for a monoclonal antibody that would prevent this.

D. Factors governing cell survival in CLL

This last demonstration really brought together the research above. We were shown an example of CLL lymphocytes (nasty critters) through a microscope (Slightly better than my normal check up readout of my figures).

Two factors were thought to promote cell survival:
a) Secretion of chemicals
b) Direct communication

In a) the cells are not necessarily crowded together, whereas in b) they do need to be tightly compact (as in the bone marrow). They found that cells surviving by b) would no longer survive when they were taken into a less crowded environment. i.e. direct contact seems to be involved. It is believed that cells say in lymph nodes are sending signals to each other to survive. Once they prove such messages exist they will try to decode them and block the messages.

CLL cells seem to survive longer than other cells, but yet they die when put into cultures where other cells survive.

All cells have sugar on the surface, take this away and you no longer have survival.

Overview of Clinical Work and Research

Prof. John Cawley was formerly a Clinical Training fellow and for the past 10 years has been researching largely with funding from the LRF . His main interests are in "the chronic lymphoproliferative diseases, particularly CLL and hairy cell leukaemias". (LRF brochure)

JC explained that there were three main branches of haematology, a) blood malignancies b) red cell related c) clotting problems (Obviously, our interest is in a))

At Liverpool, there are six purpose-built transplant units. As well as research, the department of haematology participates in clinical trials.

Basic themes of research (explained in more detail in III below)

In 'normal blood' new cells are created and destroyed all the time. In basic terms, in CLL (and other chronic blood disorders), there is defective cell death 'apoptosis' and cell differentiation. It is the focus of the research team to look at how and why this process is occurring. In particular, the patterns of blood migration involved in CLL are thought to be of particular importance.

Blood migration is obviously a normal process (if it doesn't circulate we die within minutes!) However, in CLL the pattern of migration of blood cells is different from 'healthy' people. The research group looks at problems such as: Why is there an accumulation of lymphocytes in the lymph nodes? What processes encourage accumulation of immature lymphocytes at certain sites in the body? Why is the pattern of cell migration different in CLL from, say, CML? What prevents this from happening in a person without CLL? How can the process be stopped or inhibited?

All cells transmit signals to grow, divide or migrate. A better understanding of this migratory process could lead to new therapeutic strategies.

b) Dr Grant "Anti-sense therapy in CML" ");?>

For CML, unlike CLL, a particular gene has been implicated in the onset of the disease. His work involves looking at "de-sensitising" cells to the protein that is released by the faulty gene. It was found that it is possible to destroy this gene using anti-sense oligonucleotides. This process could also be used to treat lymphomas. He is hoping that their work could lead to new treatments for CML within 12 months (but alas, not for CLL).

A. The role of GM-CSF in mature malignant B-Cell survival

Each cell has receptors, commonly found on the cell surface. It is thought that these receptors, classed as cytokines or integron (ligands) play a key role in cell survival and migration (I believe the correct term is cell motility). The research has examined both HCL and CLL. In HCL, malignant cells travel to and accumulate in the spleen but not in bone marrow or lymph nodes, whereas in the CLL they accumulate primarily in the lymph nodes and marrow (and sometimes also in the spleen). One reason for this could be to do with the way that cells are blocked from one site and not another (but I did not get a clear idea as to why although even the experts do not seem to understand fully. (See b) below for more about this process).

They found that GM-CSF (Granulocyte Macrophage-Colony-Stimulating Factor) was present on the cell surface in both CLL and HCL. Macrophages are found in nearly all parts of the body, and GMCSF plays a factor in stimulation of macrophages. Monocytes develop into macrophages after leaving the bone marrow, while macrophages play a key role in the immune system as they ingest antigens and help leukocytes recognise foreign matter. (macrophage comes from the Greek, meaning 'big eater'.)

However, in CLL, it seems that GM-CSF also plays a key role in preserving immature white cells. The cells have receptors (E.g. cytokines) that secrete the GM-CSF which in turn send back a signal to the cell to survive. Cytokines are basically small proteins on the cell surface involved in cell signalling. To explain in more detail, B-Cell receptors will secrete antibodies that bind to antigens (it is far more complicated, and I am still learning about this, but the basic idea is correct; note, antibodies is another term for IMMUNOGLOBULIN - second nature to the experts, but I only just discovered this!) As I understand it, receptors do more than just act as sites for binding to antigens. There are different types of receptors and their structure determines how foreign matter is recognised. Researchers believe that GM-CSF (which as you will recall, is produced by certain cell receptors) is also playing a role in survival of malignant cells. So although cell receptors have an important role to play in the immune system through the destruction of antigens, researchers are focusing their effort to get a better understanding of these receptors. It was significant that they did find the presence of GM-CSF in both CLL and HCL. They are looking at ways of blocking GM-CSF, or preventing the signal to the malignant cell to survive. An anti- GM-CSF antibody (a monoclonal antibody) was introduced to the cell, and they found that this inhibited the production of malignant cells. But the problem is that it is not only GM-CSF that can send such signals of cell survival. There are six other types of "CSF" involved, which adds considerably to the complexity of the problem.

B. Role of VEGF and MMP in the tissue migration of malignant B-Cells

The process of whether a cell can migrate was compared to having an open or closed door. In some cells, a signal is sent which effectively closes the door or prevents the cell from migrating to one location or another. This, put simply, determines whether an immature lymphocyte can migrate to a particular site in the body. It is thought that once such a cell finds its way to a lymph node, for example, it finds a very favourable environment for its long-term survival. This is partly due to the density of cells in such locations. For example, cells in the bone marrow are much more tightly packed than elsewhere. This helps keep the cell alive (prevents cell apoptosis). If a way can be found of blocking this migration (sending a cell signal to 'close the door'), then malignant cells will no longer have a favourable environment for their survival. (Please find the way NOW I kept thinking to myself!)

It was found that only tumour cells produce VEGF (Vascular Endothelial Growth Factor). VEGF is thought to play a role in inducing the migration of monocytes (as mentioned, monocytes are a type of white blood cell capable on ingesting infectious agents, they account for about 7 per cent of the total leukocytes). The spontaneous expression of VEGF by leuakaemic cells was investigated. VEGF was found to be present in both HCL and CLL. VEGF produce proteins called MMP (Matrix Metalloproteinases) which is thought to signal cells to pass through EC (Endothelial cell). Note that the EC cells are normally the cells that would push a cell away (i.e. prevent it migrating) This is a normal process that is happening millions of times in the human body. When this process of cell blocking fails, then you have cell accumulation in sites not found in non-CLL people. Researchers wanted to know why this process fails.

Thus, it is not so much the structure of the protein but the function of it that they are investigating. (Although I would guess that the structure was also important).

It is possible that the material cells have to pass through to migrate contains a special type of collagen (Type 4) which is rare. The MMP, which is an enzyme, is thought to digest this type-4 collagen, and thus allow the cell to migrate. However, this itself was an over-simplification. In fact, there were 20 types of MMP, only two of which can digest collagen. The researchers found that CLL and HCL cells secrete one of these enzymes called MMP-9. Once a way can be found of preventing the failure of the blocking process, then new therapies could be possible for combating CLL (but they are obviously not there yet, but believe they are "barking up the right tree!")

C. Role of hyaluronan and IL-8 in tissue localisation of mature lympocytes

Basically, cells cannot move if they do not have receptors (as was explained above). IL-8 is another example of a factor promoting cell movement. Research focuses on cell surfaces (where most of the action is). When IL-8 is added to cells, they develop such receptors and are found to move (they showed a video of cells moving). Once this was established, the researchers examined CLL (and HCL) cases and, sure enough, they saw that IL-8 was present in the spleen and bone marrow. Once again, they are looking for a monoclonal antibody that would prevent this.

D. Factors governing cell survival in CLL

This last demonstration really brought together the research above. We were shown an example of CLL lymphocytes (nasty critters) through a microscope (Slightly better than my normal check up readout of my figures).

Two factors were thought to promote cell survival:
a) Secretion of chemicals
b) Direct communication

In a) the cells are not necessarily crowded together, whereas in b) they do need to be tightly compact (as in the bone marrow). They found that cells surviving by b) would no longer survive when they were taken into a less crowded environment. i.e. direct contact seems to be involved. It is believed that cells say in lymph nodes are sending signals to each other to survive. Once they prove such messages exist they will try to decode them and block the messages.

CLL cells seem to survive longer than other cells, but yet they die when put into cultures where other cells survive.

All cells have sugar on the surface, take this away and you no longer have survival.

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