Published on Up Close (https://upclose.unimelb.edu.au) Episode 93: What Role Stem Cells in Leukaemia? What Role Stem Cells in Leukaemia? VOICEOVER Welcome to Up Close, the research, opinion and analysis podcast from the University of Melbourne, Australia. I?m Shane Huntington. Thanks for joining us. Over the past two decades stem cells have become a key area of investigation for medical research labs around the world. Looking beyond significant ethical reservations that have been voiced in some instances, researchers are finding great promise in the application of stem cell therapies to a diverse range of conditions. In this episode of Up Close we'll be discussing the role played by stem cells in cancer and the potential for new therapies based on this research. I would like to welcome Dr David Curtis, a bone marrow transplant physician and researcher at the Royal Melbourne Hospital here in Australia. David's research focuses on examining the role of stem cells in leukemia. Welcome to Up Close, David. Thanks, Shane. First of all, let's start with a discussion of what cancer is, specifically leukemia, how it works and what it does to the body. Yeah, well, leukemia is a type of cancer, a cancer of the blood cells, normally of the white blood cells. What happens is that the genes that regulate the normal growth of blood cells develop mutations - usually they're acquired, sometimes they can be inherited - and those genes which normally control the very delicate balance between making too few cells or too many cells goes wrong, and they make too many cells and that causes leukemia. The leukemia usually presents either in
children or young adults, often with either anaemia - so tiredness - or bleeding problems or infection and that's because the normal cells don't have any room in the bone marrow to grow and these leukemia cells take over the normal function of the bone marrow. The cells being produced en masse - or in short supply, I guess in some cases - are they normal, active, healthy cells or are they ones that are sort of fighting against the body in themselves? Well, they're not really normal cells, these leukemic cells tend to not be mature cells, so they can't mature into the normal, say, white cells to fight bacterial or viral infections. They tend to not be able to form those new cells and so they can't fight normal infection. For instance, the blood cells, the platelets which prevent bleeding, they don't work normally. So it's not only too many of them but they just don't work as well as normal. If we sort of start zeroing in now to the more molecular level, what sort of things are occurring with this cell formation to cause it to be in error, in a sense? Well, there seems to be a critical number of these genes which regulate normal blood cells. Our laboratory has been working on a group of these genes called basic helix-loop-helix transcription factors, which is a very long name, but it's basically just a group of proteins which form like a factory and that regulates the normal growth of normal blood cells. Sometimes when leukemia occurs there is abnormal expression of these genes, so that they're expressed in the wrong cell type; instead of being switched in the more mature cells, they continue to be expressed. Those genes then tell the cell to keep growing, so that normal regulation hasn't occurred. You mentioned earlier that leukemia can either be acquired or sometimes inherited. What's the difference between the two scenarios there and how do you acquire leukemia? Yeah, well, that's a great question. I mean, the vast majority of leukemias are acquired and we really don?t know the real underlying causes of those genetic changes that are acquired. Leukemia does increase with age, so that it is actually more common in older people, and it's thought that just the general environmental toxins may be the cause of these genetic changes. There are a few good examples of acquired causes, such as with the Chernobyl explosion - that caused an increase in the numbers of leukemia in those people. We still do see today a few people developing leukemia that have been exposed to that radiation. But, other than that, there's not a lot of known causes that causes leukemia.
I expect the answer to this question is similar, but why is it that the body is unable to correct for this error? I mean, our bodies correct for so many, and I suspect, you know, the white blood counts are a big part of that process. Yeah. But why is this not something that body is adapting to or correcting for? Most leukemias are caused by, the initial abnormality is called a chromosomal translocation, so that's where two chromosomes which are normally, say, chromosome 1 and chromosome 19 join together and you get a fusion of two genes. For some reason, it's really not known, the body just isn't able to recognise those abnormalities and correct them. But, you know, that is a terrific question and I don?t have a great answer for it. When we compare leukemia to other forms of cancers, what are the differences we see between leukemia and breast cancer or a range of other cancers? Sure. Well, I think that the major difference is this finding that in leukemia there are these chromosomal translocations. In contrast, in other types of cancer - say breast cancer or colon cancer - there tend to be mutations of specific genes, so losses or gains of genes rather than this unusual joining of chromosomes. That's the sort of major difference between leukemia and other sorts of cancers. But otherwise, you know, you can consider leukemia just like any other cancer and the same principles probably apply, certainly for the biology of the disease as well as for the potential treatments. Speaking of treatments, how do we currently go about treating leukemia and how successful are these treatments? Well, if I could specifically talk about the type of leukemia that we've published recently in our paper in January of 2010 in Science, this is type of acute lymphoblastic leukemia called T-cell lymphoblastic leukemia. It normally occurs in children but about one-third of cases are in young adults and the treatment is generally with a combination of chemotherapy. So patients usually come in for what's called induction chemotherapy, which is very high doses of chemotherapy; it makes them very sick, they often get damage to the mouth, to the bowel, it causes diarrhoea and it kills not only the leukemia cells but the normal blood cells - if you've got no normal blood cells then you may be prone to infections just like when you've
got the leukemia - and, eventually, hopefully those normal cells grow back and the leukemia ones don?t. That's really one of the major problems at the moment, is that our chemotherapies that we have just aren't specific enough and they don?t kill the leukemia without killing the normal blood cells. So, once that patient's had that induction chemotherapy then they have to have additional rounds over several months, of chemotherapy. Then usually, if they go into remission, which is probably 90 per cent of people do actually get into remission - remission's a funny word, it means that we can't detect any leukemia but we know that probably at least 50 per cent of people, even though they're in remission, they may still have some leukemia cells there. So for this type of leukemia, children and adults will go onto what's called maintenance chemotherapy, which is a tablet form of chemotherapy, and that usually is administered for two or three years. So really, these patients are often in limbo in that they're having treatment for this leukemia and when they come to see clinicians such as myself they say, how's it going. We say, well, you're still in remission but we don't know whether that leukemia's going to come back. That's the general principle for most types of leukemia, is that it's chemotherapybased. You're listening to Up Close coming to you from the University of Melbourne, Australia. Our guest today is Dr David Curtis and we're speaking about leukemia and stem cell research. David, much of your team's work revolves around stem cells and what part they play in cancer. This interplay is probably something that many of our listeners won't be aware of. They've no doubt heard of stem cells more from the controversial issues around stem cells as well as the promise for new therapies. What is, first of all, special about stem cells, before we get to the cancer part - what makes stem cells so interesting? The most interesting and most important feature of a stem cell, which is not present in any other type of cell, is a process called self-renewal, which is where the cell can divide and not only generate mature cells, but it can divide and generate a cell which is identical to itself. Therefore, that cell, or its progeny or daughters and brothers, can be maintained for the life of that person. That's the principle of why bone marrow transplants work, is that when we collect stem cells from one patient - usually a brother or sister - and give it to another person who may have leukemia, those stem cells are the things which allow the new blood cells to grow and keep growing for the life of that person who has had the transplant. So really, the critical thing that's different between a stem cell and any other cell is this property of selfrenewal. Now, there are two main sorts of areas of stem cells in terms of where they come
from, one being embryonic and the other being adult. Your work focuses in the latter area. Can you describe the differences between these two types of cells or their origins and how that affects what you can do with them? So the major difference is the potential of those cells to turn into other cell types. So adult bone marrow cells can only turn into bone marrow cells. So they can live, as I said, for the life of that person and self-renew. They can also what we call differentiate, or turn into more mature cells which are the functional sort of cells that do the work, that make the white cells, that make the red blood cells to carry oxygen. But they can't turn into any other cell types. It was about 10 years ago or 15 years ago this enthusiasm or excitement that these bone marrow stem cells could turn into other cells like heart cells or brain cells. There is still ongoing work, but less frequently now, to turn those cells into heart cells or brain cells but, really, they are restricted to just making blood cells. Embryonic stem cells can make a vast majority of different types of cells of the body. So now only can they make blood cells, they can make heart cells, they can make brain cells, they can make pancreatic cells for diabetes, for instance. So that's the major difference. They have good things and bad things. So, for instance, the bone marrow cell can only make bone marrow cells, which has an advantage in that it can't turn into other cell types, so it's not dangerous. In contrast, embryonic stem cells there is still this major problem of being able to say if you need a new pancreas for diabetes, turning that embryonic stem cell into a pancreatic cell and only a pancreatic cell is the major challenge with embryonic stem cell research and applying it to the clinic. I suppose in that sense we don?t have embryonic stem cells running around our body as adults, we only have adult stem cells because they have specific jobs to do? That's correct. Once you're an adult you only have adult stem cells and these embryonic stem cells are well and truly gone. You didn't mention that there's an inbetween type of stem cell called an induced pluripotent stem cell and that's what the major excitement in the field of stem cell biology is at the moment, is that you can then take an adult cell and turn it into an embryonic type stem cell. So there is this potential and that's really the excitement of the current field of stem cell biology. Your work in particular looks at a slightly different view of stem cells and the role that they actually play, in this case, in leukemia. Yes.
This is, I guess, the dark side of the stem cell world. Tell us about what's going on there. Yeah, well, stem cells, if they're good ones, can do great benefit, so you can use stem cells in bone marrow transplant for treating patients with leukemia. But if the mechanisms that control those stem cells - so the genes that regulate the stem cells to control their self-renewal, or the genes that regulate the ability of the cells to differentiate into the mature cell - if something goes wrong with those, those stem cells can actually turn into leukemia; that's really the basis of many cancers is that these genetic abnormalities have to occur within a cell that can self-renew. The principle of all cancers, including leukemia, is that they have to acquire multiple genetic abnormalities; one abnormality of a gene isn't enough to cause leukemia. So, the only way for a cell to acquire multiple genetic abnormalities is if it can selfrenew. Really, that's the crux of stem cells and their relationship with cancer is that it's only once a cell has this ability to self-renew and acquire additional genetic abnormalities that it can actually develop into full-blown cancer or leukemia. Has this been clinically confirmed now, that the stem cells are actually at the core of the problem, in a sense? Well, I think in the clinic it's really difficult to do the experiments to prove that those cells, or the leukemia cells, have come from stem cells. There are a few examples. In my field of haematology there is a disease called Chronic Myeloid Leukemia and that clearly is a leukemia that has arisen from stem cell. The reason I say that is that you can take those cells from those patients with Chronic Myeloid Leukemia and in the laboratory you can turn them into all the different types of blood cells. So that indicates that that cell has arisen from a stem cell that has this ability to turn into a white cell, a platelet, a red blood cell. So there are some relatively well-understood examples of where leukemia or cancer has come directly from a stem cell. Today on Up Close our guest is Dr David Curtis and we're speaking to him about leukemia and stem cell research here at the University of Melbourne, Australia. David, given this knowledge of how stem cells play this role in cancer, what does that tell us about the usefulness of traditional chemotherapy and other cancer-fighting techniques. That's a great question. So, most chemotherapy and radiation that is used for
treating leukemia or cancers kills cells that are cycling, what we call as dividing. One of the other properties I didn't mention about stem cells, not only do they selfrenew but they're also often what we call as quiescent, or they're not growing very quickly, so often they sit in special places in the body. So in the bone marrow they sit right next to the edge of the bone or next to blood vessels and they don?t actually grow very much and they only grow if they're needed to grow. So if, for instance, you develop an infection or you cut yourself and start bleeding, you need to make new white cells or new red blood cells. Then there are special signals to tell the stem cells to start growing, forming those new white cells or red blood cells. So that quiescence, or lack of cycling. of the stem cells makes them relatively resistant to our traditional chemotherapies and radiation therapies because they're not growing and so they don?t actually get killed. We know that normal stem cells are actually quite resistant to chemotherapies and radiation. So when you give somebody high doses of chemotherapy or radiation they don?t die because the stem cells don?t die, so they may kill all the normal white blood cells and red blood cells but the stem cells remain and then they can actually regenerate the rest of the blood system. So in a way, the remission process is where the stem cells are somewhat dormant, not really doing much, but sooner or later they somehow kind of work out they should switch back on and start producing cells? Exactly, yeah. In terms of surgical removal, which is often one of the ways in other cancers for treatment, are stem cells equally sort of hidden from that process? Well, I guess in solid cancers surgical removal will remove the stem cells that are generating that cancer, so in that case they can be surgically removed. But certainly in leukemia surgery doesn't really play a part for treatment because it's a disseminated disease which is throughout the bone marrow and so you can't remove with surgery. Presumably for solid cancers such as a breast cancer or a bowel cancer, which is very localised, surgery is still the best treatment and will give you the best cure, in part because you're actually removing those cells that are the ones that keep the cancer going, which is the stem cells. Given the resilience of these stem cells and their incredible ability to resist chemotherapies and radiation therapies, how do we go about combating them as a treatment for cancer?
Well, the way to combat them is to work out how they function, what are the things which keep them growing? That's what the focus of our laboratory is; trying to understand what are the pathways or what are the genes which regulate these stem cells, keep them as stem cells, what makes them be able to self-renew? If we can target those processes then that would be a much better targeted treatment. The other way of targeting these cells, which may be something which will be in the near future, is to actually try and switch the stem cells on to make them start growing and, therefore, more sensitive to our traditional chemotherapies. So if we can find ways to actually switch them on - and for Chronic Myeloid Leukemia, which I mentioned before, there are trials going on at the moment using Interferon, which is a type of growth factor; that, we know, does tell the stem cells to start growing. If you could combine that with traditional treatments - chemotherapy, radiation - that actually may be a way of trying to kill stem cells without going into all the technical stuff of trying to work out the processes or the genes that regulate stem cells. which is really going to take five to ten more years to sort out. There's obviously a lot of work being done on producing stem cells and keeping them and using them. Is there much work being done around the world on actually killing them or essentially stopping them from doing the functions they're doing? Yeah, there's probably just as much work because we know that these stem cells, or cancer stem cells, are the things which maintain the cancer and almost certainly are the ones that cause relapse; when a patient goes into remission it's those stem cells which are dormant that come back. So there is a lot of research throughout the world. In your laboratory you obviously do work on these stem cells. How do you source them? We use mice. All our work is using a mouse model of acute leukemia. The mouse that we use is one that over expresses or abnormally expresses this gene called Lmo2 and that's a gene which is a cause of one type of acute leukemia. So we have these mice that develop acute leukemia, just like humans, and that enables us to actually study these leukemia called cancer stem cells. Are there any issues with regards to using a mouse model when you compare the lifespan of humans and the treatment span that we're talking about with things like leukemia and remission and so forth that limit what we can do with a mouse model?
Mice live for two years and in this mouse model that we have we can detect these cancer stem cells right at birth, but they don?t actually develop leukemia until about eight or nine months of age. So it's actually quite similar, it's just basically a shortened time span and I think it will be applicable to the human disease. We've got to remember that in humans acute leukemia that goes into remission, if it's going to come back it'll usually come back pretty quickly, within the first year or two years. So we don?t really have to consider what would consider what would happen in 20 or 30 years' time, so I think it is a pretty good model to understand and work at better therapies for human leukemia. As we mentioned, this is relatively new a lot of this work on stem cells and cancer. How far along are we in terms of our knowledge and what sort of big things do you expect to be seeing coming out of the research in the next few years? So the description of cancer stem cells was about 15 years ago; that was predominantly isolated to acute leukemia. It's only really over the last three or fours years that people have discovered these cancer stem cells in other types of cancers. So there is now good evidence that melanoma has a cancer stem cell, colon cancer, prostate cancer, certain types of brain cancers, breast cancer. But we're really only just at the start of the field because it's only in these last few years that we're actually discovering or isolating these cells. In the next five or ten years I think there will be still quite a lot of work to do trying to test targeting of the various genes or pathways of these stem cells to see what can be then applied to humans. Has there been any clinical application at this point or is that still a fair way off with patients at the actual hospital? No, there hasn't been any application to human disease and I doubt that there will be within the next three or four years' time. It's still, I think, pretty embryonic in a way and so we've got a fair way to go. David, just finally, your research lab is obviously doing a lot of different work on stem cells. Are there other interesting applications that you're exploring at the moment with regards to the use of these cells? Yeah, well, people have looked at using bone marrow stem cells or adult stem cells for heart disease, and so we're looking at the application of using those cells to improve heart repair after a heart attack. It turns out in that scenario that these stem cells don?t actually turn into new heart muscle but actually make growth factors
which stimulate the normal heart cells to grow, and so it may turn out to be quite an interesting area for regenerative medicine. Dr David Curtis from the Royal Melbourne Hospital here in Melbourne, Australia, thank you very much for being our guest today on Up Close. Thanks, Shane. Relevant links, a full transcript and more info on this episode can be found at our website at upclose.unimelb.edu.au. Up Close is brought to you by Marketing & Communications of the University of Melbourne, Australia. Our producers for this episode were Kelvin Param and Eric van Bemmel. Audio engineering by Gavin Nebauer. Up Close is created by Eric van Bemmel and Kelvin Param. I'm Shane Huntington. Until next time, goodbye. The University of Melbourne, 2010. All Rights Reserved. Source URL: https://upclose.unimelb.edu.au/episode/93-what-role-stem-cells-leukaemia