Leukemia pathophysiology

Voiceover: So, we talked a bit about the different types of cells in the blood and how all of those cells are actually made inside the bone marrow, so inside this cavity in the center of bone. And, surprisingly, all of these very very different cells actually come from, they originate from, one cell, and that's this cell that I'm drawing in over here, and as we talked about before, this cell is called a hematopoietic stem cell, and this hematopoietic stem cell is responsible for creating all of the different cells in the blood, so instead of talking about it, I'm just going to draw that. I'm going to draw this hematopoietic stem cell creating a blood cell, and this could be any type of blood cell, but we know that since the cell was just made, it was just created, it's an immature cell. This is an immature blood cell, and we have a name for immature blood cells. We call them blast cells. So, this is an immature blast cell, and these immature blast cells are really big cells, and they have these really large nuclei. So, as you can see, the nucleus takes up pretty much the entire cell, and the DNA inside the nucleus is usually really loose and disorganized and kind of all over the place, like I'm drawing it over here, but the cell doesn't stay immature forever. Eventually, it moves along, and it starts to mature, and as the cell matures, it gets smaller, so that's really important, it gets smaller, and the nucleus inside the cell also gets smaller, and you guys are probably saying, well, obviously, as the cell gets smaller, the nucleus inside it also has to get smaller, but this is more than that. In this case, the nucleus is actually taking up a smaller percentage of the cell. So, it's taking up less room inside the cell, and even the DNA inside the nucleus changes in appearance. It becomes a little bit more organized, a little bit more like that, and then the cell continues to mature, and it passes through a couple more stages, until it reaches its final stage, and when it reaches its final stage, it's a lot smaller than when it started off, and the nucleus isn't nearly as large as it was to begin with, and the DNA is really neatly packaged and compacted inside the cell's nucleus, kind of like that. And so, this is a mature blood cell. This is a mature blood cell. And the process that I just drew out over here is what normal blood cell maturation looks like, and we throw that word around a lot. We talk about cell maturation all the time. In fact, in this video, I must have mentioned it like five or six times already, but we rarely talk about why cells go through this process of maturation. So, they go through this process so that at the end, they can become specialized, so they can become mature specialized cells, and by specialized, I mean that the cell is able to perform a specific task. So, for example, if we were looking at immature lymphoblasts over here, by the time they were finished maturing into lymphocytes, they would be able to perform certain immune functions. So, they'd be able to protect our body against invading organisms. So, that's the whole purpose of cell maturation. So, this hematopoietic stem cell continues to make more immature blood cells that then mature into these cells that are able to do their job, and hematopoietic stem cell does a really good job of doing that, so that we end up with lots of new blood cells every single day, but every once in a while, very rarely, actually, this hematopoietic stem cell messes up, and it makes an immature blast cell that's just weird, and it's not normal, and so that's the cell that I'm drawing in over here, and this is the cell's nucleus, and this is the DNA inside the nucleus, and I know what I've drawn looks like a normal blast cell. In fact, it looks almost identical to all the other immature blast cells that I've drawn, but it doesn't function like a normal cell. Specifically, it doesn't mature like a normal cell. So, it can't move on to the next stage of development. It's almost as if there's a stop sign over here, a stop sign, and so this cell is stuck in the immature blast stage, right? And the reason why it's stuck, is because there's a problem inside the cell, inside the cell's nucleus, where one of these genes or segments of DNA becomes mutated, and that gene is usually very important for helping the cell mature, so that when the gene becomes mutated and it stops working the way that it should, this cell then stops maturing the way that it should. And that's the first thing that happens in leukemia. This immature blast cell loses the ability to mature, and if that was the only thing that happened in leukemia, to be completely honest, it wouldn't be that big of a deal. So, if one cell can't mature, it's really not the end of the world, but then, unfortunately, this cell acquires another mutation, okay, and I'm putting that in a different color, and this time the mutation is in a gene that's really important for controlling cell division, so that when that gene becomes mutated and it stops working the way that it should, these cells lose control of how many times they can divide, and that leads to a picture like this, where you end up with lots of these immature blast cells accumulating and piling up, and as you can see, these cells that are piling up have the same mutations as that original weird blast cell, so they too are unable to mature, and they're dividing rapidly and out of control, okay? So, when we talk about leukemia, this is the process that we're talking about. We're talking about an immature blast cell, right, our leukemic cell, that first loses the ability to mature and then loses control over how many times it can divide, and because of that, you end up with a situation where you have lots and lots of these immature blast cells and very few of these mature specialized cells, okay? And so, you guys might be saying, well, that's not a problem, the hematopoietic stem cell can then just create some more normal blast cells that'll mature and make up for the shortage in our mature specialized cells, and you'd be completely right. The hematopoietic stem cells should be able to create more normal blast cells, but it doesn't, and to explain why it doesn't, we would have to take a look at bone marrow. So, imagine that we were looking at bone marrow over here, and this was a population or group of normal blood cells, and then on this side we have our weird leukemic blast cells, okay, that we said aren't able to mature, and we also said that they start dividing very rapidly, so that very quickly leads to these leukemic cells taking over the bone marrow, and that's a problem, because bone marrow is a contained cavity, so there's a very limited amount of space, nutrients, and growth factors, and these cells inside the bone marrow are constantly competing for these resources. So, as you can probably imagine, if these leukemic cells are dividing really rapidly, they take up all of these resources for themselves, and they leave behind very little for all the other cell types, and that's why the hematopoietic stem cell doesn't create more normal cells. It's because it doesn't have the space, the nutrients, and the growth factors to be able to do so. So, that's why when you have a patient with leukemia, if you take a look inside their bone marrow, you see that the bone marrow is almost overtaken by these leukemic blast cells, and you see a decrease in the number of all the other types of cells. So, you see a decrease in the number of red blood cells, and you see a decrease in the number of platelets, and decrease in the number of white blood cells, and really this decrease in the number of all the other types of cells is why leukemia is as devastating of a disease as it is. So, going back to our diagram over here, there's one big question, one glaring question that I feel we haven't yet addressed, and that is, number one, how does a gene become mutated, and number two, how the heck did this one cell end up with two gene mutations, okay? So, I want to talk about gene mutations and how you can get gene mutations, off onto the side. And one of the causes of gene mutation is something you may have heard of before, and that's exposure to radiation, exposure to radiation, because we know radiation damages DNA. Another thing is exposure to certain chemicals and toxins that also damage DNA, and those are called carcinogens. So, exposure to carcinogens will also cause gene mutations, and both exposure to radiation and carcinogens will usually cause an isolated mutation in DNA. So, for example, if this was a strand of DNA, and it was exposed to radiation or carcinogens, you'd usually end up with one gene being mutated, okay? A third thing that can lead to gene mutation, that's really important in the case of leukemia, is chromosome translocation, so, chromosome translocation, and translocation is an error or mistake that's made during cell division, where one part of a chromosome becomes shifted or translocated onto another chromosome, so, something like that, and because in this case we're messing around with segments of chromosomes, you end up with multiple genes being affected. So, instead of just one gene, you can end up with mutations in two or more genes, and lots of leukemias are associated with chromosome translocation, and that's why this cell very easily ended up with two gene mutations. And that's how leukemia develops.