I developed this overview of CML genetics to help CML leukemia patients understand the genetic basis of the disease. In order to keep it somewhat simple, there is much that will not be covered. This is a complicated subject, but the basics can be understood. So the hope is to make a few issues a little more clear, and allow CML patients to understand some of the terminology and issues they may face. This information is NOT "cut and pasted" from other articles, since I have never found a reasonable explanation that was understandable to the average person with CML, so I do not feel the need to give credit to any articles for this information.
Leukemia is a group of diseases of the blood cells where certain cells become abnormal and also take on a greatly enhanced capability to reproduce. It is this combination of cell mutation and out-of-control reproduction that makes leukemia so hazardous. The word leukemia is from the Greek meaning "white blood", because the blood can take on a white tone in the latter stages of the disease due to the extremely large numbers of white blood cells in the bloodstream.
Leukemia is divided into myeloid and lymphoid types, and within each of these two categories are two sub-types -- acute and chronic. When leukemia affects lymph system white blood cells (T-Cells, B-Cells, etc) it is called lymphocytic leukemia. When bone marrow white blood cells are affected (neutrophils, basophils, eosinophils) the disease is called myeloid or myelogenous leukemia, as in CML.
So the 4 main types of leukemia are divided into Lymphoid and Myeloid cell lines, each with Acute and Chronic sub-types:
Lymphoid: Acute Lymphocytic Leukemia (ALL), and Chronic Lymphocytic Leukemia (CLL)
Myeloid: Acute Myeloid Leukemia (AML), and Chronic Myeloid Leukemia (CML)
Although these 4 types of leukemia are somewhat related, the treatments are very different for each one. This is because they are actually very different at the genetic level, although they all affect the blood through cell mutations and overproduction.
The blood is made up of fluid (plasma) and three main types of blood cells - white, red and platelets, each with special functions. Two different types of white blood cells (WBCs) fight infection and disease by killing bacteria, viruses and other invaders in the bloodstream. Those two WBC types are lymph cells and myeloid (marrow) cells. These two types of WBCs have overlapping functions of protecting the body from infection and disease, but they accomplish the tasks in different ways. Generally speaking, the lymph cells can either "shoot and kill" their targets or ingest them, while the myeloid cells "eat and digest" the invaders. Red blood cells (RBCs or erythrocytes) carry oxygen from the lungs to the body's tissues and take carbon dioxide from the tissues back to the lungs, but do not have a nucleus. Platelets (also called thrombocytes) are not technically cells, but rather pieces of former Megakaryocyte cells that have broken into fragments, and these jagged fragments form clots at wound sites to control bleeding. Blood cells are normally produced in an orderly, controlled manner by a complex series of genetic and chemical signals as the body needs them, but in leukemia and other cancers that process gets out of control because new genetic/chemical signals are created by mutations inside the cells, specifically on the chromosomes. These new signals are often stronger and more aggressive than the normal ones, which means they dominate the blood cell forming process.
Chronic myeloid (or myelogenous or myelocytic or granulocytic) leukemia (CML) is characterized by the overproduction of the myeloid (marrow) type white blood cells (WBCs), namely the neutrophils, eosinophils, and basophils. CML develops when a genetic mix-up occurs, called a chromosome translocation. CML starts when a piece of chromosome 22 and a piece of chromosome 9 each break off simultaneously inside a single blood producing stem cell, and those pieces exchange places by re-attaching at the wrong chromosomes (the piece of 9 joins with the main body of 22, and the piece of 22 joins with the main body of 9). The new chromosome 22 (called the Philadelphia Chromosome) causes CML by combining two previously unrelated genes that were not intended to be in contact with each other. The combination of the BCR gene from chromosome 22, and the ABL gene from chromosome 9, create a new cancerous gene called BCR-ABL when they come together in this unnatural form. Since this mutation occurs in a blood producing stem cell, that leukemic stem cell can then reproduce and ultimately produce trillions of leukemic cells over a period of time, possibly years. It is this combination of too many cells, along with their poor function, that causes CML's symptoms and harmful effects on the body. The BCR-ABL gene on the Philadelphia Chromosome sends out a BCR-ABL messenger RNA, which in turn creates a new type of BCR-ABL signal enzyme called a tyrosine kinase, which causes the new WBCs to become leukemic, and also greatly speeds up their production. So when we discuss BCR-ABL, there are actually 3 levels of BCR-ABL, which can be the source of confusion. Those 3 types are 1) BCR-ABL gene on the Philadelphia Chromosome, 2) BCR-ABL messenger RNA, and 3) BCR-ABL tyrosine kinase. Our CML drugs inhibit this last BCR-ABL tyrosine kinase, stopping the chain of events that creates new leukemic blood cells.
The Philadelphia Chromosome (Ph+) can be one of several types, defined by where the pieces broke off from their original locations on chromosomes 9 and 22. There are two main types of Ph+ called b2a2 (now e13a2) and b3a2 (now e14a2), which make up approximately 95% of all CML cases. Others such as e1a2, e8a2, e6a2, etc are more rare. Some people can have more than one type. The e1a2 can also be associated with Acute Lymphoblastic Leukemia (ALL), so a proper diagnosis between CML and ALL is more difficult when this breakpoint is present. But when e1a2 is present at low ratio levels relative to the b2a2 and b3a2, e1a2 is generally not a significant issue.
This BCR-ABL signaling process causes leukemic WBCs to greatly overproduce, and also the leukemic cells live longer than they normally should; additionally, these cells do not function as well as normal WBCs. At the same time, the body senses that there are far too many WBCs in the blood, so it tries to decrease the level of WBCs and stops the signaling process that creates new good cells. So it shuts down only the good WBC production, since the non-leukemic WBCs are the only ones that will respond to demands to slow down blood cell production. But the leukemic cells ignore the signals to stop producing more cells. If the CML is not controlled, the leukemic WBCs eventually crowd out the normal cells including the good WBCs, red blood cells and platelets. This robs the body of oxygen and resistance to infection and disease decreases as the leukemic WBCs gradually become less functional as the disease progresses over time.
So leukemia is primarily a disease of the white blood cells (WBCs), because the leukemic mutations described above are found in the nucleus of a cell where the chromosomes are located. Since red blood cells and platelets do not have a nucleus or chromosomes, they cannot truly be considered leukemic cells (although the precursor cells that manufactured them can be leukemic cells). However, red cells and platelets can have a reduced level of effectiveness because they were produced by the same mutant (leukemic) ancestors that produce the leukemic WBCs. So the emphasis in CML is on monitoring WBC issues, but blood quality can also be reduced as seen in the RBCs and platelets. A BMB only looks at white blood cells capable of producing other WBCs, both the FISH and PCR tests only look at the BCR-ABL in the WBCs, the CBC is mainly focused on the WBC count, and so on.
Our CML drugs (Gleevec, Sprycel, and Tasigna) are called tyrosine kinase inhibitors (TKI). They are bio-engineered to "park" in a chemical slot on the leukemic BCR-ABL tyrosine kinase (discussed above), which prevents that tyrosine kinase from sending the message to produce more leukemic blood cells. When the signals stop, the production line stops -- somewhat like running out of the right parts on an assembly line which shuts down the whole process. A side benefit is that when the leukemic cell signaling process is shut down, the leukemic white blood cells become confused and they self-destruct. Unfortunately, the TKI drugs cannot shut down the originating leukemic blood stem cell(s). As a result, the leukemic stem cells keep functioning, so the TKI drugs must be continued indefinitely to keep killing off the children of those stem cells. But the TKI drugs also accomplish a second important function, which is to keep the leukemic cells from further mutations that would lead to accelerated or blast phase CML. So the TKI drugs work by 1) shutting off the signals needed to produce new leukemic blood cells, 2) causing the leukemic cells to become confused and self-destruct, and 3) reducing the genetic instability of the remaining leukemic cells. This essentially creates a continuous status of low level chronic phase CML, also called Minimum Residual Disease. That is the current goal of our CML drugs, meaning we are not cured, but can live with the disease in a form that does not harm us. This has been shown to be effective for over 90% of CML cases.
Blood cell production has a complex hierarchy with many levels. In a simplified sense, it starts with "ancient" blood stem cells, which in turn produce long-term stem cells, which in turn produce short-term stem cells, which in turn produce the final level of blood cells (which cannot reproduce). In CML, the original leukemic cell that had the original translocation is near the top of that hierarchy, which means that any cure would require killing off ancient stem cells. But these ancient stem cells have extraordinary means of survival through multiple paths, including BCR-ABL signaling, but also using other signaling methods that can get around the CML drug impact on BCR-ABL signaling. That is why our CML drugs do not cure CML, since the originating leukemic cell or cells can out-smart the drugs. They also escape by going dormant for long periods of time (quiescence), by finding alternate signaling pathways to reproduce, by hiding deep in the bone marrow next to the bone in "niches" where immune system cannot find them, and by using other self-survival mechanisms. So a cure for CML will need to find a way to defeat these very smart leukemic stems cells. To expand on the subject, these blood stem cells are divided into categories such as CD7, CD34, CD34+, CD34+CD38-, etc, etc which indicate different types of blood stem cells based on what is on the cell surface (clusters of differentiation -- CD). There is a pecking order of blood stem cells, like a geneaology, whereby one produces another. So the most primitive blood stem cells (elders of the clan) are the most important for eliminating leukemia. CML primitive stem cells and the "mothership" original translocated stem cell are in the CD34+ range (unproven but believed to be accurate). So CML starts with a very primitive stem cell compared to some other leukemias and lymphomas, which makes CML more difficult to cure. The leukemic mothership cell produces all the various types of blood cells, including both types of WBCs (neutrophils and lymph cells), RBCs, and Megakaryocytes (which form platelets). Gleevec presumably can only eliminate back to a certain level of stem cell, possibly to within a generation or so of the mothership leukemic cell. The mothership and its original children hide deep in the bone marrow where there is little oxygen so T-Cells and other hunters, and most drugs cannot go. These leukemic cells can sleep for long periods (quiescence) and only come out to reproduce on rare occasions. When they come out in the open, they presumably become more vulnerable to being spotted as invaders and killed, either by Gleevec or T-Cells. But since these primitve leukemic cells also have multiple survival pathways, Gleevec normally will not kill them. Sprycel has some additional advantages in killing them, but it is not complete either. This is where the cure will come, finding a way to kill these most primitive leukemic stem cells, including the mothership cell. Research is focused on figuring out the ways they evade and survive our current drugs, so that new drugs, maybe in combination with the current drugs, may wipe out those last, most primitive leukemic stem cell(s).
There is much more that could be covered, but this introduction to CML genetics might help clear up some of the mystery surrounding this disease.
