The Biology of Leukemia

Leukemia is a cancer of the bone marrow and blood. There are four main types of leukemia. These are: acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML). MLL stands for “mixed lineage leukemia” and means that the leukemia comes from both the myeloid and the lymphoid cell progenitors (Robien and Ulrich, 2003). The cause of leukemia is currently still unknown. It often arises as a result of DNA translocations, inversions, or deletions in genes regulating blood cell development or homeostasis. In all types of leukemia, genetic translocations, inversions, or deletions cause dysfunctional cells to replace normal hematopoietic cells in the bone marrow (Robien and Ulrich, 2003). A leukemia patient will usually die from anemia or infection because of the lack of red blood cells and immune cells (Sompayrac, 1999).

Leukemia stem cells (LSC) are thought to have been derived from haematopoietic stem cells (HSC), which are CD34+CD38-. During leukemogenesis, the LSC expresses shared surface characteristics with the HSC. It also has the capacity for producing both the clonogenic leukemic progenitors and the non-clonogenic blast cells, which make up the bulk of the leukemia (Huntly, et al. 2005). In the bone marrow there are two types of hematopoietic stem cells. In someone who does not have leukemia, the myeloid progenitor is the parent cell to granulocytes and macrophages, and the lymphoid progenitor is the parent cell to T-cells and B-cells (Janeway, et al., 1999). In adults, 85% of all leukemia cases are myeloid, with 15% being lymphoid. In children the opposite is true, with 80% of all cases being lymphoid (ALL) and only 20% being myeloid (Greaves, 2000).

In people with acute leukemia, a mistake is made in the action of the VDJ recombinase enzyme, which normally creates antibody and T-cell receptor diversity. Proto-oncogene, a gene that promotes growth and spread, is inappropriately turned on and it activates other proto-oncogenes and deactivate anti-oncogenes, which normally protect cells against cancer-causing mutations (Sompayrac, 1999). Chronic leukemias may be caused when mistakes in recombination activate genes that either cause the cell to proliferate, or cause it not to die by apoptosis or increased activity of stem cells or abnormal committed progenitor cells (Marley and Gordon, 2005). The increased life span of the cell increases the chance that enough mutations will accumulate to cause cancer (Sompayrac, 1999).

Mutations that increase the risk of leukemia can be caused by radiation, extremely low frequency electromagnetic fields, pesticides, benzene, other carcinogens, viral infections, and recombination errors that occur throughout life (Sompayrac, 1999). Cigarette smoke, high altitude, or other factors that increase exposure to radiation can be accelerating factors for cancer (Sompayrac, 1999). Rates of leukemia may also be greater following periods of population mixing. During periods of population mixing, individuals are exposed to new infectious agents. A similar hypothesis is that children who were not exposed to common infectious agents at a young age would also have higher rates of leukemia. The infectious agents would be new to their system, causing a strong and inappropriate immune response that might trigger leukemia. Studies on daycare attendance as a measure of exposure to infectious agents have had mixed results (Robien and Ulrich, 2003).

Immuno-suppressed people such as patients being treated with chemotherapy or patients who have AIDS have higher rates of leukemia, but they do not have higher rates of other types of cancer (Sompayrac, 1999). Some cells in the immune system may protect against the development of cancer. Macrophages are cells that eat and destroy old or damaged red blood cells. The macrophages recognize the cells because a fat molecule called phospotidyl-serine flips to the outside of the cell as it ages (Sompayrac, 1999). Macrophages can also destroy cancer cells, but only when they are hyperactivated. Usually when there is no inflammatory reaction in the body, the macrophages will remain resting and will not attack the cancer cells, but natural killer cells secrete cytokines when cancer cells are present and the cytokines cause the hyperactivation of the macrophages (Sompayrac, 1999). The immune system has evolved to protect against leukemia by destroying cancerous cells, but in a person whose immune system is weakened or is being exposed to many new pathogens, it is not as effective at getting rid of damaged cells.

Specific Types of Leukemia

ALL is a disease of B or T lymphocyte lineage. Childhood ALL is of the B lineage. One of the most common translocations in B-precursor childhood ALL is suggested to be t(1;19)(q23;p13). The deletion of 9p has been suggested to be an evolutionary aspect of the progression of ALL but it is also thought to play a primary role in some cases of leukemogenesis (Forestier, et al., 2000). In ALL, it seems likely that leukemia develops in two stages: a pre-natal genetic alteration that predisposes the infant to developing leukemic precursor cells, and a post-natal event that triggers this latent disease. This has been suggested by several studies, including a number of "twin studies," which compare the incidence of diseases in identical (monozygotic) and fraternal (dizygotic) twins, in order to determine the relative importance of genetics and the environment as causal factors in a specific disease. Many twin studies have shown that identical twins have high "concordance" levels for leukemia, meaning that they share the disease. Concordance has often been taken as proof that a disease is genetic. However, in this case, it may be because they share a very similar environment during their fetal development: more than half of identical twins share a placenta, while no fraternal twins do (Greaves, 1999). The leukemic genetic alteration most likely takes place in one twin and spreads to the other through the placenta. This suggests that in non-twin children, the leukemic alteration may also take place in utero, as indicated by positive results from blood samples taken soon after birth (Greaves, 1999). Concordance rates near 100% would imply that the initial leukemic genetic alteration is the sole and sufficient cause for the development of leukemia. This is the case with another type of leukemia, MLL. However, in ALL, the concordance rate is closer to 10%. This suggests that the initial genetic alteration is not enough to cause leukemia in the absence of a second genetic alteration caused by the post-natal environment (Greaves, et al, 2003).

Philadelphia chromosomeCML is caused by the reproduction of cells that have not matured properly, but continue to reproduce (Marley and Gordon, 2005). It has a distinguishing inherited characteristic called the Philadelphia chromosome (No. 22), a genetic abnormality in the blood cells that is referred to as the Ph-chromosome.  The breakage on the chromosome is referred to as "BCR" (breakpoint cluster region). A breakage on chromosome 9, known as "ABL" (Abelson) has also been noted. These two mutated genes fuse together, forming a gene called BCR-ABL.  This gene can still function properly. However, in CML patients, the protein that is produced is abnormal, causing unregulated myeloid cell production. Evidence has pointed to this abnormal protein production as the cause of the leukemic conversion of the hematopoietic stem cell (Leukemia and Lymphoma Society, 2005). Normally stem cells divide in the bone marrow to replace themselves and create differentiating cells. In CML, either the stem cells or progenitor cells are increasing at all times (Marley and Gordon, 2005).

The most common genetic abnormality in CLL is 13q14 deletion, observed in 50% of all cases. (Caporaso et al., 2004)

In addition to the four basic types of leukemia, there are a variety of other forms. Different types of leukemia are characterized by different patterns of nonrandom chromosomal aberrations, but the frequencies with which the various karyotypic subtypes are seen differ amongst geographic regions. In areas where children are not sufficiently exposed in early youth to childhood infections, there is a greater risk of developing leukemia from an abnormal immune system response.


References Cited

Created by Shannon McGlauflin, Jolene Munger, and Rebecca Nelson, 2005.