An explanation to the poor prognosis seen in some CLL patients:
Austen, B., Skowronska, A., Baker, C., Powell, J. E., Gardiner, A., Oscier, D., . . . Stankovic, T. (2007). Mutation Status of the Residual ATM Allele Is an Important Determinant of the Cellular Response to Chemotherapy and Survival in Patients With Chronic Lymphocytic Leukemia Containing an 11q Deletion. Journal of Clincial Oncology, 25(34), 5448-5457. doi:10.1200/JCO.2007.11.2649
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Chronic Lymphocytic Leukemia (CLL), which is the most common type of leukemia in the Western world, is a cancer of the blood that affects B-cells. These cells are a crucial part of the immune system because they are responsible for making antibodies to fight off infections. A genetic abnormality found in about 20% of CLL patients is the deletion of the long arm of chromosome 11, denoted as an 11q-, which is associated with a more aggressive form of the disease. One gene missing due to this deletion is ATM, an important gene that is responsible for maintaining the integrity of the DNA within our cells. Human cells are, for the most part, diploid, meaning that they possess two copies (alleles) of every gene. This means that those patients with an 11q- still potentially have one good copy of this gene. This is why researchers at the Cancer Research UK Institute for Cancer Studies looked into how the status (whether it is mutated or not) of the remaining allele in these patients affects their prognosis as well how it affected the cancer’s response to chemotherapeutics.
Results from this study showed that CLL patients with this abnormality had an increased risk of developing a mutation at the other ATM allele. This is problematic because it was also shown that cells lacking a good copy of this gene have reduced sensitivity to chemotherapy drugs. These drugs aim to kill cancerous cells by inducing a biological pathway that is controlled by this gene. Therefore, without a good copy of the gene, the cell will not respond normally to chemotherapeutics. It was also suggested that the use of the typical CLL chemotherapeutics could lead to further expansion of the cancerous cell population. In order to combat this issue researchers suggest we look into therapies that bypass the pathway controlled by ATM.
Overall, this study provides a potential explanation as to why CLL patients with an 11q- show a poorer outcome compared to those that don’t. However, this is only the tip of the ice berg as the loss of both copies ATM is unlikely to be the only cause of this poor prognosis. Additionally, this study opens up new avenues for research that can be done in order to find treatments that are effective for these CLL patients.
Results from this study showed that CLL patients with this abnormality had an increased risk of developing a mutation at the other ATM allele. This is problematic because it was also shown that cells lacking a good copy of this gene have reduced sensitivity to chemotherapy drugs. These drugs aim to kill cancerous cells by inducing a biological pathway that is controlled by this gene. Therefore, without a good copy of the gene, the cell will not respond normally to chemotherapeutics. It was also suggested that the use of the typical CLL chemotherapeutics could lead to further expansion of the cancerous cell population. In order to combat this issue researchers suggest we look into therapies that bypass the pathway controlled by ATM.
Overall, this study provides a potential explanation as to why CLL patients with an 11q- show a poorer outcome compared to those that don’t. However, this is only the tip of the ice berg as the loss of both copies ATM is unlikely to be the only cause of this poor prognosis. Additionally, this study opens up new avenues for research that can be done in order to find treatments that are effective for these CLL patients.
Figure 1: By using FISH tests, doctors are able to screen for genetic abnormalities in CLL patients. The left cell is missing a copy of the ATM gene. This can be seeing as there is only one red spot present in that cell when there should be two which is seen in the cell on the right.
This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison