CML and the Philadelphia chromosome
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CML and the Philadelphia chromosome
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[post_date] => 2024-12-23 18:02:10
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[post_content] => Practice Passage (Question 1-6)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
Like all neoplastic disorders, chronic myelogenous leukemia (CML) is characterized by the loss of important regulatory factors controlling cell growth, differentiation, proliferation, and/or cell death. The dysregulation that occurs in CML is due to the development of a unique chromosomal abnormality, commonly referred to as the “Philadelphia chromosome”. The presence of this genetic aberration is important in differentiating CML from other pathological disorders such as a leukemoid reaction. The term ‘leukemoid reaction’ simply refers to the body’s normal response to many infections, leading to a proliferation of leukocytes (leukocytosis), which may resemble CML under the microscope.
The Philadelphia chromosome arises from a translocation between chromosomes 9 and 22, producing an elongated chromosome 9, and a truncated chromosome 22, as shown in Figure 1. The result of this t(9;22) change is the fusion of the Bcr (breakpoint cluster region) gene on chromosome 22 with the Abl1 gene of chromosome 9. In its normal position, the Abl1 gene codes for a membrane-associated tyrosine kinase that is regulated by an autoinhibitory R domain. The Philadelphia translocation product gives rise to hybrid Bcr-Abl mRNA and, subsequently, a BCR-ABL fusion protein lacking the R domain.
Figure 1 The Philadelphia chromosome caused by reciprocal translocation of chromosomes 9 and 22
The chemotherapeutic agent imatinib functions as a highly specific inhibitor of BCR-ABL. Imatinib is part of a larger family of tyrosine kinase inhibitors (TKIs). Imatinib is a very effective treatment option for patients with CML, who most often harbor a Philadelphia chromosome. Figure 2 shows the rate of ATP hydrolysis by BCR-ABL in the presence and absence of imatinib.
Figure 2 Activity of BCR-ABL as measured by its hydrolysis of ATP
[post_title] => CML and the Philadelphia chromosome
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[question] => Which scenario is most likely in the cells of a patient with the Philadelphia chromosome?
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[answer] => 3
[description] => Reason for Correct Answer:
BCR-ABL lacks the R domain that normally suppresses ABL activity.
This makes the BCR-ABL tyrosine kinase constitutively active.
Kinases phosphorylate substrates, whereas phosphatases dephosphorylate substrates.
BCR-ABL’s constitutive activity means that more substrates will be phosphorylated and, consequently, fewer will be dephosphorylated.
It is most likely an increase in the ratio of phosphorylated to dephosphorylated substrates will occur downstream of BCR-ABL.
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[answers] => Array
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[0] => Array
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[each_answer] => A. The presence of an extra copy of chromosome 22, leading to more transcription of the Bcr-Abl gene and consequently higher protein activity
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[1] => Array
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[each_answer] => B. Accumulation of activated protein substrates downstream of BCR-ABL due to decreased phosphatase activity
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[2] => Array
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[each_answer] => C. An increase in the ratio of phosphorylated to dephosphorylated substrates downstream of BCR-ABL
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[each_answer] => D. A decrease in phosphorylated substrates downstream of BCR-ABL, causing withdrawal from the cell cycle and entrance into the G₀ phase
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[1] => Array
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[quiz_unique_key] => 1403770772
[question] => What effect does increasing ATP concentration have on the kinase activity of BCR-ABL?
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[answer] => 1
[description] => Reason for Correct Answer:
BCR-ABL must bind both ATP and a substrate in order to catalyze phosphorylation.
Figure 2 suggests that imatinib competes competitively with ATP for binding to BCR-ABL.
Figure 2 suggests this because as ATP concentration is increased, the enzyme’s maximum rate of catalysis, or Vmax, is restored in the presence of imatinib.
This occurs with competitive inhibitors because the substrate concentration will increase the likelihood that an enzyme will bind that substrate instead of the inhibitor – in other words, reducing the relative concentration of bound imatinib to negligible levels.
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[answers] => Array
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[0] => Array
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[each_answer] => A. Increasing the concentration of ATP causes the relative concentration of bound imatinib to be reduced to negligible levels.
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[1] => Array
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[each_answer] => B. In accordance with Le Chatelier’s Principle, increasing ATP concentration leads to an increase in ADP concentration, resulting in the phosphorylation of fewer substrates by BCR-ABL.
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[2] => Array
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[each_answer] => C. Because imatinib is a competitive inhibitor, increasing the concentration of ATP has no effect on BCR-ABL activity.
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[each_answer] => D. An increase in ATP leads to phosphorylation of imatinib by the kinase BCR-ABL, rendering it ineffective.
)
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[2] => Array
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[quiz_unique_key] => 1403770772
[question] => Suppose there is a kinase called ABC that is related to ABL and encoded by the gene Abc. Which of the following genetic occurrences would be the LEAST likely to result in a constitutively active ABC kinase?
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[answer] => 4
[description] => Reason for Correct Answer:
Constitutive activity usually comes from constitutive gene expression or the loss of a protein’s ability to be turned off.
Changes to a protein, particularly within a regulatory region, can result in an inability of a protein to be turned off.
Alterations to a phosphorylation site can also lead to this, as phosphorylation can turn off or turn on proteins.
Gene expression changes that cause constitutive expression include changes to repressor regions or promoter regions in the DNA. This can occur from point mutations or translocations that bring together regulatory regions from different genes.
Changes in the active site would UNLIKELY lead to constitutive activity. Though they could increase or decrease the rate of catalysis, they are unlikely to turn the protein on or off.
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[answers] => Array
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[0] => Array
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[each_answer] => A. A translocation that changes the tertiary structure of the R region
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[each_answer] => B. A deletion that results in the loss of a regulatory phosphorylation site
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[2] => Array
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[each_answer] => C. A point mutation in the promoter region for the Abc gene
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[each_answer] => D. A missense mutation in the active site of the ABC protein
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[quiz_unique_key] => 1403770772
[question] => According to this pathway and the information in the passage, which statement is true?
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[answer] => 4
[description] => Reason for Correct Answer:
Oncogenes are genes that promote progression through the cell cycle and/or decrease apoptosis and cell death – they are often turned ON in cancer cells.
Tumor suppressor genes are genes that promote cell cycle arrest, apoptosis, and autophagy – they are often turned OFF in cancer cells.
We know that BCR-ABL is an oncogene because its activity promotes cancer/cell cycle progression.
BCR-ABL promotes the pathway shown in the figure; we know this because there are no blunt-ended (inhibition) arrows originating from BCR-ABL. Therefore, we would expect that things in this pathway that are turned on are oncogenes and things that are turned off are tumor suppressors. We would also expect that things that counter or block steps of the pathway are tumor suppressors.
In the beginning of the pathway, you can see that BCR-ABL promotes the conversion of PIP2 to PIP3 but PTEN blocks this conversion. Since PTEN acts counter to BCR-ABL, we can assume it’s a tumor suppressor.
P53 is blocked by the BCR-ABL pathway AND it activates proteins that cause apoptosis. It must be a tumor suppressor.
BCL-2 proteins BLOCK BAX and BAK, which are proteins that promote apoptosis. Therefore, BCL-2 proteins are products of oncogenes, and are not tumor suppressors.
BAD, on the other hand, is blocked by the BCR-ABL pathway (indicated with a minus sign next to the arrow) and it blocks BCL-2. This suggests that it is a tumor suppressor.
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[answers] => Array
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[0] => Array
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[each_answer] => A. PTEN is an oncogene.
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[1] => Array
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[each_answer] => B. TP53, which encodes p53, is an oncogene.
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[each_answer] => C. BCL-2 is a tumor suppressor.
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[each_answer] => D. BAD is a tumor suppressor.
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[4] => Array
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[quiz_unique_key] => 1403770772
[question] => Many cancer cells exhibit higher levels of lactate than normal cells. What is the likely cause of this?
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[answer] => 3
[description] => Reason for Correct Answer:
Cancer cells exhibit higher metabolism than normal cells due to their growth and division.
Glycolysis (/anaerobic respiration) is less efficient in terms of ATP production compared to oxidative phosphorylation (aerobic respiration).
However, lactate is a byproduct of glycolysis, part of anaerobic respiration, and the question stem says that cancer cells produce more lactate.
The buildup of lactate in cancer cells suggests that they may exhibit a metabolic preference for glycolysis, relative to normal cells, even under aerobic conditions. (This phenomenon is known as the Warburg effect.) Reasons for this likely include:
- Rapid energy supply: Glycolysis, the first step in glucose metabolism, is a relatively fast way to generate ATP. Cancer cells often require a rapid energy supply to support their high rates of growth and division.
- Metabolic Adaptation: Cancer cells can thrive in areas of the tumor microenvironment with limited oxygen supply (hypoxia). Glycolysis, followed by lactate production, can occur without oxygen (anaerobic conditions), making it an adaptable metabolic pathway.
- Biomolecule Synthesis: The intermediates generated during glycolysis, such as pyruvate, can be used for the synthesis of various biomolecules required for cell proliferation, including nucleotides, amino acids, and fatty acids.
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[answers] => Array
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[0] => Array
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[each_answer] => A. Cancer cells will have a lower metabolism because more of their proteins are occupied in processes like DNA replication and cell division.
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[1] => Array
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[each_answer] => B. Cancer cells will conduct anaerobic fermentation in order to generate the greatest possible number of ATP molecules per molecule of glucose.
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[2] => Array
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[each_answer] => C. Cancer cells exhibit higher metabolism and a metabolic preference for aerobic respiration to in order to derive more ATP from glucose.
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[3] => Array
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[each_answer] => D. Cancer cells exhibit higher metabolism and rely on anaerobic respiration as faster way to produce ATP.
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[5] => Array
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[quiz_unique_key] => 1325138223
[question] => Which would be LEAST helpful in differentiating CML cells from cells involved in a leukemoid reaction?
[value] => Array
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[answer] => 1
[description] => Reason for Correct Answer:
As stated in the passage, CML cells have similar appearances to cells involved in a leukemoid reaction, but differ by a chromosomal translocation that results in the production of the BCR-ABL fusion protein.
Bcr-Abl transcripts will be present in CML cells. Therefore, a fluorescent probe that detects these transcripts will be able to distinguish CML cells from other cells.
BCR-ABL proteins will also be present in CML cells. Therefore, these proteins could be detected using a Western blot, allowing for CML cells to be identified.
A karyotype analysis looks at the size and shape of chromosomes; it can be used to detect chromosomal aberrations in CML.
A high proportion of cells in M phase, however, would not be as useful, as this could be seen in cancer or a leukemoid reaction, where cells are dividing and proliferating, according to the passage.
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[0] => Array
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[each_answer] => A. Detecting a high proportion of cells in M phase of the cell cycle
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[1] => Array
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[each_answer] => B. Detection of a fluorescence probe that hybridizes to mRNA transcripts
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[2] => Array
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[each_answer] => C. Comparison of protein expression using Western blotting
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[each_answer] => D. Comparing the results of karyotype analysis
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Figure 1
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