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Ch. 19 - The Genetics of Cancer
Klug - Essentials of Genetics 10th Edition
Klug10th EditionEssentials of GeneticsISBN: 9780135588789Not the one you use?Change textbook
All textbooksKlug 10th EditionCh. 19 - The Genetics of CancerProblem 26
Chapter 19, Problem 26

A study by Bose and colleagues (1998). Blood 92:3362-3367] and a previous study by Biernaux and others (1996). Bone Marrow Transplant 17:(Suppl. 3) S45–S47] showed that BCR-ABL fusion gene transcripts can be detected in 25 to 30 percent of healthy adults who do not develop chronic myelogenous leukemia (CML). Explain how these individuals can carry a fusion gene that is transcriptionally active and yet does not develop CML.

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Step 1: Understand the nature of the BCR-ABL fusion gene. This gene results from a chromosomal translocation between chromosomes 9 and 22, creating the Philadelphia chromosome, which produces a constitutively active tyrosine kinase implicated in CML development.
Step 2: Recognize that the presence of the BCR-ABL fusion gene transcript indicates that the gene is transcriptionally active, meaning it is being transcribed into RNA, but this alone does not guarantee disease manifestation.
Step 3: Consider the concept of clonal expansion and additional mutations. For CML to develop, cells carrying the BCR-ABL fusion gene must undergo clonal expansion and acquire further genetic or epigenetic changes that promote uncontrolled proliferation and leukemogenesis.
Step 4: Explore the possibility of immune surveillance and cellular control mechanisms. Healthy individuals may have immune systems or cellular regulatory pathways that suppress or eliminate cells expressing the fusion gene before they can cause disease.
Step 5: Conclude that the detection of BCR-ABL transcripts in healthy adults likely reflects low-level, transient, or non-pathogenic expression of the fusion gene without the necessary secondary events or cellular environment required for CML development.

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Key Concepts

Here are the essential concepts you must grasp in order to answer the question correctly.

BCR-ABL Fusion Gene and Its Role in CML

The BCR-ABL fusion gene results from a translocation between chromosomes 9 and 22, creating the Philadelphia chromosome. This fusion gene encodes a constitutively active tyrosine kinase that drives uncontrolled cell proliferation, a hallmark of chronic myelogenous leukemia (CML). However, presence of the gene alone does not guarantee disease development.
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Clonal Expansion and Additional Genetic Events

For CML to develop, cells carrying the BCR-ABL fusion must undergo clonal expansion and acquire additional mutations or epigenetic changes. These secondary events promote malignant transformation and disease progression, explaining why some individuals with the fusion gene remain healthy without developing leukemia.
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Gene Expression Regulation and Cellular Context

Although the BCR-ABL fusion gene may be transcriptionally active, its expression level, cellular environment, and regulatory mechanisms influence whether it causes disease. In healthy individuals, factors such as immune surveillance and controlled gene expression can prevent the fusion protein from triggering leukemogenesis.
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Related Practice
Textbook Question

Genetic tests that detect mutations in the BRCA1 and BRCA2 tumor-suppressor genes are widely available. These tests reveal a number of mutations in these genes—mutations that have been linked to familial breast cancer. Assume that a young woman in a suspected breast cancer family takes the BRCA1 and BRCA2 genetic tests and receives negative results. That is, she does not test positive for the mutant alleles of BRCA1 or BRCA2. Can she consider herself free of risk for breast cancer?

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Textbook Question

As part of a cancer research project, you have discovered a gene that is mutated in many metastatic tumors. After determining the DNA sequence of this gene, you compare the sequence with those of other genes in the human genome sequence database. Your gene appears to code for an amino acid sequence that resembles sequences found in some serine proteases. Conjecture how your new gene might contribute to the development of highly invasive cancers.

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Textbook Question

Those who inherit a mutant allele of the RB1 tumor-suppressor gene are at risk for developing a bone cancer called osteosarcoma. You suspect that in these cases, osteosarcoma requires a mutation in the second RB1 allele, and you have cultured some osteosarcoma cells and obtained a cDNA clone of a normal human RB1 gene. A colleague sends you a research paper revealing that a strain of cancer-prone mice develops malignant tumors when injected with osteosarcoma cells, and you obtain these mice. Using these three resources, what experiments would you perform to determine:

(a) Whether osteosarcoma cells carry two RB1 mutations

(b) Whether osteosarcoma cells produce any pRB protein

(c) If the addition of a normal RB1 gene will change the cancer-causing potential of osteosarcoma cells?

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