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Chapter 16: Problem 15

How do translocations such as the Philadelphia chromosome contribute to cancer?

Short Answer

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Short Answer: The Philadelphia chromosome, a chromosomal translocation between chromosomes 9 and 22, contributes to cancer by creating the fusion gene BCR-ABL1. This fusion gene produces an abnormal protein with continuous tyrosine kinase activity that disrupts cell signaling pathways, promoting uncontrolled cell growth and, ultimately, the development of chronic myelogenous leukemia (CML). Targeted therapy, like Imatinib, that inhibits the activity of the BCR-ABL1 protein, has significantly improved treatment and prognosis for individuals with Philadelphia chromosome-positive CML.

Step by step solution

01

Understand Chromosomal Translocations

A chromosomal translocation occurs when a segment of genetic material from one chromosome breaks off and reattaches to a different chromosome. This transfer of genetic information can lead to a variety of genetic disorders and health problems, including cancer. In some cases, the translocation may cause a gene to become overactive, or it could disrupt the normal function of a gene and lead to uncontrolled cell growth.
02

Introduce the Philadelphia Chromosome

The Philadelphia chromosome is a specific chromosomal translocation between chromosome 9 and chromosome 22, commonly designated as t(9;22)(q34;q11). This chromosomal abnormality is named after the city where it was first discovered, and it is associated with a particular type of blood cancer called chronic myelogenous leukemia (CML).
03

Discuss the Formation of the Philadelphia Chromosome

The Philadelphia chromosome arises from a reciprocal translocation between chromosomes 9 and 22. A piece of chromosome 9 containing the Abl1 gene is translocated onto chromosome 22, while a piece of chromosome 22 containing the BCR gene is translocated onto chromosome 9. As a result, the ABL1 gene from chromosome 9 is fused to the BCR gene located on chromosome 22, thus creating a new fusion gene known as BCR-ABL1.
04

BCR-ABL1 Fusion Gene's Role in Cancer Development

The fusion of the BCR and ABL1 genes produces an abnormal protein called BCR-ABL1, which has a continuous tyrosine kinase activity. This consistent activity disrupts the cell signaling pathways and promotes uncontrolled cell growth and proliferation. The accumulation of these abnormal cells in the bone marrow and blood results in the development of chronic myelogenous leukemia (CML). The presence of the Philadelphia chromosome is detected in approximately 95% of people with CML, making it a diagnostic hallmark and a therapeutic target for this type of cancer.
05

Targeted Therapy for Philadelphia Chromosome-Positive CML

Since the uncontrolled activity of the BCR-ABL1 tyrosine kinase drives the development of CML, targeting this abnormal protein is a critical therapeutic approach. Imatinib, also known as Gleevec, is a drug that specifically inhibits the activity of the BCR-ABL1 protein, leading to decreased cell growth and increased cell death in Philadelphia chromosome-positive CML. This targeted therapy has revolutionized the treatment of CML and has significantly improved the prognosis for individuals with this disease. In conclusion, translocations such as the Philadelphia chromosome contribute to cancer by creating fusion genes that drive uncontrolled cell growth. In the case of the Philadelphia chromosome, the BCR-ABL1 fusion gene promotes the development of chronic myelogenous leukemia.

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Key Concepts

These are the key concepts you need to understand to accurately answer the question.

Chromosomal Translocation
Chromosomal translocation refers to a genetic event where a segment of DNA from one chromosome breaks off and attaches to another chromosome. This rearrangement of genetic material can have significant biological consequences, potentially leading to disorders.
In the context of cancer, this process might activate oncogenes or disrupt tumor suppressor genes, triggering the uncontrolled growth of cells.

It's important to understand that not all translocations lead to harmful outcomes. However, when they do coincide with crucial genetic regions, they can severely disrupt cellular regulation processes, contributing to the development of cancers such as chronic myelogenous leukemia (CML).
Chronic Myelogenous Leukemia
Chronic myelogenous leukemia (CML) is a type of blood cancer characterized by the excessive growth of white blood cells in the bone marrow.
It is closely associated with the presence of the Philadelphia chromosome, a specific type of chromosomal translocation. The uncontrolled proliferation of these white blood cells leads to various symptoms and significantly impacts overall health.

In CML, the excessive cells do not function normally, which means they can crowd out healthy blood cells in bone marrow and bloodstream. Patients often experience fatigue, fever, and other symptoms due to this disruption in normal blood cell production.
BCR-ABL1 Fusion Gene
The BCR-ABL1 fusion gene results from a translocation between chromosome 9 and chromosome 22, creating what is known as the Philadelphia chromosome.
This fusion gene codes for a unique protein that has increased tyrosine kinase activity. The continuous activity of this kinase disrupts normal cellular signaling and control mechanisms.

Such abnormal signaling results in unregulated cell division and survival, contributing directly to the pathogenesis of chronic myelogenous leukemia (CML).
This fusion protein is a key target for cancer therapy, illustrating how understanding its role in cell signaling can lead to effective treatments.
Cancer Genetics
Cancer genetics deals with the study of genetic mutations and alterations that contribute to cancer development.
Chromosomal translocations, like those forming the Philadelphia chromosome, serve as a crucial element within cancer genetics.

These alterations can lead to the activation of oncogenes or the inactivation of tumor suppressor genes, both of which can set the stage for cancer.
  • The genetic basis of cancer helps in identifying specific targets for treatment, allowing for personalized therapeutic approaches.
  • Insights into genetics also aid in understanding cancer risk, helping with early diagnosis and prevention strategies.
By unraveling the complexities of genetic changes, researchers can better comprehend how cancers develop and progress, facilitating more effective interventions.

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Most popular questions from this chapter

A study by Bose and colleagues \((1998 . \text { Blood } 92: 3362-3367)\) 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 do not develop CML.

Of the two classes of genes associated with cancer, tumorsuppressor genes and oncogenes, mutations in which group can be considered gain-of-function mutations? In which group are the loss-of-function mutations? Explain.

Those who inherit a mutant allele of the \(R B 1\) gene are at risk for developing a bone cancer called osteosarcoma. You suspect that in these cases, osteosarcoma requires a mutation in the second \(R B 1\) allele, and you have cultured some osteosarcoma cells and obtained a cDNA clone of a normal human \(R B 1\) 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 \(R B 1\) mutations, (b) whether osteosarcoma cells produce any pRB protein, and (c) if the addition of a normal \(R B 1\) gene will change the cancercausing potential of osteosarcoma cells?

What is the role of the retinoblastoma protein in cell-cycle regulation? Is the retinoblastoma gene a tumor-suppressor gene or an oncogene?

Explain the role of \(p 53\) protein in protecting normal cells against cancer. With respect to this protein and its function, explain how a normal cell turns cancerous.
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