As pointed out previously (see Fig. 1), oncogene activation is not always the result of a DNA mutation. In some instances, a proto- oncogene is activated by a chromosomal change, typically a translocation. More than 40 oncogenic chromosome translocations have been described to date, primarily in sporadic leukemias and lymphomas but also in a few rare connective tissue sarcomas. Although originally detected only by cytogenetic analysis, such alterations can be detected now by whole genome or RNA sequence analysis, even using cell- free DNA in plasma samples from cancer patients.

Fig1. Different mutational mechanisms leading to proto- oncogene activation. These include a single point mutation leading to an amino acid change that alters protein function, mutations or translocations that increase expression of an oncogene; a chromosome translocation that produces a novel product with oncogenic properties; and gene amplification leading to excessive amounts of the gene product.

In some cases, translocation breakpoints lie within the introns of two genes, thereby fusing two genes into one abnormal gene that encodes a chimeric protein with novel oncogenic properties. The best- known example is the translocation between chromosomes 9 and 22, the Philadelphia chromosome that is seen in chronic myelogenous leukemia (CML) (Fig. 2). The trans location moves the proto- oncogene ABL1, a tyrosine kinase, from its normal position on chromosome 9q to a gene of unknown function, BCR, on chromosome 22q. The translocation results in the synthesis of a novel, chimeric protein, BCR- ABL1, containing a portion of the normal Abl protein with increased tyrosine kinase activity. The enhanced tyrosine kinase activity of the novel protein encoded by the chimeric gene is the primary event causing the chronic leukemia. Highly effective drug therapies for CML, such as imatinib, have been developed based on inhibition of this tyrosine kinase activity.

Fig2. The Philadelphia chromosome translocation, t(9;22) (q34;q11). The Philadelphia chromosome (Ph1) is the derivative chromosome 22, which has exchanged part of its long arm for a segment of material from chromosome 9q that contains the ABL1 oncogene. Formation of the chimeric BCR- ABL1 gene on the Ph1 chromosome is the critical genetic event in the development of chronic myelogenous leukemia.

In other cases, a translocation activates an oncogene by placing it downstream of a strong, constitutive promoter belonging to a different gene. Burkitt lymphoma is a B- cell tumor in which the MYC proto- oncogene is translocated from its normal position at 8q24 to a position distal to the immunoglobulin heavy chain locus at 14q32 or the immunoglobulin light chain genes on chromosomes 22 and 2. The function of the Myc protein is still not entirely known, but it appears to be a transcription factor with powerful effects on the expression of a number of genes involved in cellular proliferation, as well as on telomerase expression (see later discussion). The translocation brings enhancer or other transcriptional activating sequences, normally associated with the immunoglobulin genes, near the MYC gene (Table 1). These translocations allow unregulated MYC expression, resulting in uncontrolled cell division.

Table1. Characteristic Chromosome Translocations in Selected Human Malignant Neoplasms

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العتبة العباسية المقدسة تنظم المحاضرة الثالثة من محفل نهج البلاغة في مقام الإمام المهدي (عجّل الله فرجه)

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الآخبار الصحية

الشاي والقهوة وتدهور الذاكرة.. دراسة تكشف نتائج جديدة

هل يساعد الزنك على تحسين النوم والطاقة؟

علامات يجب عدم تجاهلها بعد تناول مكملات "فيتامين د"

لتجنب ارتفاع سكر الدم.. ما أفضل وقت لتناول الحلوى؟

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الإمارات ترسخ مكانتها كأحد أبرز قادة الذكاء الاصطناعي عالميا !

"أوبن إيه آي" تحذر المشرعين الأميركيين من تحايل "ديب سيك" ؟

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سلاح طبي في ساحات الحرب.. رذاذ يوقف النزيف خلال ثانية !

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مواضيع ذات صلة

Cytogenetic Changes in Cancer

Telomerase as an Oncogene

Imaging of the Pituitary: Adenomas

T pit Family of tumours

Pit- 1 Family of tumours

Pituitary Adenomas

Molecular Mechanisms of Carcinogenesis

Chronic Myeloid Leukemia, BCR-ABL Gene, and Disease Monitoring

Application of Liquid Biopsy to Non-small- Cell Lung Cancer Lung

Circulating Tumor DNA

Biomarkers in the Blood and in Tissues: A Complementary Approach

Biomarkers in Oncology: An Evolving Concept