The Philadelphia chromosome is the result of a translocation between chromosomes 9 and 22 leading to the generation of a chimeric tyrosine kinase gene, BCR-ABL. This chromosomal abnormality is associated with which of the following disorders?
(A) burkitt lymphoma
(B) chronic myeloid leukemia
© fanconi anemia
(D) Li-Fraumeni syndrome (LFS)
(E) von Hippel-Lindau syndrome (VHL)
Explanation:
(B) Chronic myeloid leukemia is characterized as a pluripotent stem cell disease of the hematopoietic system that results from a consistent chromosomal translocation. This translocation is known as the Philadelphia chromosome and results from a translocation between chromosomes 9 and 22. The translocation occurs within the protooncogenic tyrosine kinase gene, c-abl on chromosome 9 and the bcr locus on chromosome 22 (t9:22). The ABL gene was first identified as the transforming protein of Abelson murine leukemia virus. Therefore, the term c-abl differentiates the cellular version from the viral version (v-abl). The bcr (breakpoint cluster region) locus is so named because it was a region on chromosome 22 identified in numerous chromosomal breakpoints. The result of the Philadelphia translocation is a fusion protein, bcr-abl, that has uncontrolled tyrosine kinase activity leading to the ability to transform cells. Burkitt lymphoma (choice A) results with high frequency due to a chromosomal translocation between chromosomes 8 and 14 (t8:14). The translocation occurs within the protooncogene MYC on chromosome 8 and the immunoglobulin heavy chain locus on chromosome 14. The result of the translocation is the placement of the strong immunoglobulin gene enhancer element near the MYC gene, leading to uncontrolled MYC expression. Fanconi anemia (choice C) is caused by chromosomal instability and frequent breakage leading to a predisposition to acute myelogenous leukemia. LFS (choice D) is a rare inherited form of cancer that involves breast and colon carcinomas, soft-tissue sarcomas, osteosarcomas, brain tumors, leukemia, and adrenocortical carcinomas. These tumors develop at an early age in LFS patients. The tumor suppressor gene found responsible for LFS is p53. Mutant forms of p53 are found in approximately 50% of all tumors. The normal p53 protein functions as a transcription factor that can induce either cell cycle arrest or apoptosis (programmed cell death) in response to DNAdamage. VHLsyndrome (choice E) is an inherited form of renal carcinoma that is caused by mutations in a tumor-suppressor gene identified as the VHLgene.