PHILADELPHIA CHROMOSOME

Alternate Names: Philadelphia translocation, Ph (or Ph') chromosome, t(9;22)(q34.1;q11.2)

Overview: It is a specific chromosomal abnormality, associated with chronic myelogenous leukemia (CML) as a result of a reciprocal translocation between chromosome 9 and 22. This translocation takes place in a single bone marrow cell and, through the process of clonal expansion (the production of many cells from this one mutant cell), it gives rise to the leukemia.

Phenotype/Characteristics: It is associated with chronic myelogenous leukemia which has the following symptoms: often asymptomatic at diagnosis, initially indicated with an elevated white blood cell count, enlarged spleen causing pain on the left side, malaise, joint and/or hip pain, low-grade fever, increased susceptibility to infections, anemia, and thrombocytopenia with easy bruising (although an increased platelet count (thrombocytosis) may also occur in CML).

May also be associated with acute lymphoblastic leukemia and acute myeloid leukemia and show the respective characteristics.

Frequency: 95% of people with chronic myeloid leukemia have the Philadelphia chromosome,

Diagnosis: Patients can be subjected to immunophenotyping and conventional karyotyping. FISH can be used in failed cases of conventional cytogenetics analysis to quantify disease and to prove positive BCR-ABL gene fusion.

Causes: A large portion of a proto-oncogene, called ABL, on chromosome 9 is translocated to the BCR gene on chromosome 22. The two gene segments are fused and ultimately produce a chimeric protein that is larger than the normal ABL protein. The malignant state is a consequence of this process since the gene that encodes a protein with deregulated (uncontrolled) tyrosine kinase activity is a strong evidence of its pathogenetic (disease-causing) role. The result of the BCR-Abl fusion is to speed up cell division, inhibiting DNA repair, causing genomic instability and potentially causing the feared blast crisis in CML.

Treatment/Recommendations/Therapies: Tyrosine kinase inhibitors greatly limit the growth of the tumor clone and decreased the risk of the feared "blast crisis" (rapid progression and short survival of CML cells, indicating the onset of disease).  Other pharmacological inhibitors are being developed, which are more potent and/or are active against the emerging resistant BCR-abl clones in treated patients. 

Blood or marrow transplants is a potentially curative but risky procedure but chemotherapy is favored by some for achieving first remission.

References:

Atfy, M et al. (2011). Incidence of Philadelphia-chromosome in acute myelogenous leukemia and biphenotypic acute leukemia patients: And its role in their outcome. PubMed. Retrieved March 12, 2013 from the URL: http://www.ncbi.nlm.nih.gov/pubmed/21612824

Medicine.net (2012). Definition of Philadelphia chromosome (Ph). Medicine.Net. retrieved March 12, 2013 from the URL: http://www.medterms.com/script/main/art.asp?articlekey=4870

Sattler, M, and Griffin JD (2001). Mechanisms of transformation by the BCR/ABL oncogene. PubMed. Retrieved March 12, 2013 from the URL: http://www.ncbi.nlm.nih.gov/pubmed/11345193

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