What is the Philadelphia Chromosome?
The
Philadelphia Chromosome is a specific genetic abnormality in chromosome 22 of leukemia cancer cells (particularly chronic myeloid leukemia cells). It forms when there is a translocation between chromosome 9 and chromosome 22, resulting in the fusion of the BCR (breakpoint cluster region) gene from chromosome 22 with the ABL1 (Abelson murine leukemia viral oncogene homolog 1) gene from chromosome 9.
How is it Formed?
The Philadelphia Chromosome is formed through a process called
translocation. Specifically, it is a reciprocal translocation, designated as t(9;22)(q34;q11). This means that a piece of chromosome 9 breaks off and attaches to chromosome 22, and vice versa. The breakpoints on these chromosomes are at the q34 region on chromosome 9 and the q11 region on chromosome 22.
Molecular Consequences
The translocation results in the creation of a fusion gene called
BCR-ABL. This gene encodes a hybrid protein with increased tyrosine kinase activity, which leads to uncontrolled cell division and contributes to the malignant transformation of cells. The BCR-ABL protein is a constitutively active tyrosine kinase, which means it does not require activation signals to function.
Histological Findings
In the context of histology, the Philadelphia Chromosome is most commonly associated with
Chronic Myeloid Leukemia (CML). Histologically, CML is characterized by an increased number of granulocytes and their precursors in the bone marrow. The bone marrow is hypercellular, with a marked left shift in granulocytic series, meaning that immature granulocytes are found in increased numbers.
Diagnostic Techniques
Cytogenetic techniques, such as karyotyping, can be used to detect the Philadelphia Chromosome. This involves culturing cells and arresting them in metaphase, staining them, and examining the chromosomes under a microscope. Another method is
FISH (Fluorescence in situ Hybridization), which uses fluorescent probes that bind to specific parts of the chromosome. Polymerase Chain Reaction (PCR) can also be used to detect the BCR-ABL fusion gene at the molecular level.
Clinical Implications
The presence of the Philadelphia Chromosome has significant clinical implications. It is a hallmark of CML but can also be found in some cases of
Acute Lymphoblastic Leukemia (ALL) and
Acute Myeloid Leukemia (AML). Patients with the Philadelphia Chromosome-positive leukemias generally have a different prognosis and may respond differently to treatment compared to those without this genetic feature.
Treatment
The discovery of the Philadelphia Chromosome has led to targeted therapies, most notably the development of
tyrosine kinase inhibitors (TKIs) such as imatinib (Gleevec). These drugs specifically inhibit the BCR-ABL protein, thereby reducing the uncontrolled cell proliferation. This has dramatically improved the prognosis for patients with Philadelphia Chromosome-positive leukemias.
Conclusion
The Philadelphia Chromosome is a critical genetic abnormality with profound implications in the diagnosis, prognosis, and treatment of certain leukemias. Advances in cytogenetic and molecular techniques have made it possible to detect this chromosome and develop targeted therapies that have significantly improved patient outcomes.
