BCR-ABL

BCR-ABL

The BCR-ABL fusion gene is a genetic abnormality in which parts of two different chromosomes, chromosome 9 and chromosome 22, break and exchange portions. This translocation results in the formation of the Philadelphia chromosome, which is associated with chronic myeloid leukemia (CML) and other types of leukemia. The BCR-ABL gene encodes a tyrosine kinase protein that is constitutively active, leading to uncontrolled cell division and the development of cancer.

Structure and Function

The BCR-ABL fusion protein is a result of the translocation t(9;22)(q34;q11), which fuses the BCR (Breakpoint Cluster Region) gene on chromosome 22 with the ABL (Abelson murine leukemia viral oncogene homolog 1) gene on chromosome 9. The resulting BCR-ABL protein has increased tyrosine kinase activity compared to the normal ABL protein, which is tightly regulated.

The BCR-ABL protein is a constitutively active tyrosine kinase that phosphorylates various substrates involved in cell cycle regulation, apoptosis, and cell adhesion. This leads to increased proliferation and survival of hematopoietic stem cells, contributing to the pathogenesis of CML.

Clinical Significance

The presence of the BCR-ABL fusion gene is a hallmark of chronic myeloid leukemia (CML), and it is also found in some cases of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The detection of the BCR-ABL gene is crucial for the diagnosis and management of these leukemias.

Diagnosis

The BCR-ABL fusion gene can be detected using various techniques, including:

• Polymerase Chain Reaction (PCR): A sensitive method to detect the presence of BCR-ABL transcripts in blood or bone marrow samples.
• Fluorescence In Situ Hybridization (FISH): A cytogenetic technique that uses fluorescent probes to detect the Philadelphia chromosome in cells.
• Karyotyping: A method to visualize chromosomes and identify the Philadelphia chromosome.

Treatment

The discovery of the BCR-ABL fusion gene led to the development of targeted therapies, such as tyrosine kinase inhibitors (TKIs). These drugs specifically inhibit the BCR-ABL kinase activity, leading to reduced proliferation of leukemic cells. Common TKIs include:

• Imatinib (Gleevec): The first TKI approved for the treatment of CML.
• Dasatinib (Sprycel): A second-generation TKI used for patients resistant to imatinib.
• Nilotinib (Tasigna): Another second-generation TKI with increased potency against BCR-ABL.

Prognosis

The introduction of TKIs has significantly improved the prognosis for patients with CML. Most patients achieve a complete cytogenetic response and have a normal life expectancy with appropriate treatment.

Also see

• Chronic Myeloid Leukemia
• Tyrosine Kinase Inhibitors
• Philadelphia Chromosome
• Acute Lymphoblastic Leukemia