BCR/ABL(P190) Translocation

BCR-ABL refers to a gene sequence found in an abnormal chromosome 22 of some people with certain forms of leukaemia. Humans normally have 23 pairs of chromosomes, including 22 pairs of non-sex-determining chromosomes (also known as autosomes) and 1 pair of sex chromosomes (XX for females, XY for males). Chromosomes contain a person's inherited genetic information. The genes that reside there form the blueprints for the production of countless proteins. Sometimes changes can occur to a person's chromosomes and/or genes during their lifetime, because of exposures to radiation, toxins, or for unknown reasons.

The BCR-ABL gene sequence is one such acquired change that is formed when pieces of chromosome 9 and chromosome 22 break off and switch places. When this occurs, the ABL region in chromosome 9 fuses with the BCR gene region in chromosome 22. This is referred to as reciprocal translocation and this particular one is commonly expressed as t(9;22). A derivative chromosome 22 that has the BCR-ABL gene sequence is known as the Philadelphia (Ph) chromosome. It is strongly associated with chronic myeloid leukaemia (CML) and, less commonly with one type of acute lymphoblastic leukaemia (ALL). At diagnosis, around 90-95% of cases of CML are found to have the Philadelphia chromosome. All cases have the BCR-ABL fusion gene, including the Philadelphia chromosome-negative cases. In this small fraction of cases the genes have fused on a more microscopic scale, not involving large chromosomal segments.

These BCR-ABL gene sequences at the fusion site encode an abnormal protein. The abnormal BCR-ABL protein is a tyrosine kinase enzyme, a normal signalling protein which has become permanently switched “on” and is responsible for the development of CML and a type of ALL. When large numbers of abnormal leukaemic cells start to crowd out the normal blood cell precursors in the bone marrow, signs and symptoms of leukaemia start to emerge. Treatment of these leukaemias typically involves a tyrosine kinase inhibitor (TKI), given as daily tablets.

Testing for BCR-ABL detects the Ph chromosome (the derivative chromosome 22) and BCR-ABL fusion gene or its transcripts, the RNA copies made by the cell from the abnormal stretches of DNA. The presence of the BCR-ABL abnormality confirms the clinical diagnosis in CML or a type of ALL. These are distinguished by the typical appearances of the cells through a microscope and, in the case of ALL, by flow cytometry (or “immunophenotyping”), which looks at molecules expressed inside the cells or more commonly expressed on the leukaemic cell surfaces.

There are several different types of BCR-ABL test available, including:

• Cytogenetics (Chromosome analysis or Karyotyping)
  This test looks at chromosomes under a microscope to detect structural and/or numerical abnormalities. Cells in a sample of blood or bone marrow are grown in the laboratory and then examined to determine if the Philadelphia chromosome is present. Other chromosomal abnormalities can also be detected.
• Fluorescence in situ hybridization (FISH)
  This test method uses differently-coloured fluorescent dye-labelled probes to "light up" the BCR and the ABL gene sequences. Cells are examined under a microscope to determine the proportion if any where the coloured dots are fused together, indicating a BCR-ABL translocation.
• Genetic molecular testing, qualitative or quantitative
  The polymerase chain reaction (PCR)-based qualitative and quantitative tests detect and measure BCR-ABL gene transcripts, or gene product units, in a patient's blood and/or bone marrow samples. This is the most sensitive test for BCR-ABL and is used to diagnose the minority of cases negative for the Philadelphia chromosome. It is also used to check the response to tyrosine kinase inhibitors (TKIs). Variant mutations of BCR-ABL can also be analysed if indicated. These mutations are responsible for treatment resistance to TKIs. If the response to treatment is suboptimal, mutational analysis may tell your doctor which TKIs will be more effective.