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BCR ABL 1 Gene Rearrangement

The Philadelphia chromosome (Ph) can be detected in 90 to 95% of patients with chronic myelogenous leukemia (CML). Cytogenetic demonstration of the Ph chromosome is an important feature in the differential diagnosis of CML. The Ph chromosome is also present in approximately 20% of adults and 5% of children with acute lymphoblastic leukemia and 2% of adults with acute myelogenous leukemia. The presence of the Philadelphia chromosome in acute leukemia connotes a poorer prognosis.

The Ph chromosome arises from a reciprocal translocation of most of the cellular abl proto-oncogene on chromosome 9 to the breakpoint cluster region (bcr) gene on chromosome 22 [t(9;22)(q34;q11)]. The resultant bcr-abl 1 fused gene codes for an aberrant tyrosine kinase with increased activity that adversely affects control of cell growth.

Although various breakpoints within the BCR and ABL genes have been described, >95% of CML cases contain mRNA in which either the BCR exon 13 (e13) or BCR exon 14 (e14) is fused to the ABL exon 2 (a2), yielding fused genes e13/a2 and e14/a2, respectively. The e13/a2 and e14/a2 fusion forms produce a 210-kDa protein (p210). More than 50% of patients with BCR/ABL-positive ALL have the e1/a2 fusion, which produces a 190-kDa protein (p190), and the majority of the remaining patients have either the e13/a2 or e14/a2 variants. Other fusions are very rare in any of the neoplasms known to harbor BCR/ABL.

When looking for the presence of mRNA from BCR/ABL (bcr/abl) at the time of diagnosis, it is important to use a qualitative polymerase chain reaction (PCR) assay that detects as many of the fusions as possible and identifies which fusion is present. This avoids false-negative results at diagnosis and assures the test subsequently selected for monitoring during therapy will detect the appropriate fusion product in each patient.

The introduction of imatinib and later-generation tyrosine kinase inhibitors has revolutionized treatment of CML. The majority of patients in chronic phase CML achieve complete cytogenetic remission. Therefore, more sensitive quantitative PCR methods are needed for monitoring bcr/abl levels during treatment.

Real time quantitative reverse transcription PCR is technically challenging to perform. Precision of this assay at low bcr/abl levels is relatively poor. Minor variations in specimen collection, transport, processing and testing can result in changes of bcr-abl 1 levels up to 0.5 log (three-fold). Consequently, changes less than 0.5 log should not be considered clinically significant. For example, if a result is given as 0.1% bcr/abl:abl, then any result between 0.05% and 0.5% should be considered essentially equivalent.

Significant changes during monitoring should be verified with a subsequent specimen.

Also, results from different laboratories are usually not comparable. Therefore, it is recommended that the same laboratory test a patient’s serial specimens. Some patients have significantly different levels of bcr-abl 1 in the peripheral blood and bone marrow, so it is necessary to compare results from the same source.

Either blood or bone marrow can be used for initial diagnosis. Specimen requirement is 4 mL of blood or 3 mL of bone marrow drawn into an EDTA (lavender top) Vacutainer tube. Blood is the preferred specimen for monitoring treatment.

Reference value for qualitative PCR is no gene rearrangement detected. Quantitative PCR is reported as the ratio of bcr/abl (p210) to abl with conversion to a percentage (i.e., bcr/abl (p210) as a percentage of total abl). The result is then converted to an international scale.

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