Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Chronic Myeloid Leukemia (CML) [92.10]

OMIM numbers: 608232, 151410 (BCR-ABL1)

Dipl.-Ing. (FH) Tanja Hinrichsen

Scientific Background

Chronic myeloid leukemia (CML) originates from abnormal pluripotent myeloid stem cells and is always associated with the presence of the BCR-ABL1 fusion gene. It belongs to the group of myeloproliferative neoplasms (see also MPN). Upon diagnosis, in 90-95% of all patients, the characteristic reciprocal translocation t(9;22) (q34;q11.2) is found, which forms what is known as the philadelphia chromosome (der(22)). In the remaining cases, there are either variant translocations with a third or fourth chromosome being involved in addition to chromosome 9 and 22 or cryptic translocations of 9q34 (ABL1) and 22q11.2 (BCR) are found that are not detectable in cytogenetic analysis. The BCR-ABL1 fusion gene, however, is also present in these cases and can be detected with FISH or RT-PCR analysis. If not treated, CML exhibits two or three phases: the chronic phase, the accelerated phase and the blast crisis. At the point of transformation, 80% of all patients exhibit additional cytogenetic abnormalities: major route abnormalities such as trisomy 8, i(17q), trisomy 19 as well as an additional philadelphia chromosome and minor route abnormalities such as -7, -17, +17, +21 and -Y as well as t(3;21) (q26;q22) are being distinguished. A chromosome analysis should therefore be carried out in regular intervals to detect or rule out additional aberrations after a CML diagnosis.

With the highly sensitive qRT-PCR, the BCR-ABL1 fusion gene is detected even when cytogenetically there is no longer any indication for a philadelphia translocation. Analysis of the BCR-ABL1 fusion transcript with RT PCR can reliably identify and quantify the splice variants e13a2, e14a2, e13a3, e14a3 and e1a2, which constitute 95% of all fusion transcripts. This is of significance especially for detecting minimal residual disease and for therapy monitoring (decrease or increase of the BCR-ABL1 fusion transcripts).

Identification of the exact breakpoint using fragment analysis can moreover provide information on the phenotype of the disease. While in CML the breakpoint in the BCR gene is usually located in the major breakpoint cluster region (M-BCR), a breakpoint in the minor breakpoint cluster region (m-BCR) is more likely to be associated with a philadelphia chromosome-positive ALL (see ALL) and a breakpoint in the micro breakpoint cluster region (?-BCR) with a neutrophil maturation and/or abnormal thrombocytosis.

The formation of the BCR-ABL1 fusion gene leads to a constitutive activation of the ABL tyrosine kinase. The detection of the fusion transcript therefore serves as an indication for treatment with tyrosine kinase inhibitors (e.g. imatinib, Glivec). Due to the increased cell division rate, patients who have been treated with tyrosine kinase inhibitors may exhibit spontaneous mutations in the ABL1 region of the fusion gene, which then lead to acquired resistance to treatment due to clonal selection of resistant cells. Mutations in the ATP-binding pocket may also lead to loss of binding of the tyrosine kinase inhibitor. Mutations can be identified by DNA sequencing of the respective part of the gene. Currently there are more than 20 different known mutations in the ABL1 binding region which can partially be overcome by combination therapy or increase of dosage of e.g. imatinib. Successors from the 2nd generation such as dasatinib and nilotinib circumvent the majority, yet not all, of resistance caused by mutations. Therefore, early identification of resistance is of great significance for the treatment strategy.