Chronic Myeloid Leukemia Molecular Mechanisms

Genetic Abnormalities

The American Society of Hematology notes that the BCR-ABL1 fusion gene is the hallmark of Chronic Myeloid Leukemia (CML), resulting from the reciprocal translocation t(9;22)(q34;q11) between chromosomes 9 and 22 1, 2
The BCR-ABL1 fusion gene produces a chimeric BCR::ABL1 protein with deregulated tyrosine kinase activity, which is the primary driver of CML pathogenesis 1, 2
The European Society for Medical Oncology states that the Philadelphia chromosome (Ph) is the derivative chromosome 22, described in 1960 as the first recurrent chromosomal anomaly associated with a human malignancy 1, 2

The National Comprehensive Cancer Network recommends that CML diagnosis requires demonstration of the Philadelphia chromosome or the BCR-ABL1 fusion gene in a patient with characteristic peripheral blood findings 3, 6
Conventional cytogenetics detects the Ph chromosome in 90-95% of cases at diagnosis, while FISH (fluorescence in situ hybridization) is mandatory for cases with insufficient metaphases or normal karyotype to exclude cryptic rearrangements 3, 7
Qualitative RT-PCR identifies the type of BCR-ABL1 transcript 6

The identification of the BCR-ABL1 fusion gene is crucial because the BCR::ABL1 protein is the specific target of tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib, nilotinib, bosutinib, ponatinib, and asciminib, which have revolutionized CML treatment 1