By definition, the BCR-ABL fusion gene is always present in chronic myeloid leukemia.
In over 95% of cases, the BCR-ABL chimera gene is present on chromosome 22, t(9;22)(q34,q11) . The resulting chromosome 9 achieves an elongation of the long arm, which is not apparent when looking at the chromosomes during cell division under a microscope (karyotyping, cytogenetic examination). In contrast, the resulting chromosome 22 becomes conspicuously shortened in its long arm. This may be seen during cytogenetic examination.
The short chromosome 22 received the name Philadelphia chromosome (Ph) after the location of its discovery.
In chronic myeloid leukemia without visible Ph, the BCR-ABL gene is often created by translocations involving more chromosomes than chromosome 9 and 22. In these cases, the karyotype changed in a way that a typical Ph is not recognized. Polymerase chain reaction analyses (PCR) will catch the presence of BCR-ABL regardless of where the gene is located in the genome. This is the most sensitive method for finding the fusion gene.
In rare cases, clinical and laboratory findings may be consistent with chronic myeloid leukemia without finding Ph or BCR-ABL. These cases are classified as atypical chronic myeloid leukemia and represent another disease entity.
The Philadelphia chromosome is not only found in chronic myeloid leukemia. It is also present in about 20% of adults and 2–5% of children with acute lymphatic leukemia.
The ABL gene always splits between exon 1 and exon 2 from the rest of chromosome 9, while the BCR gene can break in multiple places from chromosome 22. The consequence is that in different patients, there can be different lengths of the fusion gene and thereby the fusion protein. The normal fusion protein of chronic myeloid leukemia is 210 kD (p210). Chronic myeloid leukemia can sometimes have a benign course and is then often associated with a longer form, p230. Ph+ acute lympatic leukemia, which is an aggressive disease, is often found in a shorter form, p190.
The ABL protein is a tyrosine kinase enzyme, which when transcribed from chromosome 9, is under "strict control" by the N-terminus which has a self-inhibiting effect on the tyrosine kinase activity. When the gene moves to chromosome 22, the N-terminus of the protein is derived from the BCR gene. This does not have a self-inhibiting effect on the tyrosine kinase activity. Consequently, there is uninhibited tyrosine kinase activity. Phosphorylation of tyrosine is an important mechanism for intracellular signaling and we know that the tyrokinase BCR-ABL affects many signal pathways which are important for cell division, cell differentiation, ahesion, apoptosis, and transcription regulation.
It is striking that the p190 BCR-ABL gene, often found in acute lymphatic leukemia, has a higher tyrosine activity than p210 BCR-ABL, which is most common in chronic myloid leukemia. The gene p230 BCR-ABL has the lowest tyrosine activity and is associated with a less aggressive clinical course. It appears the degree of tyrosine kinase activity is of importance for the aggressiveness of the disease.