Parts of two chromosomes, 9 and 22, swap places. The result is that a fusion gene is created by juxtapositioning the Abl1 gene on chromosome 9 (region q34) to a part of the BCR ("breakpoint cluster region") gene on chromosome 22 (region q11). This is a reciprocal translocation, creating an elongated chromosome 9 (der 9), and a truncated chromosome 22 (the Philadelphia chromosome). In agreement with the International System for Human Cytogenetic Nomenclature(ISCN), this chromosomal translocation is designated as t(9;22)(q34;q11). Abl stands for "Abelson", the name of a leukemia virus which carries a similar protein.
Translocation results in an oncogenic BCR-ABL gene fusion that can be found on the shorter derivative 22 chromosome. This gene encodes for a Bcr-abl fusion protein. Depending on the precise location of fusion, the molecular weight of this protein can range from 185 to 210 kDa. Consequently, bcr-abl is referred to as p210 or p185.
Three clinically important variants are the p190, p210, and p230 isoforms. p190 is generally associated withacute lymphoblastic leukemia (ALL), while p210 is generally associated with chronic myeloid leukemia but can also be associated with ALL. p230 is usually associated with chronic neutrophilic leukemia. Additionally, the p190 isoform can also be expressed as a splice variant of p210.
Because the Abl gene expresses a membrane-associated protein, a tyrosine kinase, the BCR-Abl transcript is also translated into a tyrosine kinase. The activity of tyrosine kinases is typically controlled by other molecules, but the mutant tyrosine kinase of the BCR-Abl transcript codes for a protein that is "always on" or continuously activated, which results in unregulated cell division (i.e. cancer). Although the BCR region also expresses serine/threonine kinases, thetyrosine kinase function is very relevant for drug therapy. Tyrosine kinase inhibitors (such as imatinib and sunitinib) are important drugs against a variety of cancers including CML, renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GISTs).
The fused BCR-Abl protein interacts with the interleukin-3 receptor beta(c) subunit. The ABL tyrosine kinase activity of BCR-Abl is elevated relative to wild-type ABL. Since ABL activates a number of cell cycle-controlling proteins and enzymes, the result of the BCR-Abl fusion is to speed up cell division. Moreover, it inhibits DNA repair, causing genomic instability and potentially causing the feared blast crisis in CML.