The Philadelphia chromosome is a reciprocal translocation between the long arms of chromosomes 9 and 22: t(9,22)(q34;q11).
The gene encoding the protein Abelson kinase 1 (ABL1) resides on chromosome 9 (region q34).
ABL1 is a nonreceptor tyrosine kinase with active roles in regulation of the cell cycle, DNA damage repair, and apoptosis.
The BCR gene is located on chromosome 22 (region q11), and encodes a 160 kDa cytoplasmic protein with multiple functional domains.
The most common t(9;22) fusion protein breakpoint in CML encodes for p190, p210, or p230 fusion proteins.
Presence of the p210 fusion protein leads to the active ABL tyrosine kinase found in chronic phase CML in most cases.
The p190 fusion protein is most commonly associated with a more aggressive form of CML and is seen in Ph+ acute lymphoblastic leukemia (ALL).
The BCR-ABL1 fusion protein dimerizes, and is an active tyrosine kinase.
BCR-ABL1 protein acts through multiple signaling pathways, including up-regulation of the MAPK (mitogen-activated protein kinase) pathway and activation of cyclin-dependent kinases, such as cyclin D1.
BCR-ABL1 protein can circumvent cell death signaling by inhibiting the Bcl-xL deamidation pathway, thus allowing Bcl-xL to prohibit activation of Bax/Bak–induced apoptosis.
The natural history of untreated CML consists of CML-CP for 3 to 5 years after diagnosis, followed by an accelerated phase for a period of months, and ultimately blast crisis (CML-BC) or acute leukemia.
The BCR-ABL1 translocation increases the replicative index and cell growth, and leads to increased genetic instability, creating further chromosomal ab2242ations.
Common genetic alterations found in patients with accelerated phase or blast crisis CML include duplication of the Ph chromosome, trisomy 8, and isochromosome 17q.
Increased activity of the BCR-ABL1 fusion protein with detection of higher levels of mRNA expression can be found up to 18 months prior to transformation to the accelerated phase or blast crisis.
In blast crisis, 30% of patients have mutations in the tumor suppressor p53, and others have mutations in Rb and p16, resulting in further deregulation of the cell cycle, DNA repair, and apoptosis and serving as additional genetic hits in the progression to a more aggressive acute leukemia.