Philadelphia chromosome

Results from a reciprocal translocation between the long arms of chromosomes 9 and 22 with the molecular consequence the generation of the fusion protein BCR-ABL, an activated tyrosine kinase, which is present in virtually all patients with CML

The BCR-ABL fusion gene which encodes for a constitutively activated tyrosine kinase signaling protein that sustains CML

Present in 15% to 30% of adult acute lymphoid leukemia patients, 3%-5% of childhood ALL patients and 2% of acute myeloblastic leukemia patients.

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).

BCR-ABL1 fusion protein dimerizes, and is an active tyrosine kinase.

BCR-ABL1 protein acts through multiple signaling pathways, it up-regulates the MAPK (mitogen-activated protein kinase) pathway, and activates cyclin-dependent kinases, such as cyclin D1, while circumvents 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 (chronic phase) pfor 3 to 5 years after diagnosis, followed by an accelerated phase for a period of months (CML-AP), 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 aberrations.

Common genetic alterations 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.

With blast crisis, 30% of patients have mutations in the tumor suppressor p53, and many others have mutations in Rb and p16, resulting in further deregulation of the cell cycle, DNA repair, and apoptosis

Associated with a poor prognosis.

Positivity in adults with ALL associated with a 5-year survival rate of less than 10%.

The PH Chromosome abnormality is rare in children with ALL with an incidence of 2 to 5%.

PH positivity however represents the most common genetic sub group in ALL in adults with an overall incidence of 20 to 25%.

PH positive incidence in ALL increases with age and accounts for more than 50% of ALL in patients who are older than 50.

The presence of BCR-ABL rearrangement is the worst prognostic factor for ALL.

Children with positivity of Philadelphia chromosome in ALL treated with chemotherapy have survival rates of 25-30% and worse outcomes with WBC counts greater than 100,000.

Long-term survival of patients with Philadelphia chromosome positive ALL treated with imatinib and intensive chemotherapy have improved event free survival compared with historical controls treated without imatinib and comparable to patients treated with allogeneic stem cell transplant: five year disease free survival around 70%.

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