Philadelphia Chromosome and Oncogenic BCR ABL Gene Translocation in CML

Translocation is a Structural Aberration of Chromosome

Translocation is a type of structural aberration of the chromosome where a segment of chromosome gets translocated to another chromosome. There may be two types of translocation based on the nature of the exchange. They are:

(1). Homologous Translocation
(2). Heterologous Translocation

In homologous translocation, the exchange of chromosomal segments occurs between the homologous chromosomes. In heterologous translocation, the chromosomal segments are exchanged between non-homologous chromosomes. The heterologous translocation in most of the cases will be a reciprocal translocation (exchange of segments between chromosomes).

Translocation causes ‘Position Effect’

The translocation of chromosomes leads to a phenomenon in molecular genetics called the ‘Position Effect’. The position effect is the change in the expression pattern of a gene due to its current position in the chromosome. For example, a normally active gene may be converted to an inactive gene when it is translocated into a new position or vice versa.

Philadelphia Chromosome is formed by a Heterologous Reciprocal Translocation

The Philadelphia Translocation is the most studied chromosomal translocation process in human. It was first described in Philadelphia (hence the name) in 1959 by David A. Hungerford and Peter Nowell.

The Philadelphia translocation is a heterologous and reciprocal translocation in which the chromosome segments are exchanged between chromosome-9 and chromosome-22. A short portion of the q arm of chromosome-9 is translocated into the q-arm of chromosome-22. Similarly, a portion from the chromosome-22 is translocated into the chromosome-9. Thus due to this translocation, two chimeric chromosomes are produced, a large chromosome-9 and a short chromosome-22. The short chromosome-22 is called the Philadelphia Chromosome or PH.

Philadelphia Translocation Creates a Hybrid Oncogene in Human cause CML

Patients with the Philadelphia chromosome develop leukemia cancer, particularly Chronic Myelogenous Leukemia (CML). The exact reason for this cancer development is the formation of a hybrid oncogene due to the Philadelphia translocation.

Genetic consequences of Philadelphia Translocation

The Philadelphia translocation is too small to be visible in the usual karyotype preparations. The size of the translocated segment of chromosome-9 is ~ 5000 kb. This 5000 kb region of chromosome-9 contains a gene called ‘ABL1. In Philadelphia translocation, the ABL1 region of chromosome-9 is inserted into the ‘BCR’ region of the chromosome-22. The BCR region (Break-point Cluster Region) is about 5.8 kb in size located in the chromosome-22 where the breakpoint occurs. Thus, after Philadelphia translocation, the ABL1 gene of the chromosome-9 is juxtaposed onto the BCR gene on the chromosome 22. This creates an oncogenic BCR-ABL chimeric gene which on expression produces a hybrid protein called Bcr-abl fusion protein. Based on the exact point of the breakage, the Bcr-abl fusion protein may be 185 to 210 kDa in weight.

Bcr-abl Fusion Protein is a Continuously Expressed Tyrosine Kinase Enzyme

The Bcr-abl fusion protein is oncogenic. In normal cells, the ABL1 gene produces a membrane associated tyrosine kinase enzyme whose activity is strictly regulated by an auto-regulatory mechanism. The Bcr-abl fusion gene also produces (Bcr-abl fusion protein) a tyrosine kinase enzyme. However, the Bcr-abl fusion protein lacks the auto-regulatory mechanism and thus it is always ‘kept on’ or continuously expressed. The continuous expression of Bcr-abl fusion protein activated cell proliferation leading to the unregulated division of cells and ultimately cancer.

In Bcr-abl fusion protein, the N-terminal sequence is derived from the BCR gene. This change in the N-terminus region is the reason for its oncogenic properties. The change in the N-terminal region of the Bcr-abl protein due to the Philadelphia translocation over activates the tyrosine kinase activity and thus it become oncogenic. The Bcr-abl fusion protein can activate the Ras pathway in the cell to activate its transformation into cancerous cells.

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