Molecular biology[ edit ] Schematic of the Philadelphia chromosome formation The chromosomal defect in the Philadelphia chromosome is a reciprocal translocation , in which parts of two chromosomes, 9 and 22, swap places. The result is that a fusion gene is created by juxtaposing the ABL1 gene on chromosome 9 region q34 to a part of the BCR breakpoint cluster region gene on chromosome 22 region q This is a reciprocal translocation, creating an elongated chromosome 9 termed a derivative chromosome, or der 9 , and a truncated chromosome 22 the Philadelphia chromosome, 22q-. The symbol ABL1 is derived from Abelson , the name of a leukemia virus which carries a similar protein. The symbol BCR is derived from breakpoint cluster region, a gene which encodes a protein that acts as a guanine nucleotide exchange factor for Rho GTPase proteins  Translocation results in an oncogenic BCR-ABL1 gene fusion that can be found on the shorter derivative 22 chromosome. Depending on the precise location of fusion, the molecular weight of this protein can range from to kDa.
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Received Oct 25; Accepted May 3. This article has been cited by other articles in PMC. Abstract The truncated chromosome 22 that results from the reciprocal translocation t 9;22 q34;q11 is known as the Philadelphia chromosome Ph and is a hallmark of chronic myeloid leukemia CML. In leukemia cells, Ph not only impairs the physiological signaling pathways but also disrupts genomic stability. This aberrant fusion gene encodes the breakpoint cluster region-proto-oncogene tyrosine-protein kinase BCR-ABL1 oncogenic protein with persistently enhanced tyrosine kinase activity.
The kinase activity is responsible for maintaining proliferation, inhibiting differentiation, and conferring resistance to cell death. During the progression of CML from the chronic phase to the accelerated phase and then to the blast phase, the expression patterns of different BCR-ABL1 transcripts vary.
Each BCR-ABL1 transcript is present in a distinct leukemia phenotype, which predicts both response to therapy and clinical outcome. Besides CML, the Ph is found in acute lymphoblastic leukemia, acute myeloid leukemia, and mixed-phenotype acute leukemia.
Here, we provide an overview of the clinical presentation and cellular biology of different phenotypes of Ph-positive leukemia and highlight key findings regarding leukemogenesis. The Philadelphia chromosome Ph is the truncated chromosome 22 generated by the reciprocal translocation t 9;22 q34;q11 and was first identified in in a patient with CML [ 3 ].
These aberrantly activated kinases disturb downstream signaling pathways, causing enhanced proliferation, differentiation arrest, and resistance to cell death [ 6 , 7 ]. However, therapeutic resistance and disease progression are the current barriers to improve the prognosis of patients with Ph-positive leukemia [ 8 — 10 ]. The presence of the Ph results in patients with different leukemia phenotypes having substantially different prognoses.
In addition, other concurrent genomic abnormalities are more common in leukemia cells with Ph than in those without. These genomic variations, in combination with BCR-ABL1 transcripts, play an important role during leukemogenesis [ 18 — 20 ].
However, the extent of the occurrence of the Ph and the types of BCR-ABL1 transcripts found in different leukemia phenotypes, the exact role of the translocation in leukemogenesis, and the culprit of therapeutic resistance are still not fully elucidated. Here, we review the current understanding of this topic. Both transcripts result in a hybrid kDa protein.
The Philadelphia chromosome in leukemogenesis
Chromosome Refresher In the nucleus of each cell, the DNA molecule is packaged into thread-like structures called chromosomes. Each chromosome is made up of DNA tightly coiled—many times—around proteins called histones. Unless a cell is dividing in two, chromosomes are not visible within the nucleus—not even under a microscope. However, the DNA that makes up chromosomes becomes very tightly packed during cell division and is then visible under a microscope as a chromosome. Each chromosome has its own characteristic shape, and the location of specific genes can be found in relation to the shape of a chromosome. When all the genetic material in the cell of a human being gets packaged up, there are 23 pairs of chromosomes, for a total of 46 chromosomes in each cell. In fact, different species of plants and animals have differing set numbers of chromosomes.
Overview of the Philadelphia Chromosome