PH and Cancer
Definition
of Philadelphia chromosome (Ph)
Philadelphia
chromosome (Ph): The chromosome abnormality that causes
chronic myeloid leukemia (CML). Abbreviated as the Ph chromosome.
The
Ph chromosome is an abnormally short chromosome 22 that
is one of the two chromosomes involved in a translocation
(an exchange of material) with chromosome 9. This translocation
takes place in a single bone marrow cell and, through the
process of clonal expansion (the production of many cells
from this one mutant cell), it gives rise to the leukemia.
The
discovery in Philadelphia in 1960 of the Ph chromosome was
a landmark. It was the first consistent chromosome abnormality
found in any kind of malignancy. The discovery led to the
identification in CML cells of the BCR-ABL fusion gene and
its corresponding protein. ABL and BCR are normal genes
on chromosomes 9 and 22, respectively. The ABL gene encodes
a tyrosine kinase enzyme whose activity is tightly regulated
(controlled). In the formation of the Ph translocation,
two fusion genes are generated: BCR-ABL on the Ph chromosome
and ABL-BCR on the chromosome 9 participating in the translocation.
The BCR-ABL gene encodes a protein with deregulated (uncontrolled)
tyrosine kinase activity. The presence of this protein in
the CML cells is strong evidence of its pathogenetic (disease-causing)
role. The efficacy in CML of a drug that inhibits the BCR-ABL
tyrosine kinase has provided the final proof that the BCR-ABL
oncoprotein is the unique cause of CML.
The
Ph chromosome is also found in a form of acute lymphoblastic
leukemia (ALL). It seems highly probable that this form
of ALL is due to the same chromosomal and molecular mechanisms
as CML.
Philadelphia
chromosome The hallmark of chronic myeloid leukemia (CML).
The Philadelphia (Ph) chromosome is an abbreviated chromosome
22 that was shortchanged in an a reciprocal exchange of
material with chromosome 9. This translocation occurs in
a cell in the bone-marrow cell, and causes CML It is also
found in a form of acute lymphoblastic leukemia (ALL). On
a molecular level the Philadelphia chromosome translocation
results in the production of a fusion protein. A large portion
of a proto-oncogene, called ABL, on chromosome 9 is translocated
to the BCR gene on chromosome 22. The two gene segments
are fused and ultimately produce a chimeric protein that
is larger than the normal ABL protein. The malignant state
is a consequence of this process. Understanding this process
led to the development of the drug imatinib mesylate (Gleevec)
the first in a new class of genetically targeted agents,
a major advance in cancer treatment.
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