Biomedical Engineering Reference
In-Depth Information
Treatment of CML patients in the last century was based
predominantly on radiotherapy, busulfan, hydroxyurea and
interferon-alfa. Allogeneic hematopoietic stem cell transplantation
is the only curative therapy currently for CML. A series of discoveries
led to the recognition that the BCR-ABL protein, which results from a
balanced, reciprocal translocation involving chromosomes 9 and 22,
has a central role in the pathogenesis of CML. Important mile stones
in our understanding of the biological basis of the disease were
the discovery of the Philadelphia (Ph) chromosome in 1960, the
characterization of the breakpoint cluster region on chromosome
22 in 1984 and the demonstration of the BCR-ABL fusion gene in
1986 [1]. The BCR-ABL Protein (now known as BCR-ABL1) functions
as a constitutively activated tyrosine kinase. This knowledge laid
the foundation for the preclinical work and led to the development
of imatinib mesylate (formerly ST1571), which inhibits the kinase
activity of BCR-ABL1 protein. While most patients benefit from
imatinib treatment, a substantial number either are initially
refractory (primary resistance) or develop resistance during the
course of treatment (acquired resistance). Several new BCR-ABL
tyrosine kinase inhibitors have substantial activity in patients with
imatinib resistance and are now being compared with imatinib
for newly diagnosed patients. Integration of the various treatment
modalities and determining optimal therapy or response to therapy
is evolving rapidly.
8.1
Pathogenesis
The Philadelphia chromosome is a shortened chromosome
22(22q-), resulted from balanced reciprocal translocation between
the long arms of chromosomes 9 and 22, (t 9, 22) (q34; q11) [2
3].
The (9; 22) translocation resulted in the formation of BCR-ABL
chimeric gene and protein, which played the central role in the
pathogenesis of CML [1, 4]. The (9; 22) translocation transposes
the ABL (Abelson) proto-oncogene from chromosome 9 into a
relatively small 5.8 kb genomic region on chromosome 22 named
the breakpoint cluster region (BCR) [5]. The break point is almost
always occur upstream of the second axon (a2) resulting in the
translocation of all except exon 1 of ABL. Depending on the precise
,
