Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Pharmacogenomics and Laboratory Medicine
113
BCR-ABL
The Philadelphia (Ph) chromosome is an abnormally short chromosome 22,
resulting from a reciprocal translocation between chromosomes 9 and 22, which
is specifically designated as t(9;22)(q34;q11) (Nowell and Hungerford 1960). This
translocation occurs in a single bone marrow cell, which subsequently produces
many cells (a process termed as clonal expansion by cytogenetics) and gives rise to
leukemia. In fact, the seminal discovery of the Ph chromosome provides the first
example of consistent chromosome abnormality found in cancer. The Ph chromosome
is a hallmark of chronic myeloid leukemia (CML). About 95% of patients with
CML have this abnormality and the remainder have either a cryptic translocation
that is invisible by traditional chromosome study, or a variant translocation involving
one or more other chromosomes in addition to chromosomes 9 and 22 (Talpaz
et al. 2006). The presence of Ph chromosome is also found in 25–30% of adult
acute lymphoblastic leukemia (ALL) and 2–10% of pediatric ALL cases, as well as
occasionally in acute myelogenous leukemia (AML).
At the molecular level, a fusion gene BCR-ABL is generated by juxtapositioning
the ABL gene on chromosome 9q34 to a part of the BCR (“breakpoint cluster
region”) on chromosome 22q11 (Heisterkamp and Groffen 1991). ABL gene encodes
for a membrane-associated tyrosine kinase, and the BCR-ABL fusion transcript is
also translated into a tyrosine kinase. Three clinically important variants of BCR-
ABL—the p190, p210, and p230 isoforms—are produced, dependent on the precise
location of fusion (Advani and Pendergast 2002). The p190 is typically associated
with ALL, while p210 is usually associated with CML but can also be associated
with ALL (Pakakasama et al. 2008). The p230 is generally associated with chronic
neutrophilic leukemia. Additionally, the p190 isoform can also be expressed as a
splice variant of p210 (Lichty et al. 1998).
Usually in normal cells, the tyrosine kinase activity of the ABL gene product is
tightly regulated (controlled). However, the tyrosine kinase of the BCR-ABL gene
is deregulated (uncontrolled) with continuous activity resulting in unregulated cell
division and consequently malignant state. Understanding this process led to the
development of the first genetically targeted drug imatinib mesylate (Gleevec),
which specifically binds to and inhibits the tyrosine kinase activity of the BCR-ABL
fusion protein (Druker et al. 1996). This discovery provides a prominent example of
molecular targeted therapies against specific oncogenic events. Besides ABL, imatinib
also directly inhibits other tyrosine kinases, such as ARG (ABL2), KIT, and
PDGFR. This drug has had a major impact on the treatment of CML and other blood
neoplasma and solid tumors with etiologies based on activation of these tyrosine
kinases. Analyses of CML patients resistant to BCR-ABL suppression by imatinib
coupled with the crystallographic structure of ABL complexed with this inhibitor
have shown how structural mutations in ABL can circumvent an otherwise potent
anticancer drug. The successes and limitations of imatinib hold general lessons for
the development of alternative molecular targeted therapies in oncology.
BCR-ABL fusion can be detected by FISH using LSI BCR/ABL Dual Color, Dual
Fusion probe (Abbott Molecular; www.abbottmolecular.com) (Figure 5.1b) or chromosome
study (standard cytogenetics, Figure 5.1a). Figure 5.1c shows the crystal