Our
understanding in CML disease and process has dramatically increased with
evolving new molecular biology techniques. Discovery of Philadelphia
chromosomes in 1960 by Peter Nowell and David Hungerford was first step towards
understanding disease and mechanism in CML. The Philadelphia chromosomes abnormality is present in
all CML and associated with the malignant disease. It was not until 1973 when
Janet Rowley, using banding technique, described the translocation between
chromosomes 9 and 22 (figure 1).Alikian et al 2017) and further studies
in early 80s revealed that the fusion of BCR-ABL genes is the cause of CML. This BCR-ABL form active tyrosin
kinase which endorse proliferation and replication.(Jabour and Kantrajian,
2014).

ABL is a non-receptor tyrosine kinase that is present in
most tissues. It is found in both cytoplasm and nucleus of cells, and transport
between the two compartments. It regulates cytoskeleton structure by
transducing signals from cell-surface for growth and adhesion receptors. BCR on
other hand have multiple modular domain and also function as signalling
protein.
The expression of the ABL1 tyrosine kinase is tightly regulated. (Chen et al., 2009). In CML fusion of BCR to ABL enhance
the tyrosin kinase activity of ABL and form new motifs and generate different
types of BCR-ABL protein (Figure 2).

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Figure
 2.  Shows locations of various breakpoints in the ABL and BCR genes
and structure of the BCR/ABL mRNA transcripts derived from the various break
points (uptodate).

 

 

Figure 2 highlights the
breakpoints of both BCR and ABL. The ABL gene breakpoint can be upstream exon
1a, among exon 1a and 1b or downstream exon 1b, however in CML it is almost
always upstream exon 2. Apart from rare exception most transcripts of BCR-ABL
gene have exon 2-11 of the ABL gene (Ref). Due to variable nature of BCR
breakpoints, they determine the pathogenic properties of the BCR-ABL gene as
well as the size of the gene (Table 1). The breakpoints on the BCR gene are present
very closely in three region commonly known as micro cluster, minor cluster and
major cluster. Three different types of proteins are synthesized, as shown in
figure 2, by BCR genes depending on location of break point on the gene (Ref).

The p230 is one of the largest BCR-ABL1
transcripts and occurs rarely. It is associated with much slower course of
disease and mainly present in patients with uncommon chronic neutrophilic
leukaemia (Ref). The minor BCR protein (p190) is associated with Ph- positive ALL and
some patients of chronic myeloid leukaemia. The CML with this minor BCR
mutation show increase monocytosis in aggressive disease (Ref). The p210
BCR gene protein is associated with chronic myeloid leukaemia as well as some Philadelphia
(Ph) positive acute lymphoblastic leukaemia (ALL). This
by product of BCR-ABL gene is essential for transformation of CML and accountable
for the phenotypic abnormalities of CML (Ref). Protein p210 increase the tyrosine kinase
activity leading to phosphorylation of various cellular substrate and
autophosphorylation which induce binding of several proteins and adoptors
molecules. This activation of signlans pathways by p210 protein interfere with
cellular process including cell differentiation, proliferation, cell adhesion
and survival (Ref).
 Studies have shown that p210 activates
signal transduction pathways including RAS/MAPK, CRKL pathways, PI-3 kinase, JAK-STAT
and the Src pathway as shown in figure 3. It is proposed that the RAS, Jun-kinase,
and PI-3 kinase pathways are associated in transformation and proliferation,
while inhibition of apoptosis is thought to result from activation of the PI-3
kinase and RAS pathways (Ref). Furthermore  p210BCR/ABL effects on CRKL,
c-CBL, and on proteins associated with the organization of the cytoskeleton and
cell membrane that result in cell adhesion defects and structural abnormalities
which are characteristic of CML cells (Ref). It is also thought that cell
adhesion and migration proteins are phosphorylated by BCR-ABL genes which may
lead to premature release of myeloid cells in circulation. Increased reactive
oxygen species in CML patients leads to DNA damage by inducing DNA double
strand breaks. This leads to addition mutations which are considered to be responsible
for accelerated and blast crisis in chronic myeloid patients (Ref).

 

In BCR-ABL1 gene translocation, the BCR gene replaces the N
terminal segment of the ABL1 gene, resulting in constitutive expression of ABL1
tyrosine kinase. The number or size of the N terminal amino acids added by BCR established
the clinical properties of the fusion gene (Ref).

Table1.

 

Synonym

Location on gene (Exons)

Type of protein

Disease

Major-cluster

M-BCR

12-16

p210

– CML
– Ph+ALL
-Thrombocytosis (in e14a2)
 

Minor-cluster

m-BCR

Between (2, e2′ and e2)

p190

–         
PH+ALL
–         
CML (monocytosis and aggressive
disease)

Micro-cluster

u-BCR

Between (e19 – e20)

p230

–         
Chronic Neutrophilic leukaemia
 

 

 

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