The of disease and mainly present in

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 (Deo, 2015). The minor
BCR (m-bcr) protein (p190) is associated with Ph- positive acute lymphoblastic leukaemia
and sometime present in chronic myeloid leukaemia patient. The CML with this
minor BCR mutation shows increase monocytosis in aggressive disease (Reckel
et al., 2017). The p210 BCR gene product is found in chronic myeloid leukaemia as
well as some Philadelphia (Ph) positive acute lymphoblastic leukaemia (ALL). This
BCR-ABL gene product (p210) is essential for transformation of CML and
accountable for the phenotypic abnormalities of CML (Maru,
2012). The p210 BCR-ABL gene products increase the
tyrosine kinase activity leading to phosphorylation of various cellular
substrate and autophosphorylation which induce binding of several proteins and
adaptors molecules. This activation of signals pathways by p210 oncoprotein
interfere with cellular process including cell differentiation, proliferation,
cell adhesion and survival (Ernst and
Hochhaus, 2012). 

 

Figure 4: Shows BCR-ABL downstream pathways and impact on cellular function:
Activation of  JAK/STAT pathways enhance  cell growth, RAS pathway activation  increases proliferation of BCR-ABL-positive
leukemic cells, PI3K activates AKT which cause apoptosis by suppressing
proteins such as BAD or FOXO and C/EBP? is a regulator of myeloid differentiation.

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 (Webersinke, 2016)

 

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 4 (Webersinke, 2016). 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 (Maru,
2012). Furthermore p210 effects on CRKL, c-CBL as well as
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 (Apperley, 2015). It is also thought that cell adhesion and migration proteins are
phosphorylated by BCR-ABL genes which may lead to premature appearance of
myeloid cells in blood circulation. Increased reactive oxygen species in CML
patients leads to DNA damage by breaking DNA double strands. This leads to
addition mutations which are considered to be responsible for accelerated and
blast crisis in chronic myeloid patients (Soverini et al., 2015). CML progress from chronic phase to more aggressive accelerated and
blastic phase. Studies have shown that in 75% of CML cases, the disease
progression results due to additional chromosomal abnormalities for example
mutation in p53 gene which is a tumour suppressor gene are found in patients in
blast phase of disease (Webersinke, 2016).