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Inflammation And Chronic Myeloid Leukaemia (cml):
Role of tyrosine kinase Inhibitor.
Date : 13/05/2016
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Uploaded by : Hasnain Ali
Uploaded on : 13/05/2016
Subject : Pathology
Inflammation roots go back to second century when
ancient Greek mentioned its manifestation in the old scrolls Hippocrates (460
C- 365 BC) first to describe inflammation (Dunn, 1993). Furthermore, in 1863
Rudolf Virchow described leukocyte in cancerous tissue and made a link between
inflammation and cancer (Blakwill and Mantovani et al., 2001) Virchow was
the first person to recognise leukaemia (Schultz, 2008).Moreover, inflammation
also plays diverse role in many biological processes and it is associated with pain,
swelling, redness, heat, and loss of cellular function (Punchard, 2004).
Furthermore, inflammation is triggers normally in response to injury and infection,
aimed at returning the body to homeostasis (Egger, 2012). Nonetheless,
inflammatory cells and
cytokines found in neoplasms are more likely to underwrite tumor progression
and immunosuppression rather than mounting an effective host anti-neoplastic
response (Figure 3c) (Karin et al., 2006). Consequently, inflammation may be related to chronic
myeloid leukaemia (CML) as well. However, the precise
aetiology of leukaemia has yet to be identified (Cancer Research UK, 2016). Furthermore, CML was branded
by the presences of fusion protein BCR-ABL1, transforming the ABL1 kinase into constitutively active tyrosine
kinase (Figure 2b). which promotes growth and expansion of myeloid lineage cells
(Figure 1a) (Askmyr et
al., 2014). In addition, risk factors such as age,
radiation exposure or inflammatory bowel diseases (Askling et al., 2004) have been suggested. Overall CML accounts for 1 in every
100,000 new cancer diagnoses (Table 1) (Cancer
Research UK, 2016).Therefore, to treat CML, tyrosine kinase
inhibitors (TKIs) are being used as a therapy i.e. imatinib, nilotinib, dasatinib (Cancer Research UK, 2016). Moreover, multidrug
resistant CML (mutation type – T315I) may be refractive to all other TKIs
except ponatinib (O’Hare et al.,
2009). On the other hand, Phase 3 trial of ponatinib was terminated in 2013
(ARIAD, 2016) due to serious sides effects. The aim of
this review was to summarize the link of inflammation to (CML). In addition,
use of TKIs pharmacotherapy and development of drug resistance. Key Words: Inflammation,
chronic myeloid leukaemia (CML), tyrosine kinase inhibitors (TKIs) DiscussionUnregulated
Inflammation can trigger excess cytokines, growth factors and inhibition of
tumour suppressor genes, which in turn can lead to DNA damage, angiogenesis,
vascular damage and tissue remodelling resulting in tumour development or
enhancement (Figure 1c) (Blakwill and Mantovani, 2001). Some chemokines (i.e. IL8) are essential for the
directional migration of leukocytes during normal inflammatory response (Proost,
et al., 1996). Evidently, Zhang et al. (2012) found alterations of
chemokines expression in CML BCR-ABL mice. Nevertheless, some
inconsistencies were noted in their statists and methodology (Table 2).Similarly, in the
past Boggs et al., (1959) observed cellular
composition of inflammatory exudates in the human leukaemias and suggested that
inflammation may play different roles in different types of leukaemia.
Conversely, their methodology found not to be rigorous enough (Table 2). An
association between the inflammatory bowel diseases as a risk of haematopoietic
cancer (CML) has been suggested in an epidemiological study by Askling et al. (2005). In contrary, the data
shown minimal statistical support and discrepancies in the sample size for IBD
related CML (Table 7).According to
Askmyr et al. (2014) neoplastic
disorders also involved in the interaction of inflammatory pathway
deregulations however, possible contamination (cell sorting error) may have
confounded their results (Table 2). Evidently, transformed BCR-ABL1 oncogene
showed constitutive activation of downstream RAS, RAF, MYC, JUN kinase and STAT
pathways in the several forms of human and mice leukaemias. which
involved in the deregulation of cellular differentiation, proliferation and
apoptosis (Sawyer et al., 1992 Mandanas et al., 1993 Okuda et al., 1994 Raitano et al., 1995 Shuai et al., 1996 Jabbour, 2016). Nevertheless, Hoelbl
et al. (2006) study has shown that
cytokines like interleukins (IL2, IL4 and IL7) regulate an important aspect of
transcri ption factor STAT5a and STAT5b (function: induce cell cycle
progression), which was found to be constitutively active in a large variety of
leukaemia’s. Though, this finding may have a distinct relationship with
inflammation, but this link still not has been explored yet. Thus, unregulated
persistent assault from inflammatory cytokines may lead to haematopoietic
disorders like CML. In another
study, IIaria and Etten (1996) illustrated that the product of chromosome
translocation P201 BCR/ ABL (Tyrosine kinases) for CML and P120
BCR/ ABL (Tyrosine kinases) for ALL, have the ability to transform
hematopoietic cytokines dependent cell lines to cytokines independent in the leukaemogenesis.
Conversely, opposite finding was reported by Kanwar et al. (1996) which may have confounded their results (Table 3).Moreover,
studies have been identified in which TKIs are effective in inducing remission
and prolonging survival in CML (Druker et
al., 2001a, b 2006c Kantarijian et
al., 2010). However, their results may have been affected by poorly matched
control subjects and inconsistence statistical comparisons (Table 3). In
addition, despite the new TKIs usefulness, these inhibitors could not eradicate
all the CML cells in vitro (Copland et al., 2006). Moreover, CML stem cells use
survival signals other than BCR-ABL kinase to sustain their viability in the
presences of TKIs (Graham et al.,
2002 Holtz et al., 2002 Corbine et al., 2011).To further
examine the consequence of TKIs, Krauth MT. et
al. (2010) noted extensive serosal
inflammation and pericardial effusion induced by drug dasatinib (TKI).
Similarly, Agarwal et al. (2015)
reported isolated pericardial effusion in acute form of leukeamia induced by nilotinib
(TKI) (Table 3 and 4).Moreover, on the
resistance of TKIs Gorre et al. (2001)
stated amplification or genetic mutation of BCR-ABL gene to (Cancer therapy
STI-571) a TKIs equally, Perrotti et al. (2010) testified genetic anomalies accumulate over time
leading to CML disease development from chronic phase to advance accelerated
phase and blast crisis.Consequently,
further studies are warranted in this area. Zhao et al. (1997) witnessed expression of
(Methotrexate) MTX-resistance DHFR (dihydrofolate- reductase) gene and
(antisense) AS sequence seen stable for 1 year in vitro and 70 days in vivo.
Though, not much investigation to this breakthrough has been done so far. Having
said that yet, the sustainable gene transplantation expression remained the
biggest challenge to the scientific community.Conclusions and Future Directions.In summary, in CML, myeloid lineage cells
undergo massive clonal expansion and proliferation. There has been some
association of CML with progression of inappropriate inflammatory response.
However, whether the inflammation manifestation triggers the CML or CML
instigate inflammation, that’s has not been very well understood yet. Furthermore, CML current curative therapy was
only considered to be allogeneic stem cell transplantation but it carries risks
of morbidity and mortality (Zhao
et al.,1997).
Besides induction of TKIs like ponatinib
changes the refractory CML progression and profiling to some extent. Nonetheless,
those inhibitors cannot eradicate all CML cells and their safety and future efficacy
is still in question. Moreover, treatment for CML still involves the use of imatinib
(National Health Service UK, 2016) albeit imatinib was not efficacious enough
in the past. Above and beyond imatinib may be further involve in CML gene
amplification/mutation Clearly, (NHS) treatment policies inference need to be revised
in the light of current data. Last but not least, future direction is more
pointing toward gene transplantation therapy to CML patients. Finally, in the last
few decades CML disease progression has been improved due to better genetic
and molecular understanding of the neoplasms. In other words, one step closer
to cure but not close enough yet. Word
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This resource was uploaded by: Hasnain Ali