Inflammation And Chronic Myeloid Leukaemia (cml):

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)

Discussion

Unregulated 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.

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