CML is a result of the reciprocal translocation between chromosome 9 and chromosome 22 (Apperley, 2015). Abnormal chromosome 22 is also referred to as the Philadelphia chromosome (Ph), since it was in Philadelphia, USA where scientists first discovered it (Apperley, 2015). The Abl gene is a non-receptor tyrosine kinase and is located on chromosome 9 (Corey & Cortes, 2010). Abl stands for Abelson murine Leukemia viral oncogene homolog and it is the human homologue of the v-able oncogene (Deniniger et al., 2000). SH1, SH2 and SH3 are the 3 SRC homology domains found on Abl (Deniniger et al., 2000). SH1 domain is important in carrying out tyrosine kinase function, whereas SH2 & SH3 allow Abl to interact with other proteins (Deniniger et al., 2000). The Bcr gene is located on chromosome 22, and it is a serine/threonine kinase that is involved in the activation of GTPases, such as RAC1 (cell growth/proliferation) and CDC42 (cell cycle progression) (Corey & Cortes, 2010). Bcr stands for breakpoint cluster region, due to the different breakpoints that are found at the site for transcription (Corey & Cortes, 2010). Chromosome 9 has a constant breakpoint, whereas, chromosome 22 can have breakpoints in up to 3 different areas: m-bcr, M-bcr, and µ-bcr (Hurtado et al., 2007). These three breakpoints produce proteins that contain different molecular weights: p190, p210, or p230 (Hurtado et al., 2007). The protein with molecular weight p210 is the one that is seen in 95% of CML patients (Hurtado et al. , 2007).

When the partial gene, Abl fuses with another partial gene, Bcr, this results in a Bcr-Abl mRNA transcript that gets further translated into Bcr-Abl protein (Corey & Cortes, 2010). Due to the many different breakpoints located on Bcr , it results in two types of Bcr-Abl mRNA, named b2a2 and b3a2 (Hurtado et l., 2007). The Bcr-Abl protein leads to upregulated, cytoplasmic tyrosine kinase, causing an excessive proliferation of leukemia cells, adhesion and the inhibition of apoptosis, without the need for cytokine signalling (Corey & Cortes, 2010). As a result, genes that promote cell survival, growth and proliferation are always transcribed (Corey & Cortes, 2010). There are several ways to deregulate the Abl tyrosine kinase. The SH3 domain is an essential domain on the Abl gene, and is involved in negatively regulating activity (Deniniger et al., 2000). It has been found that the deletion or the change in position of the SH3 domain can activate the kinase and turn Abl into an oncogene (Deniniger et al., 2000). Since, the serine/kinase part that tells Bcr to turn off is replaced by Abl’s tyrosine kinase, and the SH3 domain that tells Abl to turn off is deleted, the protein never stops working. Moreover, oxidative stress such as ionizing radiation has been found to oxidize a protein called Pag/Msp23 (Deniniger et al., 2000). This oxidation leads to the dissociation of this protein from Abl, leading to the activation of the kinase (Deniniger et al., 2000).

When Abl is in its proto-oncogene form, it is weakly active and functions like a normal gene (Corey & Cortes, 2010). Abl serves a complex role in the human body, when it is in its proto-oncogene form. As a normal gene, it serves in regulating the cell cycle, responding to genotoxic stress, and using integrin signals to influence decisions regarding cell cycle and apoptosis (Corey & Cortes, 2010). However, when it fuses to Bcr, Abl acts as a constitutively active tyrosine kinase protein (constantly active) (Corey & Cortes, 2010). This transformation of the Abl proto-oncogene into an Abl oncogene, is a leading cause of the elevation in tyrosine kinase activity (Corey & Cortes, 2010). This activity is essential for the transforming functions of the protein (Druker, 2008).

There are several substrates that have the potential in binding to Bcr-Abl and becoming tyrosine phosphorylated (Deniniger et al., 2000). These may include adaptor molecules, proteins that play a role in the organization of cell membranes and cytoskeletons, and proteins involved in catalytic function (Deniniger et al., 2000). The choice of substrate is dependent upon the type of cell they function and reside in (Deniniger et al., 2000). Under physiologic conditions, tyrosine phosphatases function to regulate tyrosine kinases (Deniniger et al., 2000). Syp83 and PTP1B,84 are two tyrosine phosphatases that have the ability to dephosphorylate Brc-Abl (Deniniger et al., 2000). Therefore, more research needs to be conducted to on these tyrosine phosphatases, in order to determine a way to manage this disease. β1 integrins are important transmembrane receptors, since they allow progenitor cells to attach and interact with the stroma (Deniniger et al., 2000). This allows for the inhibition of proliferation (Deniniger et al., 2000). In CML, an adhesion-inhibitory variant of β1 integrin is present, which causes a decrease in the adhesion of progenitor cells to bone marrow and extracellular matrix (Deniniger et al., 2000). This results in the over proliferation of leukemia cells (Deniniger et al., 2000).

The Ras and the MAP kinase pathways play an important role in the activation of mitogenic signaling (Deniniger et al., 2000). An adaptor molecule known as Grb-2 acts as a substrate and is tyrosine phosphorylated by Brc-Abl (Deniniger et al., 2000). It binds to the Sos protein, which allows for the activation of Ras from its GDP bound form to its DTP bound form (Deniniger et al., 2000). Two other adaptor molecule known as Shc and Crkl act as substrates of Brc-Abl and are also capable of activating the Ras GTP bound form (Deniniger et al., 2000). The SH2 domain on Shc and the SH3 domain on Crkl allows for the binding to Brc-Abl (Deniniger et al., 2000). Unlike tumours, Ras activation does not involve active mutations, it causes the pathway to stay consistently active (Deniniger et al., 2000). When IL-3 cytokine receptors are stimulated, this leads to the activation of Ras (Deniniger et al., 2000). After this occurs, a serine/threonine kinase known as Raf is recruited to the cell membrane (Deniniger et al., 2000). Mek1/Mek2 and Erk are serine/threonine kinases involved in the gene transcription (Deniniger et al., 2000). Ras signaling may be relayed through Rac (the GTP-GDP exchange factor), then to germinal center kinase (Gckr) and then to Sapk (Deniniger et al., 2000). The 3rd part of the MAP pathway involves Rac relaying information to p38, which is activated in the same way by the Bcr-Abl complex (Deniniger et al., 2000).

Jak-Stat pathways has also been found to play a role in mitogenic signaling (Deniniger et al., 2000). For blood cells to be made, they need a signal (Deniniger et al., 2000). Shown is the protein, erythropoietin, which is a protein kinase receptor associated with Jak kinase (Deniniger et al., 2000). When STAT5 proteins get phosphorylated, they dimerize, go inside the nucleas, and allow for transcription of apoptotic genes, which is a driver of proliferation of Philadelphia chromosome-positive CML (Deniniger et al., 2000). Bcr- Abl constitutively phosphorylates and activates target proteins involved in cell growth and proliferation of Jak2, such as the STAT5 transcription factor (Fabbro, 2012). Bcr-Abl can act as a switch that turns on phosphorylation all the time, without the need for erythropoietin (Fabbro, 2012). As well, it can identify any tyrosine residue and phosphorylate it (Fabbro, 2012).

There are several ways in inhibiting apoptosis (Deniniger et al., 2000). One way is by blocking the release of cytochrome C from the mitochondria, thereby blocking the activation of cysteine-aspartic proteases through Bcr-Abl. Bcr-Abl causes the upregulation of a family of proteins known as Bcl-2 in a Ras (Deniniger et al., 2000). The upstream effect of cysteine-aspartic proteases activation are mediated by Bcl-2 (Deniniger et al., 2000). Another, way to inhibit apoptosis is through the protein Bad. Bad is phosphorylated by Raf-1 (Deniniger et al., 2000).

[1] Apperley, J. (2015). Chronic myeloid leukaemia. The Lancet. 385: 9976, 1447–1459.

[2] Corey, S., Cortes, J. (2010). Chronic Myeloid Leukemia: Pathophysiology and Therapeutics.

[3] Deniniger, M., Goldman, J., Melo, J. (2000). The Molecular Biology of Chronic Myeloid Leukemia. Blood, 96(10), 3343 - 3356.

[4] Hurtado et al. (2007). Chronic Myeloid Leukemia Current Concepts in Physiopathology and Treatment. Cancerología, 2, 137-147.

[5] Druker, B. (2008). Translation of the Philadelphia chromosome into therapy for CML. Blood, 12(13), 4808 - 4817.

[6] Fabbro, D. (2012). BCR-ABL signaling: A new STATus in CML. Nature Chemical Biology, 8, 228-229.