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group_5_presentation_2_-_chronic_myeloid_leukemia [2016/03/11 22:55] hanaf2 |
group_5_presentation_2_-_chronic_myeloid_leukemia [2018/01/25 15:18] (current) |
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| {{:cml.jpg|}} | {{:cml.jpg|}} | ||
| + | Powerpoint: | ||
| + | {{:group_5_chronic_myeloid_leukemia.pptx|}} | ||
| ====== CHRONIC MYELOID LEUKEMIA ====== | ====== CHRONIC MYELOID LEUKEMIA ====== | ||
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| - | {{:group5pic9.png|}}**Figure 4**: Abl gene with its respective exons | + | {{:group5pic9.png|}} |
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| + | **Figure 4**: Abl gene with its respective exons | ||
| The Bcr gene is located on chromosome 22, and it is a serine/threonine kinase that is involved in the activation of RAc and CDc42 GTPases (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). | The Bcr gene is located on chromosome 22, and it is a serine/threonine kinase that is involved in the activation of RAc and CDc42 GTPases (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). | ||
| - | {{:group5pic8.png?550}}**Figure 5**: Bcr gene with its respective exons | + | {{:group5pic8.png?550}} |
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| + | **Figure 5**: Bcr gene with its respective exons | ||
| 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 al., 2007). The Bcr-Abl protein leads to upregulated tyrosine kinase activity, causing an excessive proliferation of leukemia cells, and the inhibition of apoptosis of HSC or progenitors (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 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 al., 2007). The Bcr-Abl protein leads to upregulated tyrosine kinase activity, causing an excessive proliferation of leukemia cells, and the inhibition of apoptosis of HSC or progenitors (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). | ||
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| ===== Therapeutics ===== | ===== Therapeutics ===== | ||
| - | ==== Options: ==== | + | === Options: === |
| The only truly curative treatment is bone marrow transplant or allogeneic stem cell transplant. However, these treatments can be invasive and hence other treatment options include tyrosine kinase inhibitors. | The only truly curative treatment is bone marrow transplant or allogeneic stem cell transplant. However, these treatments can be invasive and hence other treatment options include tyrosine kinase inhibitors. | ||
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| **Figure 9**: Curative treatment options for CML | **Figure 9**: Curative treatment options for CML | ||
| - | ==== Inhibiting Bcr-Abl as a potential drug target: ==== | + | === Inhibiting Bcr-Abl as a potential drug target: === |
| CML is caused by the reciprocal translocation between chromosome 9 (location of Abl1 gene) and 22 (location of BCR gene) which creates the Philadelphia chromosome. This molecular pathogenesis generates the Bcr-Abl fusion protein which has elevated tyrosine kinase activity. The Bcr-Abl fusion protein is found predominately in CML cells and thus provides the desired specificity (minimized systemic toxicity) for an inhibitor or therapeutic to interfere with this fusion protein’s function (Deininger, Goldman, Melo 2000). It is easy to target the ATP pocket of this fusion protein (something common to kinase proteins) than other protein-protein interactions as ATP pockets are well defined and mimicking ATP is an easy starting point for drug development (Deininger, Goldman, Melo 2000). | CML is caused by the reciprocal translocation between chromosome 9 (location of Abl1 gene) and 22 (location of BCR gene) which creates the Philadelphia chromosome. This molecular pathogenesis generates the Bcr-Abl fusion protein which has elevated tyrosine kinase activity. The Bcr-Abl fusion protein is found predominately in CML cells and thus provides the desired specificity (minimized systemic toxicity) for an inhibitor or therapeutic to interfere with this fusion protein’s function (Deininger, Goldman, Melo 2000). It is easy to target the ATP pocket of this fusion protein (something common to kinase proteins) than other protein-protein interactions as ATP pockets are well defined and mimicking ATP is an easy starting point for drug development (Deininger, Goldman, Melo 2000). | ||
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| **Figure 10**: Bcr-Abl kinase being inhibited by a compound, imatinib, in red | **Figure 10**: Bcr-Abl kinase being inhibited by a compound, imatinib, in red | ||
| - | ==== Gleevec: a tyrosine kinase inhibitor ===== | + | === Gleevec: a tyrosine kinase inhibitor === |
| Gleevec (imatinib mesylate) is a therapeutic that was FDA approved for CML treatment in 2001. It is now used to treat gastrointestinal stroll tumours (Pray, 2008). Though at first the rationale was that Gleevec would compete with ATP in the active Bcr-Abl conformer, however that wasn't the case. Gleevec doesn’t compete with ATP, instead it just keeps the kinase in a closed state preventing ATP from binding to the conformer. There has been vast improvement seen for CML patient survival over other therapeutics. However, there is acquired drug resistance seen too. Drug resistance is common for chemotherapies due to prolonged exposure to drugs. In particular, some CML cell populations survive due to a genetic mutation in Bcr-Abl, giving rise to a new population of Bcr-Abl CML cells that are resistant to Gleevec. This mutation is at Thr315Ile location and it pushed Gleevec out of its pocket (Pray, 2008). | Gleevec (imatinib mesylate) is a therapeutic that was FDA approved for CML treatment in 2001. It is now used to treat gastrointestinal stroll tumours (Pray, 2008). Though at first the rationale was that Gleevec would compete with ATP in the active Bcr-Abl conformer, however that wasn't the case. Gleevec doesn’t compete with ATP, instead it just keeps the kinase in a closed state preventing ATP from binding to the conformer. There has been vast improvement seen for CML patient survival over other therapeutics. However, there is acquired drug resistance seen too. Drug resistance is common for chemotherapies due to prolonged exposure to drugs. In particular, some CML cell populations survive due to a genetic mutation in Bcr-Abl, giving rise to a new population of Bcr-Abl CML cells that are resistant to Gleevec. This mutation is at Thr315Ile location and it pushed Gleevec out of its pocket (Pray, 2008). | ||
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| **Figure 11**: Pharmacodynamics of imatinib, Gleevec | **Figure 11**: Pharmacodynamics of imatinib, Gleevec | ||
| - | ==== Results from tyrosine kinase inhibitors: ==== | + | === Results from tyrosine kinase inhibitors: === |
| In the study by Deininger, Goldman, Lydon and Melo (1997), Bcr-Abl positive CML cells were exposed to tyrosine kinase inhibitor CGP57148B. Of all the cell lines examined, most showed a drastic reduction showing that tyrosine kinase inhibitors were effective in treating CML cells. Two cells that were resistant to the initial 1.0uM were treated with 10uM of the inhibitor. | In the study by Deininger, Goldman, Lydon and Melo (1997), Bcr-Abl positive CML cells were exposed to tyrosine kinase inhibitor CGP57148B. Of all the cell lines examined, most showed a drastic reduction showing that tyrosine kinase inhibitors were effective in treating CML cells. Two cells that were resistant to the initial 1.0uM were treated with 10uM of the inhibitor. | ||
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| **Figure 12**: Results from study showing effectiveness of tyrosine kinase inhibitors on Bcr-Abl positive CML cells | **Figure 12**: Results from study showing effectiveness of tyrosine kinase inhibitors on Bcr-Abl positive CML cells | ||
| - | ==== Implications of treatment: ==== | + | === Implications of treatment: === |
| One strategy to overcome resistance is to develop new inhibitors of Bcr-Abl. For example, Dasatinib inhibits most Bcr-Abl mutants, except for the Thr351Ile mutant. Also Ponatinib is able to inhibit the T35I mutant (Shah, Tran, Lee, Chen, Norris, Sawyers 2004). | One strategy to overcome resistance is to develop new inhibitors of Bcr-Abl. For example, Dasatinib inhibits most Bcr-Abl mutants, except for the Thr351Ile mutant. Also Ponatinib is able to inhibit the T35I mutant (Shah, Tran, Lee, Chen, Norris, Sawyers 2004). | ||
