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group_5_presentation_3_-_chronic_myeloid_leukemia [2017/11/28 16:07] mohamesb [Treatment] |
group_5_presentation_3_-_chronic_myeloid_leukemia [2018/01/25 15:18] (current) |
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| ====== Chronic Myeloid Leukemia ====== | ====== Chronic Myeloid Leukemia ====== | ||
| - | {{::screen_shot_2017-10-01_at_6.19.43_pm.png?525|}} | + | {{ ::screen_shot_2017-10-01_at_6.19.43_pm.png?525 |}} |
| - | **Figure 1**: Normal blood versus blood of a CML patient. | + | **Figure 1**: normal blood versus blood of a CML patient. |
| - | LS4M03 CML ppt slides: https://docs.google.com/presentation/d/1yjxDywKLHAQyuMUwxRe52624DxmA9ek-3qR8e3BM-jw/edit?usp=sharing | + | Link to PPT presentation: https://docs.google.com/a/mcmaster.ca/presentation/d/1yjxDywKLHAQyuMUwxRe52624DxmA9ek-3qR8e3BM-jw/edit?usp=sharing |
| ====== Introduction ====== | ====== Introduction ====== | ||
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| <box 35% round right | > {{ ::screen_shot_2017-11-10_at_8.57.39_am.png?410 |}} </box| Figure 7: Reciprocal translocation of the BCR protein and ABL gene generating an oncogene that constitutively activates unregulated myeloid cell growth leading to CML. > In 1960, Peter Nowell and David Hungerford, working in Philadelphia, described a consistent chromosomal abnormality in patients with CML (Druker, 2008). They consistently reported an acrocentric chromosome that was thought to be a chromosomal deletion (Druker, 2008). Through this discovery, CML became known as the first human malignant disease to be linked to an acquired genetic abnormality (Kantarjian, Talpaz, Giles, O’Brien, & Cortes, 2006). | <box 35% round right | > {{ ::screen_shot_2017-11-10_at_8.57.39_am.png?410 |}} </box| Figure 7: Reciprocal translocation of the BCR protein and ABL gene generating an oncogene that constitutively activates unregulated myeloid cell growth leading to CML. > In 1960, Peter Nowell and David Hungerford, working in Philadelphia, described a consistent chromosomal abnormality in patients with CML (Druker, 2008). They consistently reported an acrocentric chromosome that was thought to be a chromosomal deletion (Druker, 2008). Through this discovery, CML became known as the first human malignant disease to be linked to an acquired genetic abnormality (Kantarjian, Talpaz, Giles, O’Brien, & Cortes, 2006). | ||
| - | The characteristic genetic abnormality of CML, the Philadelphia chromosome, is present in the bone marrow cells of more than 90% of all patients with CML (Kantarjian, Talpaz, Giles, O’Brien, & Cortes, 2006). The reciprocal chromosomal translocation between the long arms of chromosomes 9 and 22, as illustrated below in figure x, is the hallmark of CML (Kantarjian, Talpaz, Giles, O’Brien, & Cortes, 2006). This process fuses the Abelson murine Leukemia viral oncogene homolog (ABL) on chromosome 9 with the breakpoint cluster region (BCR) protein on chromosome 22, generating an oncogene that encodes the BCR-ABL protein, a constitutively active cytoplasmic form of the ABL kinase (Kantarjian, Talpaz, Giles, O’Brien, & Cortes, 2006). It is this translocation of the two chromosomes and consequent expression of the BCR-ABL kinase that is considered to be the initiating factor in the pathogenesis of CML (Smith, Burthem, & Whetton, 2003). Furthermore, this reciprocal translocation occurs only in somatic cell lines and ultimately, the BCR-ABL fusion kinase leads to increased and unregulated growth of myeloid cells in the bone marrow. | + | The characteristic genetic abnormality of CML, the Philadelphia chromosome, is present in the bone marrow cells of more than 90% of all patients with CML (Kantarjian, Talpaz, Giles, O’Brien, & Cortes, 2006). The reciprocal chromosomal translocation between the long arms of chromosomes 9 and 22, as illustrated below in figure 7, is the hallmark of CML (Kantarjian, Talpaz, Giles, O’Brien, & Cortes, 2006). This process fuses the Abelson murine Leukemia viral oncogene homolog (ABL) on chromosome 9 with the breakpoint cluster region (BCR) protein on chromosome 22, generating an oncogene that encodes the BCR-ABL protein, a constitutively active cytoplasmic form of the ABL kinase (Kantarjian, Talpaz, Giles, O’Brien, & Cortes, 2006). It is this translocation of the two chromosomes and consequent expression of the BCR-ABL kinase that is considered to be the initiating factor in the pathogenesis of CML (Smith, Burthem, & Whetton, 2003). Furthermore, this reciprocal translocation occurs only in somatic cell lines and ultimately, the BCR-ABL fusion kinase leads to increased and unregulated growth of myeloid cells in the bone marrow. |
| ==== The "Philadelphia Chromosome" ==== | ==== The "Philadelphia Chromosome" ==== | ||
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| ===Gleevac (Imatinib)==== | ===Gleevac (Imatinib)==== | ||
| - | <box 32% round right | > {{ :gleevac_chart.png?360 |}} </box| Figure 10: Surival rates of CML patients on Gleevac compared to other therapies> | + | <box 33% round right | > {{ :gleevac_chart.png?300 |}} </box| Figure 10: Surival rates of CML patients on Gleevac compared to other therapies> |
| When Gleevec first came out it was called the miracle drug since it seemed as though it was able to cure CML due to its huge success rate. Gleevac works by binding to the closed/inactive conformer of BCR-ABL. This keeps the binding site for ATP closed and thus inhibiting the downstream signaling pathway which contributes to the progression of CML. During one of its first clinical trial conducted by Druker et al (2001), they looked at 54 patients with CML and prescribed them Gleevac of 300mg daily. Out of the 54 patients, 53 had a complete hematologic response within 4 weeks of therapy. A hematologic response is used to measure the recovery process of a CML patients by looking at whether their blood counts have returned back to normal and that there are no more immature cells in the blood. Druker et al (2006) did a 5-year follow-up study and found that after 60 months on Gleevac, 98% of all their patients showed a complete hematologic response. The more outstanding result was that after 60 months the survival rates for patients were 89%. This is a huge improvement since only 30% of patients survived 5 years after being diagnosed with CML. Although within one year of the drug being released, some individuals started showing resistance to the drug due to CML cells having constant exposure to it. However, Gleevac still is the recommended and first line of drug for CML patients. | When Gleevec first came out it was called the miracle drug since it seemed as though it was able to cure CML due to its huge success rate. Gleevac works by binding to the closed/inactive conformer of BCR-ABL. This keeps the binding site for ATP closed and thus inhibiting the downstream signaling pathway which contributes to the progression of CML. During one of its first clinical trial conducted by Druker et al (2001), they looked at 54 patients with CML and prescribed them Gleevac of 300mg daily. Out of the 54 patients, 53 had a complete hematologic response within 4 weeks of therapy. A hematologic response is used to measure the recovery process of a CML patients by looking at whether their blood counts have returned back to normal and that there are no more immature cells in the blood. Druker et al (2006) did a 5-year follow-up study and found that after 60 months on Gleevac, 98% of all their patients showed a complete hematologic response. The more outstanding result was that after 60 months the survival rates for patients were 89%. This is a huge improvement since only 30% of patients survived 5 years after being diagnosed with CML. Although within one year of the drug being released, some individuals started showing resistance to the drug due to CML cells having constant exposure to it. However, Gleevac still is the recommended and first line of drug for CML patients. | ||
| ===Dasatinib=== | ===Dasatinib=== | ||
| - | After resistance grew on Gleevac, there was a development of another variation of the drug called Dasatinib. Unlike Gleevac, this drug targets the open/active conformer of BCR-ABL by binding to the active site and directly competing with ATP. During Clinical trials it showed it showed promising results. The researchers tested on 670 CML patients and broke them up into 4 groups, which were prescribed varying doses. At the end of their trials, 86-92% of patients saw complete hematologic response (Aguilera & Tsimberidou, 2009). There is research being done on combine drug therapy with Dasatinib and tyrosine kinase inhibitors. They have shown to work synergistically really well in producing growth inhibition and inducing apoptosis in CML cells (Aguilera & Tsimberidou, 2009). Dasatinib is currently used as a form of treatment for CML and is an effective therapy. <box 28% round left | > {{::gleevac_dasatinib.png?300 |}} </box| Figure 11: Target binding sites of Gleevac and Dasatinib > | + | After resistance grew on Gleevac, there was a development of another variation of the drug called Dasatinib. Unlike Gleevac, this drug targets the open/active conformer of BCR-ABL by binding to the active site and directly competing with ATP. During Clinical trials it showed it showed promising results. The researchers tested on 670 CML patients and broke them up into 4 groups, which were prescribed varying doses. At the end of their trials, 86-92% of patients saw complete hematologic response (Aguilera & Tsimberidou, 2009). There is research being done on combine drug therapy with Dasatinib and tyrosine kinase inhibitors. They have shown to work synergistically really well in producing growth inhibition and inducing apoptosis in CML cells (Aguilera & Tsimberidou, 2009). Dasatinib is currently used as a form of treatment for CML and is an effective therapy. <box 33% round middle | > {{ :gleevac_dasatinib.png?250 |}} </box| Figure 11: Target binding sites of Gleevac and Dasatinib > |
| ===Hydrea (Hydroxyurea)=== | ===Hydrea (Hydroxyurea)=== | ||
