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--- group_5_presentation_3_-_chronic_myeloid_leukemia [2017/11/21 03:44]
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+++ group_5_presentation_3_-_chronic_myeloid_leukemia [2018/01/25 15:18] (current)
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 ====== Chronic Myeloid Leukemia ======
-{{::screen_shot_2017-10-01_at_6.19.43_pm.png?550 |}}
+{{ ::screen_shot_2017-10-01_at_6.19.43_pm.png?525 |}}
+**Figure 1**: normal blood versus blood of a CML patient.
+Link to PPT presentation: https://docs.google.com/a/mcmaster.ca/presentation/d/1yjxDywKLHAQyuMUwxRe52624DxmA9ek-3qR8e3BM-jw/edit?usp=sharing
 ====== Introduction ======
+{{ youtube>YeC90N5NOGg?medium}} Chronic myeloid leukemia (CML) is a cancer of white blood cells that begins in the bone marrow where blood cells are formed. CML distinguishes itself from other types of leukemia by the abnormal and unregulated growth of myeloid cells – specifically granulocytes. A genetic abnormality, called the Philadelphia chromosome, is consistent with CML; this abnormality involves a reciprocal translocation of the tails of chromosome 9 and 22, which results in a BCR-ABL fusion gene shown to have a significant role in CML occurrence (Goldman, 2010). CML is the only type of myeloproliferative neoplasm that is characterized by being BCR-ABL positive (Vardiman, et al., 2009). Although there is a genetic factor in CML, there is no familial link. According to the Canadian Cancer Society, the only known risk factors that increase the chances of having CML are exposure to intense radiation, old age, and being male. Since the late 1990s to early 2000s, tyrosine kinase inhibitors (TKI) have become the most effective treatment of CML, and their use has shown a significant improvement in CML patient prognosis and quality of life (Druker & Lydon, 2000).
 ====== History ======
@@ Line 23: / Line 28: @@
 ====== Hierarchy of Blood Cell Development - Hematopoiesis ======
-<box 38% round right | > {{ ::screen_shot_2017-10-01_at_6.17.34_pm.png?445 |}} </box| Figure X: Development and differentiation of blood stem cells into progenitor cells and fully mature cells.> Hematopoiesis is the process of blood cell development (Smith, Burthem, & Whetton, 2003). Figure x illustrates the development of blood cells in a committed, step-wise fashion (Smith, Burthem, & Whetton, 2003). New cells are continually generated by the proliferation of self-renewing hematopoietic stem cells that give rise to non self-renewing progenitor cells (Smith, Burthem, & Whetton, 2003). Disruption of this molecular mechanism can lead to abnormal production of blood cell count (Smith, Burthem, & Whetton, 2003). These progenitor cells are committed to give rise to cells that are more restricted in differentiation potential and perform a variety of functions.
+<box 38% round right | > {{ ::screen_shot_2017-10-01_at_6.17.34_pm.png?445 |}} </box| Figure 2: Development and differentiation of blood stem cells into progenitor cells and fully mature cells.> Hematopoiesis is the process of blood cell development (Smith, Burthem, & Whetton, 2003). Figure 2 illustrates the development of blood cells in a committed, step-wise fashion (Smith, Burthem, & Whetton, 2003). New cells are continually generated by the proliferation of self-renewing hematopoietic stem cells that give rise to non-self-renewing progenitor cells (Smith, Burthem, & Whetton, 2003). Disruption of this molecular mechanism can lead to the abnormal production of blood cell count (Smith, Burthem, & Whetton, 2003). These progenitor cells are committed to giving rise to cells that are more restricted in differentiation potential and perform a variety of functions.
-Hematopoietic stem cells (HSCs) are considered multipotent stem cells, which can differentiate into any blood cell type. Specifically, HSCs give rise to the lymphoid and myeloid lineages of blood cells. The myeloid stem cell gives rise to red blood cells, platelets, and granulocytes (i.e., neutrophils, basophils and eosinophils) while the lymphoid stem cells gives rise to B lymphocytes, T lymphocytes and Natural Killer Cells .
+Hematopoietic stem cells (HSCs) are considered multipotent stem cells, which can differentiate into any blood cell type. Specifically, HSCs give rise to the lymphoid and myeloid lineages of blood cells. The myeloid stem cell gives rise to red blood cells, platelets, and granulocytes (i.e., neutrophils, basophils and eosinophils) while the lymphoid stem cells give rise to B lymphocytes, T lymphocytes, and Natural Killer Cells.
@@ Line 34: / Line 39: @@
   * **Myelogenous Leukemias**: develop from abnormal myeloid stem cells
-Moreover, the types of leukemia are further grouped based on how quickly the leukemia develops and grows. Acute leukemias start suddenly, developing within days or weeks, and chronic leukemias develop slowly over months or years. The four main types of leukemia are outlined in figure X below.
+Moreover, the types of leukemia are further grouped based on how quickly the leukemia develops and grows. Acute leukemias start suddenly, developing within days or weeks, and chronic leukemias develop slowly over months or years. The four main types of leukemia are outlined in figure 3 below.
 {{::screen_shot_2017-11-07_at_4.24.53_pm.png?600|}}
-**Figure X**: Development of the four main types of leukemia
+**Figure 3**: Development of the four main types of leukemia
 ====== Signs and Symptoms ======
-<box 34% round right | > {{ :leukemia.png?375 |}} </box| Figure X: Symptoms of chronic myeloid leukemia.>
+<box 34% round right | > {{ :leukemia.png?375 |}} </box| Figure 4: Symptoms of chronic myeloid leukemia.>
 Symptom onset differs depending on the type of leukemia. In acute myeloid leukemia, symptoms develop rapidly, often initially presenting as flu (Sawyers, 1999). However, in chronic myeloid leukemia symptoms develop more slowly, and severity depends on the production levels of unregulated myeloid cells in the bone marrow. Due to the slow progression of the chronic phase, symptoms often develop slowly and diagnosis results from routine blood tests initially performed to diagnose other hypothesized diseases (Sawyers, 1999).
 In chronic myeloid leukemia, symptoms result from an increased white blood cell, specifically granulocytes. The typical symptoms include:
   -  **Fatigue**
-      - Due to a relative decrease in RBCs compared to WBCs. Relative reduction of RBCs results in symptoms of anemia resulting from low iron levels.
+      - Due to a relative decrease in RBCs compared to WBCs. The relative reduction of RBCs results in symptoms of anemia resulting from low iron levels.
   - **Weight loss**
       - WBCs become localized in the spleen and liver, causing damage to these organs and resulting in enlargement of the liver and spleen.
@@ Line 53: / Line 58: @@
       - Due to the high production of WBCs (specifically granulocytes) which outcompetes the production of platelets (responsible for the blood clotting phenomenon).
   - **Frequent infections**
-      - The overproduction of granulocytes are released into the blood from the bone marrow as immature cells that are incapable of their normal, pathogen fighting mechanisms.
+      - The overproduced granulocytes are released into the blood from the bone marrow as immature cells that are incapable of their normal, pathogen-fighting mechanisms.
   - **Bone pain**
-      - Resulting from hyperplasia in the bones. The high turnover rate of myelogenous progenitors leads to pressure buildup in the bones.
+      - Resulting from hyperplasia of the bones. The high turnover rate of myelogenous progenitors leads to pressure buildup in the bones.
@@ Line 71: / Line 76: @@
 === Complete Blood Count (CBC) ===
-This is often a routine test showing the number of red blood cells, white blood cells, and platelets in the blood.  In a patient with CML, leukocytosis is seen with a remarkable left shift (Quintás-Cardama and Cortes, 2006). This means that there are a high number of immature white blood cells present in the blood, as a result of their early release from the bone marrow. Leukocytosis is mostly prevalent for basophils and eosinophils. Red blood cells are usually present in less than normal levels, as they are outnumbered by the white blood cells (Sessions, 2007). This usually results in mild anemia. The platelet count may also be slightly elevated, but this case of thrombocytosis does not result in any symptoms directly related to it (Sessions, 2007).
+This is often a routine test showing the number of red blood cells, white blood cells, and platelets in the blood.  In a patient with CML, leukocytosis is seen with a remarkable left shift (Quintás-Cardama and Cortes, 2006). This means that there are a high number of immature white blood cells present in the blood, as a result of their early release from the bone marrow. Leukocytosis is most prevalent in basophils and eosinophils. Red blood cells are usually present in less than normal levels, as they are outnumbered by the white blood cells (Sessions, 2007). This usually results in mild anemia. The platelet count may be less than normal, as the WBC production outcompetes it (Sessions, 2007).
 {{:cml_blood_smere_.jpg?300|}}
-**Figure x**: CML blood smear showcasing increased WBC count and left shift.
+**Figure 5**: CML blood smear showcasing increased WBC count and left shift.
 === Bone Marrow Biopsy ===
-This test removes a small amount of bone filled with marrow to confirm blood test findings. In CML, the bone marrow is hypercellular with evidence of myeloid hyperplasia (Sessions, 2007). The primary biologic defect is not unregulated proliferation of leukemic stem cells, but rather a slight delay in myeloid maturation resulting in increased myeloid cell mass (Quintás-Cardama and Cortes, 2006).
+This test removes a small amount of bone filled with marrow to confirm blood test findings. In CML, the bone marrow is hypercellular with evidence of myeloid hyperplasia (Sessions, 2007). The primary biologic defect is not the unregulated proliferation of leukemic stem cells, but rather a slight delay in myeloid maturation resulting in increased myeloid cell mass (Quintás-Cardama and Cortes, 2006).
 === Cytogenetics (karyotyping) ===
 This test is performed on a bone marrow biopsy. Cells are cultured for 1-3 days, allowing the chromosomes to be condensed and enter into the metaphase state (Sessions, 2007). At this point, cells are stained in order to identify the sizes and patterns of the chromosome bands. The sizes and patterns of the bands allow the identification of chromosomal abnormalities such as translocations, amplifications, and deletions ((Sessions, 2007).
-The Ph chromosome is identified as a result of the translocation of chromosome 9 at band q34.1 that transposes the 3’ segment of the ABL1 gene to the 5’ segment of the BCR gene on chromosome 22 at band q11.21(Quintás-Cardama and Cortes, 2006). The Ph chromosome is detected in 95% of patients with CML, and is therefore required for a conclusive diagnosis of CML ((Quintás-Cardama and Cortes, 2006).
+The Ph chromosome is identified as a result of the translocation of chromosome 9 at band q34.1 that transposes the 3’ segment of the ABL1 gene to the 5’ segment of the BCR gene on chromosome 22 at band q11.21(Quintás-Cardama and Cortes, 2006). The Ph chromosome is detected in 95% of patients with CML and is therefore required for a conclusive diagnosis of CML ((Quintás-Cardama and Cortes, 2006).
-{{:screen_shot_2017-11-16_at_11.30.26_am.png?300|}}
+{{:karyotype.gif?300|}}
-**Figure x** : Fluorescent in situ hybridization (FISH) showing the fusion of BCR-ABL.
+**Figure 6** : Karyotype showing the translocation of genetic material to produce the Ph chromosome.
 ====== Molecular Pathogenesis of Chronic Myeloid Leukemia ======
-<box 35% round right | > {{ ::screen_shot_2017-11-10_at_8.57.39_am.png?410 |}} </box| Figure X: 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, Chronic Myeloid Leukmemia (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" ====
 == Normal Physiology of BCR Gene ==
-The normal cellular BCR gene, found on chromosome 22, encodes a 160,000 dalton phosphoprotein associated with serine/threonine kinase activity (Maru & Witte, 1991). This kinase activity enables BCR to phosphorylate proteins containing the amino acids serine and threonine (Maru & Witte, 1991). Furthermore, studies show that the BCR protein activates GTPases such as RAC1, which is involved in cell growth/proliferation, and CDC42, which is invovled in cell signaling and cell cycle progression (Genetics Home Reference 2017; GeneCards, 2017).
+The normal cellular BCR gene, found on chromosome 22, encodes a 160,000 dalton phosphoprotein associated with serine/threonine kinase activity (Maru & Witte, 1991). This kinase activity enables BCR to phosphorylate proteins containing the amino acids serine and threonine (Maru & Witte, 1991). Furthermore, studies show that the BCR protein activates GTPases such as RAC1, which is involved in cell growth/proliferation, and CDC42, which is involved in cell signaling and cell cycle progression (Genetics Home Reference 2017; GeneCards, 2017).
 == Normal Physiology of ABL Gene ==
@@ Line 102: / Line 107: @@
 {{::cdr533336-750.jpg?475|}}
-**Figure X:** The reciprocal translocation between chromosome 9 and 22, a hallmark of CML, generating the Philadelphia Chromosome BCR-ABL.
+**Figure 8:** The reciprocal translocation between chromosome 9 and 22, a hallmark of CML, generating the Philadelphia Chromosome BCR-ABL.
 ==== Mechanism of Action of the BCR-ABL Fusion Kinase ====
 In vitro analysis has shown that BCR-ABL expression transforms lineage committed HSCs to growth factor independence (Smith, Burthem, & Whetton, 2003). Several downstream signaling pathways are influenced by the fusion of BCR-ABL. The kinase activity of the BCR-ABL oncogene appears to be important in the pathogenesis of CML (Sattler & Salgia, 1997). Of the several signaling pathways activated by BCR-ABL, which include the Ras-Raf-ERK, JAK-STAT, PI3K, JNK/SAPK, NF-κB and c-Myc pathways, the JAK-STAT pathway appears to play a critical role in the maintenance of CML (Fabbro, 2012).
@@ Line 108: / Line 113: @@
 **Normal physiology of JAK-STAT pathway**
-In normal hematopoietic stem cells, cytokines (such as Epo or IL-3) bind to target cytokine receptors and lead to the activation the JAK-STAT pathway (Darnell, Kerr, and Stark, 1994; Fabbro, 2012). Cytokines receptors are dimers, which are normally embedded in a cell membrane, with intracellular and extracellular components. Several cytokines will bind to the extracellular components, while JAK2 (Janus Kinase) is embedded in the intracellular components of these receptors (Schindler, Levy, and Decker, 2007). Binding of cytokines to its receptors result in the auto-phosphorylation of two JAK2 kinases being brought in close proximity to each other. As a result, activated JAK2 kinases phosphorylate tyrosine on the cytokine receptors, creating docking sites for STAT5 proteins (Darnell, Kerr, and Stark, 1994).  STAT5 (Signal Transducer and Activator of Transcription) proteins are always present in the cytoplasm, waiting to be phosphorylated by JAK2 kinases (Schindler, Levy, & Decker, 2007). Once phosphorylated, the two STAT5 transcription factors dissociate from the receptor and create a STAT5 dimer (Darnell, Kerr, and Stark, 1994). The resulting dimer is an active transcription factor, and is able to travel to the nucleus of a cell and activate transcription of target genes (Darnell, Kerr, and Stark, 1994).
+In normal hematopoietic stem cells, cytokines (such as Epo or IL-3) bind to target cytokine receptors and lead to the activation the JAK-STAT pathway (Darnell, Kerr, and Stark, 1994; Fabbro, 2012). Cytokines receptors are dimers, which are normally embedded in a cell membrane, with intracellular and extracellular components. Several cytokines will bind to the extracellular components, while JAK2 (Janus Kinase) is embedded in the intracellular components of these receptors (Schindler, Levy, and Decker, 2007). Binding of cytokines to its receptors results in the auto-phosphorylation of two JAK2 kinases being brought in close proximity to each other. As a result, activated JAK2 kinases phosphorylate tyrosine on the cytokine receptors, creating docking sites for STAT5 proteins (Darnell, Kerr, and Stark, 1994).  STAT5 (Signal Transducer and Activator of Transcription) proteins are always present in the cytoplasm, waiting to be phosphorylated by JAK2 kinases (Schindler, Levy, & Decker, 2007). Once phosphorylated, the two STAT5 transcription factors dissociate from the receptor and create a STAT5 dimer (Darnell, Kerr, and Stark, 1994). The resulting dimer is an active transcription factor and is able to travel to the nucleus of a cell and activate transcription of target genes (Darnell, Kerr, and Stark, 1994).
 **JAK-STAT pathway influenced by BCR-ABL **
-However, in CML patients, the fusion of BCR-ABL results in a constitutively activated intracellular tyrosine kinase which phosphorylates the STAT5 transcription factor independent of JAK kinase activation (Fernandez-Luna, 2000; Steelman et al., 2004; Fabbro, 2012). This oncogenic pathway differs from the normal pathway in several ways. First, the phosphorylation cascade is independent of cytokine binding. Second, BCR-ABL constitutively activates STAT5 transcription factors, independent of JAK kinase activity (Steelman et al., 2004). As a result, STAT5 dimers will continuously activate transcription of genes responsible for increased proliferation of HSCs and decreased apoptosis of HSCs (Steelman et al., 2004). Therefore, this pathway maintains CML as it gives rise to a high number of immature myelogenous cells that are unable to differentiate properly (Fernandez-Luna, 2000; Steelman et al., 2004; Fabbro, 2012).
+However, in CML patients, the fusion of BCR-ABL results in a constitutively activated intracellular tyrosine kinase which phosphorylates the STAT5 transcription factor independent of JAK kinase activation (Fernandez-Luna, 2000; Steelman et al., 2004; Fabbro, 2012). This oncogenic pathway differs from the normal pathway in several ways. First, the phosphorylation cascade is independent of cytokine binding. Second, BCR-ABL constitutively activates STAT5 transcription factors, independent of JAK kinase activity (Steelman et al., 2004). As a result, STAT5 dimers will continuously activate transcription of genes responsible for the increased proliferation of HSCs and decreased apoptosis of HSCs (Steelman et al., 2004). Therefore, this pathway maintains CML as it gives rise to a high number of immature myelogenous cells that are unable to differentiate properly (Fernandez-Luna, 2000; Steelman et al., 2004; Fabbro, 2012).
 {{::screen_shot_2017-11-14_at_9.03.56_am.png?600|}}
-**Figure X:**
+**Figure 9**: Normal JAK-STAT pathway versus JAK-STAT pathway of a CML patient, influenced by BCR-ABL.
 ====== Treatment ======
@@ Line 122: / Line 127: @@
 ===Gleevac (Imatinib)====
-<box 27% round right | > {{ :gleevac_chart.png?300 |}} </box| Figure X: >
+<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 chronic myeloid leukaemia (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 signalling 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===
-<box 26% round right | > {{ :gleevac_dasatinib.png?300 |}} </box| Figure X: >
+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 >
-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.
 ===Hydrea (Hydroxyurea)===
-Traditional chemotherapeutics can still be used once TKI’s (Tyrosine Kinase Inhibitors) have stopped working. Hydroxyurea is taken orally in pill form with managable side effects. The mechanism acts via inhibition of the enzyme ribonucleotide reductase. This enzyme is required to convert ribonucleoside diphosphates into deoxyribonucleoside diphosphates, disrupting the DNA replication process of dividing cancer cells in the body. Thereby preventing cells from leaving the G1/S phase of the cell cycle halting the cell cycle and triggering apoptosis of cancerous cells. (Koç A, Wheeler LJ, Mathews CK, Merrill GF 2004). It can bring the white blood cell count down back to normal levels and can prolong the life of CML patients.
+Traditional chemotherapeutics can still be used once TKI’s (Tyrosine Kinase Inhibitors) have stopped working. Hydroxyurea is taken orally in pill form with manageable side effects. The mechanism acts via inhibition of the enzyme ribonucleotide reductase. This enzyme is required to convert ribonucleoside diphosphates into deoxyribonucleoside diphosphates, disrupting the DNA replication process of dividing cancer cells in the body. Thereby preventing cells from leaving the G1/S phase of the cell cycle halting the cell cycle and triggering apoptosis of cancerous cells. (Koç A, Wheeler LJ, Mathews CK, Merrill GF 2004). It can bring the white blood cell count down back to normal levels and can prolong the life of CML patients.
 ===Synribo (Omacetaxine Mepesuccinate)===
-Used as treatment for patients who become resistance to or build up tolerance to TKIs. It is a protien translation inhibitor, inhibiting protien translation by preventing the initial elongation step of protien synthesis. It specifically interacts with the ribosomal A-site and prevents the correct positioning of AA side chains of incoming aminoacyl-tRNAs. At the molecular level omacetaxine mepesuccinate reduces levels of the Bcr-Abl oncoprotein expression (responsible for the rapid pathogenisis of cancerous lymphocytes) and the Mcl-1 anti-apopotosis oncoprotien (prevents apopotosis). Effective as it directly interferes with the production of the oncoprotiens allowing the abnormal lymphocytes to proliferate uncontrollably. (Cortes et al., 2012)
+Synribo is used as a treatment for patients who become resistant to or build up a tolerance to TKIs. It is a protein translation inhibitor, inhibiting protein translation by preventing the initial elongation step of protein synthesis. It specifically interacts with the ribosomal A-site and prevents the correct positioning of AA side chains of incoming aminoacyl-tRNAs. At the molecular level omacetaxine mepesuccinate reduces levels of the Bcr-Abl oncoprotein expression (responsible for the rapid pathogenesis of cancerous lymphocytes) and the Mcl-1 anti-apoptosis oncoprotein (prevents apoptosis). Synribo is effective as it directly interferes with the production of the oncoproteins allowing the abnormal lymphocytes to proliferate uncontrollably (Cortes et al., 2012).
+Synribo is administered in liquid form subcutaneously, a standard treatment plan involes an  initial dosage followed by maintenance dosing. Initial dosage includes 1.25 mg/m2 administered subcutaneously twice daily for 14 consecutive days every 28 days, over a 28-day cycle. Cycles should be repeated every 28 days until patients achieve a hematologic response (no further increase in WBC). Upon achieving a hematologic response maintenance dosing involves 1.25 mg/m2 administered subcutaneously twice daily for 7 consecutive days every 28 days, over a 28-day cycle. Treatment with synribo should continue as long as patients are hematologically benefitting from therapy.
+====== Future Research ======
+**Lonafarnib**
+A potential emerging chemotherapeutic has demonstrated significant preclinical success. Lonafarnib is a type of farensyl transferase inhibitor (FTI), which target the farensyltransferase (FTase)enzyme. FTase are responsible for the post-translational attachment of prenyl groups to proteins. One of the targets of FTase include the cyseine residue on the Ras protien. The Ras protein is a G protein (dependent on GTP binding for function) that relays a growth signal from a growth factor receptor on the plasma membrane of cells which triggers an internal cascasde leading to protein kinase activation ultimately mobilizing cell proliferation proteins. FTIs such as Lonafarnib are able to block this post-translational modification to the Ras protein and thereby attenuate this cell-proliferation response.
+A study published in the American Cancer Society launched a pilot clinical study with lonafarnib in patients in the chronic and accelerated stages of CML who were resistant to imatinib therapy. The small sample size of 13 patients were treated with lonafarnib at a dose of 200mg orally twice daily. Average treatment plan with lonafarnib lasted for about 8 weeks (ranging from 2-41 weeks). (Borthakur et al., 2005)
+Out of this small pilot study 2 patients responded. A patient in the accelerated phase returned to the chronic phase (a response which lasted for 3 months) and another patient in the chronic phase, had a lowering of the leukocyte count without the need for hydroxyurea. Overall limited success has been seen with lonafarnib on its own in this small sample size study, currently the possiblity of combination therapy with imatinib is being investigated. Results still remain inconclusive. (Borthakur et al., 2005)
@@ Line 147: / Line 163: @@
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+Borthakur, G., Kantarjian, H., Daley, G., Talpaz, M., O'Brien, S., Garcia‐Manero, G., . . . Cortes, J. (2005, December 08). Pilot study of lonafarnib, a farnesyl transferase inhibitor, in patients with chronic myeloid leukemia in the chronic or accelerated phase that is resistant or refractory to imatinib therapy. Retrieved November 21, 2017, from http://onlinelibrary.wiley.com/doi/10.1002/cncr.21590/full
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+Cortes, J., Lipton, J. H., Rea, D., Digumarti, R., Chuah, C., Nanda N, et al. (2012) On behalf of the Omacetaxine 202 Study Group Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood, 120(13), 2573-2580.
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+Daley, G. Q., Van Etten, R. A., Baltimore, D. (1990). Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science, 247 (1990), 824-830.
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+Darnell Jr, J. E., Kerr, I. M., & Stark, G. R. (1994). Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science-AAAS-weekly paper edition-including guide to scientific information, 264(5164), 1415-1420.
 Druker, B. J. (2008). Translation of the Philadelphia chromosome into therapy for CML. Blood, 112(13), 4808–4817. https://doi.org/10.1182/blood-2008-07-077958
+Druker, B. J., François, G., O’Brien, S. G., Gathmann, I., Kantarjian, H., Gattermann, N., et al. (2006). Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia. New England Journal of Medicine, 355(23), 2408–17. https://doi.org/10.1056/NEJMoa062867.
+Druker, B. J., Lydon, N. B. (2000) Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. Journal of Clinical Investigation, 105, 3-7.
+Druker, B. J., Talpaz, M., Resta, D. J., Peng, B., Buchdunger, E., Ford, J. M., et al. (2001). Efficacy and Safety of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia. The New England Journal of Medicine, 344(14), 1031–37. https://doi.org/10.1056/NEJM200104053441401.
 Fabbro, D. (2012). BCR-ABL signaling: A new STATus in CML. Nature Chemical Biology, 8(3), nchembio.900. https://doi.org/10.1038/nchembio.900
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+Hoglund, M., Sandin, F., & Simonsson, B. (2015). Epidemiology of chronic myeloid leukaemia: an update. Ann Hematol, 94(Suppl 2): S241–S247. doi:10.1007/s00277-015-2314-2
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-Koç A, Wheeler LJ, Mathews CK, Merrill GF (January 2004). "Hydroxyurea arrests DNA replication by a mechanism that preserves basal dNTP pools". J. Biol. Chem. 279 (1)
+Zech, N. H., Shkumatov, A., & Koestenbauer, S. (2007). The magic behind stem cells. Journal of Assisted Reproduction and Genetics, 24(6), 208-214.
-Cortes J, Lipton JH, Rea D, Digumarti R, Chuah C, Nanda N, Benichou AC, Craig AR, Michallet M, Nicolini FE, Kantarjian H; on behalf of the Omacetaxine 202 Study Group Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood 2012 Sep 27;120(13):2573-2580

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