Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic myelogenous leukemia (CML) results from the transformation of a primitive hematopoietic cell by the BCR/ABL gene. BCR/ABL signaling has been studied in cell lines and murine models, but the transforming effects of BCR/ABL are highly dependent on cellular context, and mechanisms responsible for the transformation of primitive human hematopoietic cells remain poorly understood. Current targeted therapies fail to eliminate malignant CML progenitors, and improved understanding of crucial molecular mechanisms of progenitor transformation may facilitate the development of improved therapeutic approaches. We investigated the role of BCR/ABL tyrosine 177 (BCR/ABL-Y177) in CML progenitor transformation by comparing the effects of expression of Y177-mutated BCR/ABL, wild-type BCR/ABL, or green fluorescent protein alone on normal CD34(+) cells. We show that BCR/ABL-Y177 plays a critical role in CML progenitor expansion, proliferation, and survival. BCR/ABL expression results in enhanced Ras and Akt activity but reduced mitogen-activated protein kinase activity in human hematopoietic cells, which is reversed by BCR/ABL-Y177 mutation. Blocking BCR/ABL-Y177-mediated signaling enhances targeting of CML progenitors by imatinib mesylate. Our studies indicate that BCR/ABL-Y177 plays an essential role in Ras and Akt activation and in human hematopoietic progenitor transformation in CML.
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PMID:BCR-tyrosine 177 plays an essential role in Ras and Akt activation and in human hematopoietic progenitor transformation in chronic myelogenous leukemia. 1763 18

Activation of p38 MAPK is a critical requisite for the therapeutics activity of the antitumor agent cisplatin. In this sense, a growing body of evidences supports the role of c-Abl as a major determinant of p38 MAPK activation, especially in response to genotoxic stress when triggered by cisplatin. Here, we demonstrate that p38 MAPK activation in response to cisplatin does not require the tyrosine kinase activity of c-Abl. Indeed, c-Abl can activate the p38 MAPK signaling pathway by a mechanism that is independent of its tyrosine kinase activity, but that instead involves the ability of c-Abl to increase the stability of MKK6. Similar results were obtained in chronic myeloid leukemia-derived cell lines, in which a chimeric Bcr/Abl protein mimics the effects of c-Abl overexpression on p38 MAPK activation. These findings may explain why a clinically used c-Abl inhibitor, imatinib mesylate, fails to inhibit the p38 MAPK pathway alone or in combination with cisplatin, and provide evidence of a novel signaling mechanism in which these antitumor agents act.
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PMID:c-Abl activates p38 MAPK independently of its tyrosine kinase activity: Implications in cisplatin-based therapy. 1789 73

Over-expression of two members of MAP kinase family (JNK2 and p38) has been already observed in chronic myeloid leukemia (CML). In the present study, significance of this deregulation was investigated. Impacts of JNK2/p38 suppression on gene expression profile of CML cell lines (K562/KU-812) were studied using an experimental approach that combines siRNA-mediated specific inhibition of the genes and array-based expression analyses. After JNK2 depletion, 27 out of 588 tested genes showed significant expression changes, with 13 down-regulated genes and 14 up-regulated genes. Among others, expression of MSH2 and MSH6, mdm2, and caspase-2 was reduced and, on the other hand, MKK1 and MKK6, RFC2, cytokeratins K18 and K19, BAD, and DR5 expression was up-regulated. In the case of p38 silencing, 20 genes were considered as significantly deregulated (7 genes reduced, 13 over-expressed). These genes included caspase-10, SOD1, and Notch4 (down-regulation) and caspase-2 and caspase-3, CDC2, CDK4, and c-kit (up-regulation). In conclusion, comparison of expression profiles after JNK2 or p38 gene silencing revealed distinct sets of affected genes. The results implied an unequal impact of the MAPK deregulation on the CML cells. Further, we demonstrated that neither JNK2 nor p38 siRNAmediated inhibition led to significant change of CML cell proliferation. It suggests that there are other important, likely upstream regulators essential for CML malignant cell growth/transformation; therefore, separate inhibition of JNK2 or p38 MAPK gene is not sufficient for a proliferation arrest.
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PMID:JNK2 and p38 MAPK over-expressions do not represent key events in chronic myeloid leukemia transformation. 1794 34

CML (chronic myeloid leukaemia) is a myeloproliferative disease that originates in an HSC (haemopoietic stem cell) as a result of the t(9;22) translocation, giving rise to the Ph (Philadelphia chromosome) and bcr-abl oncoprotein. The disease starts in CP (chronic phase), but as a result of genomic instability, it progresses over time to accelerated phase and then to BC (blast crisis), becoming increasingly resistant to therapy. bcr-abl is a constitutively active tyrosine kinase that has been targeted by TKIs (tyrosine kinase inhibitors), including IM (imatinib mesylate), nilotinib and dasatinib. We have developed various flow cytometry techniques to enable us to isolate candidate CML stem cells from CP patients at diagnosis that efflux Hoechst dye, express CD34, lack CD38 and are cytokine-non-responsive in culture over periods of up to 12 days in growth factors. These stem cells have been shown to regenerate bcr-abl-positive haemopoiesis in immunocompromised mice upon transplantation. We previously demonstrated that IM was antiproliferative for CML stem cells but did not induce apoptosis. Clinical experience now confirms that IM may not target CML stem cells in vivo with few patients achieving complete molecular remission and relapse occurring rapidly upon drug withdrawal. Our recent efforts have focused on understanding why CML stem cells are resistant to IM and on trying to find novel ways to induce apoptosis of this population. We have shown that CML stem cells express very high levels of functional wild-type bcr-abl; no kinase domain mutations have been detected in the stem cell population. Dasatinib, a more potent multitargeted TKI than IM, inhibits bcr-abl activity more efficiently than IM but still does not induce apoptosis of the stem cell population. Most recently, we have tested a number of novel drug combinations and found that FTIs (farnesyl transferase inhibitors) have activity against CML. BMS-214662 is the most effective of these and induces apoptosis of phenotypically and functionally defined CML stem cells in vitro, as a single agent and in combination with IM or dasatinib. The effect against CML stem cells is selective with little effect on normal stem cells. The drug is also effective against BC CML stem cells and equally effective against wild-type and mutant bcr-abl, including the most resistant mutant T315I. In association with apoptosis, there is activation of caspase 8 and caspase 3, inhibition of the MAPK pathway, IAP-1 (inhibitor of apoptosis protein-1), NF-kappaB (nuclear factor kappaB) and iNOS (inducible nitric oxide synthase). Furthermore, BMS-214662 synergizes with MEK1/2 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 1/2] inhibitors, suggesting a second mechanism other that RAS inhibition for induction of apoptosis. Our intentions are now to explore the activity of BMS-214662 in other cancer stem cell disorders and to move this preclinical work to a clinical trial combining dasatinib with BMS-214662 in CML.
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PMID:Characterization of cancer stem cells in chronic myeloid leukaemia. 1795 48

Imatinib mesylate (imatinib) is highly effective in the treatment of chronic myeloid leukemia (CML) but is less effective in eliminating CML stem cells. We investigated whether SKI-606, a potent Bcr-Abl and Src kinase inhibitor without anti-PDGF or c-Kit activity, could effectively target primitive CML progenitors. CML and normal progenitors were cultured with SKI-606 or imatinib. SKI-606 effectively inhibited Bcr-Abl kinase activity in CML CD34(+) cells and inhibited Src phosphorylation more potently than imatinib. However, SKI-606 and imatinib resulted in similar suppression of CML primitive and committed progenitor proliferation and growth in CFC and LTC-IC assays. Exposure to either agent alone or in combination resulted in only modest increase in apoptosis. Evaluation of downstream signaling pathways indicated that Akt and STAT5 activity was not changed, but a delayed increase in MAPK activity was seen at high concentrations of SKI-606. SKI-606 inhibited normal progenitor proliferation to a lesser extent than imatinib. SKI-606 effectively inhibits Bcr-Abl and Src kinase activity and inhibits CML progenitor growth with relatively little effect on normal progenitors. However, SKI-606 does not demonstrate increased ability to eliminate primitive CML progenitors by apoptosis compared with imatinib, emphasizing the need for additional strategies besides Bcr-Abl kinase inhibition for curative therapy of CML.
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PMID:Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual Src/Abl kinase inhibitor SKI-606. 1805 43

Targeting kinases is central to drug-based cancer therapy but remains challenging because the drugs often lack specificity, which may cause toxic side effects. Modulating side effects is difficult because kinases are evolutionarily and hence structurally related. The lack of specificity of the anticancer drug imatinib enables it to be used to treat chronic myeloid leukemia, where its target is the Bcr-Abl kinase, as well as a proportion of gastrointestinal stromal tumors (GISTs), where its target is the C-Kit kinase. However, imatinib also has cardiotoxic effects traceable to its impact on the C-Abl kinase. Motivated by this finding, we made a modification to imatinib that hampers Bcr-Abl inhibition; refocuses the impact on the C-Kit kinase; and promotes inhibition of an additional target, JNK, a change that is required to reinforce prevention of cardiotoxicity. We established the molecular blueprint for target discrimination in vitro using spectrophotometric and colorimetric assays and through a phage-displayed kinase screening library. We demonstrated controlled inhibitory impact on C-Kit kinase in human cell lines and established the therapeutic impact of the engineered compound in a novel GIST mouse model, revealing a marked reduction of cardiotoxicity. These findings identify the reengineered imatinib as an agent to treat GISTs with curbed side effects and reveal a bottom-up approach to control drug specificity.
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PMID:An anticancer C-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic. 1806 25

The therapeutic success of imatinib in chronic myeloid leukemia (CML) is hampered by persistence of malignant stem cells. We investigated whether nilotinib, a more potent BCR-ABL kinase inhibitor could target CML primitive progenitors more effectively than imatinib. CML and normal progenitor cells were cultured with nilotinib or imatinib in growth factor supplemented medium. Nilotinib inhibited BCR-ABL kinase activity at lower concentrations than imatinib. Nilotinib inhibited mitogen-activated protein kinase (MAPK), AKT and STAT5 phosphorylation in CML CD34(+) cells in the absence of growth factors (GFs), but did not suppress AKT and STAT5 activity, and resulted in increased MAPK activity, in the presence of GFs. Nilotinib and imatinib resulted in similar suppression of CML primitive and committed progenitors in long-term culture-initiating cell and colony-forming cell assays. Inhibition of progenitor growth was related to marked reduction in proliferation, but only a modest increase in apoptosis. Nilotinib did not show increased efficacy in reducing nondividing CML progenitors compared with imatinib. These results indicate that more potent tyrosine kinase inhibitors by themselves will not be more effective in eliminating CML progenitors than imatinib and that additional mechanism required for maintenance of malignant stem cells need to be identified to improve targeting of leukemia stem cells.
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PMID:Enhanced BCR-ABL kinase inhibition does not result in increased inhibition of downstream signaling pathways or increased growth suppression in CML progenitors. 1827 48

Imatinib mesylate (imatinib) inhibits the c-Kit-dependent tyrosine kinase activities and highly effective in the treatment of CML and GIST patients. Although pancreatic cancer is reported to express c-Kit, imatinib does not effectively inhibit pancreatic cancer cell growth at physiological concentrations. Therefore, we investigated the mechanism of resistance of pancreatic cancer to imatinib treatment. Imatinib inhibited growth of pancreatic cancer cell lines in concentration and time-dependent fashion regardless of c-Kit expression. However, 5 microM imatinib, which is almost a mean maximal plasma concentration in clinical setting, failed to suppress pancreatic cancer cell growth. Western blot analysis demonstrated that 5 microM imatinib treatment for 1h activated the MEK-MAPK pathway and the activation was independent of Ras activation. Administration of 5 microM imatinib and 1 microM U0126 (MEK inhibitor) significantly suppressed pancreatic cell growth. Our results indicate that a combination therapy of imatinib and MEK inhibitor can be a new therapeutic strategy to suppress the progression of pancreatic cancer.
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PMID:MEK inhibitor enhances the inhibitory effect of imatinib on pancreatic cancer cell growth. 1834 44

Interferon-alpha (IFN-alpha) has been used in the treatment of several cancers, including chronic myeloid leukemia. Artemisinin, a sesquiterpene lactone endoperoxide that exists in several medicinal plants, is a well known anti-malarial agent. We previously reported that artemisinin by itself caused a relatively low level of HL-60 cell differentiation. In this study, we investigated the effects of IFN-alpha in combination with artemisinin on cell growth and differentiation in HL-60 leukemia cells. Combination of IFN-alpha and artemisinin synergistically induced the levels of leukemia cell differentiation, although IFN-alpha by itself did not affect cell proliferation and differentiation. The increased cell differentiation by IFN-alpha and artemisinin was significantly suppressed by the inhibitors for protein kinase C (PKC), extracellular signal-regulated kinase (ERK) and jun N-terminal kinase (JNK), but not by the inhibitors for phosphatidylinositol 3-kinase (PI3-K) and p38 mitogen-activated protein kinase (MAPK). Furthermore, co-treatment with IFN-alpha increased levels of PKC alpha and phosphorylated ERK. Taken together, these results indicate the enhancement of artemisinin-induced HL-60 cell differentiation by IFN-alpha through the activation of a PKC alpha/ERK signaling pathway, and suggest a possible use of IFN-alpha and artemisinin in the treatment of leukemic diseases.
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PMID:Interferon-alpha enhances artemisinin-induced differentiation of HL-60 leukemia cells via a PKC alpha/ERK pathway. 1845 55

Since differentiation-induction therapy represents an attractive strategy for treatment of a wide range of malignancies, universal efforts have been devoted to find new and potent differentiation inducers devoid of general toxicities. In that respect, 3-hydrogenkwadaphnin (3-HK), a novel daphnane-type diterpene ester from Dendrostellera lessertii (Thymelaeaceae), was found to be an effective inducer of megakaryocytic differentiation in chronic myelogenous leukemia (CML) K562 cells without any adverse effects on normal cells [Moosavi, M.A., Yazdanparast, R., Sanati, M.H., Nejad, A.S., 2005. 3-Hydrogenkwadaphnin targets inosine 5'-monophosphate dehydrogenase and triggers post-G1 arrest apoptosis in human leukemia cell lines. International Journal of Biochemistry and Cell Biology 37, 2366-2379]. In this study, we found that inhibition of cellular replication and maturation, induced by the drug, are dependent upon ERK/MAPK activation. Inhibition of MEK activity by PD98059 reversed the growth arrest, decreased adhesive properties, induction of polyploidization and blocked the expression of GPIIb integrin, induced by 3-HK. Immunoblot analyses also showed that 3-HK-induced sustained activation of ERK1/2 from early exposure times, before the onset of differentiation, up to 96 h. Moreover, our results revealed that cyclin D1 and p21(Cip/WAF1) were increased during differentiation. Consequently, it is concluded that up-regulation of cyclin D1, accompanied by the persistent activation of ERK/MAPK, is involved in the megakaryocytic differentiation of K562 cells under the influence of 3-HK.
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PMID:Involvement of ERK/MAPK pathway in megakaryocytic differentiation of K562 cells induced by 3-hydrogenkwadaphnin. 1858 50


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