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

Increased understanding of the cellular mechanisms associated with various malignancies has allowed researchers to develop agents that selectively target the cellular proteins and pathways implicated in the pathogenesis of malignancy. Tipifarnib is a specific and potent farnesyltransferase inhibitor that demonstrates in vivo and in vitro activity against a variety of human cancers. Although tipifarnib was initially thought to target the Ras protein, recent evidence suggests that the presence of ras mutations is not necessary for the antitumor effects of tipifarnib, and that tipifarnib may exert its effects downstream of Ras. The oral administration and favorable toxicity profile of tipifarnib, combined with its activity in a variety of intracellular pathways that have been implicated in the pathogenesis of hematologic malignancies, make it an especially attractive agent for use in patients with acute myeloid leukemia (AML), myelodysplastic syndromes, chronic myelogenous leukemia (CML), and multiple myeloma. Because hematologic malignancies are likely driven by multiple genetic aberrations, the most effective treatment strategy will likely combine multiple agents with complementary mechanisms of action. Thus, additional studies of combination regimens that incorporate tipifarnib with other antineoplastic agents are crucial. Early results from studies combining tipifarnib with imatinib or etoposide in CML and AML have been promising and warrant further evaluation in larger clinical trials.
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PMID:Farnesyltransferase inhibition in hematologic malignancies: the clinical experience with tipifarnib. 1849 98

RASSF1A, a key cell cycle related gene, is expressed in all hematopoietic cells, it is implicated in ras signaling pathway and its promoter hypermethylation is observed in a wide variety of solid tumors. Till now, RASSF1A methylation status has not been investigated in patients with chronic myeloid leukemia (CML). In this study, we analyzed 41 patients carrying the BCR-ABL rearrangement, in different stages of the disease. No patient displayed RASSF1A promoter methylation, although the K562 erythroleukemia cell line, bearing the BCR-ABL rearrangement, was found methylated. Thus, our findings indicate that RASSF1A methylation does not appear to represent a critical step in the pathogenesis and/or the progression of CML.
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PMID:Methylation status of RASSF1A in patients with chronic myeloid leukemia. 1919 34

Bcr-abl signals for leukemogenesis of chronic myeloid leukemia (CML) and activates ras. Since the function of promyelocytic leukemia protein (pml) is provoked by ras to promote apoptosis and senescence in untransformed cells, the function is probably masked in CML. Imatinib specifically inhibits bcr-abl and induces apoptosis of CML cells. As reported previously, p53(wild) CML was more resistant to imatinib than that lacking p53. Here, we searched for an imatinib-induced p53 independent proapoptotic mechanism. We found imatinib up-regulated phosphorylation of p38 mitogen-activated protein kinase (MAPK), checkpoint kinase 2 (chk2) and transactivation-competent (TA) p73; expression of pml and bax; formation of PML-nuclear body (NB); and co-localization of TAp73/PML-NB in p53-nonfunctioning K562 and p53(mutant) Meg-01 CML cells, but not in BCR-ABL(-) HL60 cells. In K562 cells, with short interfering RNAs (siRNAs), knockdown of pml led to dephosphorylation of TAp73. Knockdown of either pml or TAp73 abolished the imatinib-induced apoptosis. Inhibition of p38 MAPK with SB203580 led to dephosphorylation of TAp73, abolishment of TAp73/PML-NB co-localization, and the subsequent apoptosis. Conversely, interferon alpha-2a (IFNalpha), which increased phosphrylated TAp73 and TAp73/PML-NB co-localization, increased additively apoptosis with imatinib. The imatinib-induced TAp73/PML-NB co-localization was accompanied by co-immpunoprecipitation of TAp73 with pml. The imatinib-induced co-localization was also found in primary CML cells from 3 of 6 patients, including 2 with p53(mutant) and one with p53(wild). A novel p53-independent proapoptotic mechanism using p38 MAPK /pml/TAp73 axis with a step processing at PML-NB and probably with chk2 and bax being involved is hereby evident in some imatinib-treated CML cells.
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PMID:Pml and TAp73 interacting at nuclear body mediate imatinib-induced p53-independent apoptosis of chronic myeloid leukemia cells. 1929 93

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that functions as a key regulator of cell growth, protein synthesis, and cell-cycle progression through interactions with a number of signalling pathways, including PI3K/AKT, ras, TCL1, and BCR/ABL. Many haematological malignancies have aberrant activation of the mTOR and related signalling pathways. Accordingly, mTOR inhibitors, a class of signal transduction inhibitors that were originally developed as immunosuppressive agents, are being investigated in preclinical models and clinical trials for a number of haematological malignancies. Sirolimus and second-generation mTOR inhibitors, such as temsirolimus and everolimus, are safe and relatively well-tolerated, making them potentially attractive as single agents or in combination with conventional cytotoxics and other targeted therapies. Promising early clinical data suggests activity of mTOR inhibitors in a number of haematological diseases, including acute lymphoblastic leukaemia, chronic myeloid leukaemia, mantle cell lymphoma, anaplastic large cell lymphoma, and lymphoproliferative disorders. This review describes the rationale for using mTOR inhibitors in a variety of haematological diseases with a focus on their use in leukaemia.
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PMID:Mammalian target of rapamycin inhibitors and their potential role in therapy in leukaemia and other haematological malignancies. 1934 92

We attempted to detect the bcr-abl fusion gene and ras gene family in CML by the in vitro focus forming assay and the tumorigenicity assay. Eight of 14 chronic phase and both of two blastic phase cases showed transforming activity in the tumorigenicity assay. However, only one chronic phase sample was positive in the in vitro focus forming assay. Among these 10 transformants, we found N-ras activation in one chronic phase, and K-ras activation in another chronic phase case. The bcr-abl fusion gene was activated in one chronic phase and all of the blastic phase cases by the tumorigenicity assay. The present result showed that the bcr-abl fusion gene transfected N1H3T3 cells formed tumors in nude mice in contrast to the in vitro focus forming assay. The bcr-abl fusion gene may play important roles in the progression as well as the pathogenesis of CML.
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PMID:Activation of bcr-abl fusion gene and ras oncogenes in chronic myelogenous leukemia. 2126 77

Mutations that activate ras genes were demonstrated to be associated with certain types of malignancies. Multiple point mutations were predominantly found in the N-ras and occasionally in the K-ras genes. The analysis of 4 MDS, 23 AML and 11 CML patients from Yugoslavia revealed the prevalence of the N-ras mutation (83%) over K-ras mutations (17%). Although the frequencies of the N- and K-ras mutations in these patients were similar to the ones reported for patients from USA and Japan, the N-ras mutational spectra considerably differed. The prevailing type of mutation in patients from Yugoslavia was G-to-T transversion at the first position in the codon 12 of the N-ras gene. This study supports a hypothesis that different geographical and environmental factors may cause the accumulation of different type of point mutations in the same target gene.
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PMID:Distinct spectrum of N-ras mutations in aml and mds patients in yugoslavia. 2160 14

Chronic myelogenous leukemia (CML) results from the transformation of a primitive hematopoietic cell by the bcr-abl gene. RalA, one of the Ras superfamily of small GTPases, is a downstream molecule of bcr-abl fusion protein in ras signaling pathway, but its role in CML is poorly understood. Here, we first detected RalA level in CML cells, which is highly expressed and distributed mainly in the cytoplasm and/or partially in endomembrane. Next, siRNA was used to deplete RalA expression for elucidating its function. The results showed that siRNA RalA effectively inhibited cell viability, induced apoptosis and enhanced sensitivity of arsenic trioxide (ATO), and there are some synergistic effects of anti-CML between RalA siRNA and ATO. Finally, we found that ATO also could downregulate protein level of bcr-abl in K562 and KCL-22. Our research provides evidence that RalA might also serve as linchpin modulators in leukemia, and combinatorial therapies of dual inhibition of bcr-abl and ras signaling pathways have a great potential in treatment of CML.
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PMID:Inhibition of small GTPase RalA regulates growth and arsenic-induced apoptosis in chronic myeloid leukemia (CML) cells. 2233 69

MicroRNAs (miRNAs) are a class of short RNAs that regulate gene expression through either translational repression or mRNA cleavage. miRNA-181a (miR-181a), one of the many miRNAs conserved among vertebrates, is differentially expressed in a variety of leukemia. However, its function in leukemia, particularly chronic myelogenous leukemia (CML), is poorly understood. Here we have reported the identification of miR-181a targets by combining TargetScan software prediction and expression profiling through overexpression of miR-181a mimic in leukemic K562 cells. Four overlapping genes were found to be the likely targets of miR-181a. Among the four genes, RalA is a downstream molecule of bcr-abl fusion protein in ras signaling pathway. However, its role in CML remains elusive. Luciferase reporter and Western blot assays confirmed that RalA is a direct target of miR-181a. overexpression of miR-181a effectively suppresses cell growth and induces G2-phase arrest and apoptosis partially by targeting RalA in leukemic K562 cells. Using the KEGG database combined with recent publications, downstream signaling pathway of RalA was graphed by cytoscape software. Therefore, our study is the first to report that RalA is directly regulated by miR-181a and plays an important role in CML. The approach of computational prediction combined with expression profiling might be valuable for the identification of miRNA targets in animal.
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PMID:miR-181a post-transcriptionally downregulates oncogenic RalA and contributes to growth inhibition and apoptosis in chronic myelogenous leukemia (CML). 2244 71

Success of imatinib in chronic myeloid leukemia (CML) therapy has undoubtedly proved utility of signalling molecules as therapeutic targets. However, development of imatinib resistance and progression to blastic crisis are the current challenges in clinics. To develop therapeutic alternatives for CML, understanding of signalling events downstream of bcr-abl might be helpful. Current CML cell lines do not give comprehensive picture of signalling events involved in pathogenesis of CML. Hence, there is a major unmet need for a better preclinical model for CML. Here, we report on development of RIN9815/bcr-abl, a novel cell line model that mimics signalling events in CML PMNL. Studies on crucial signalling molecules i.e., ras, rac, rhoA and actin in this cell line identified rhoA as the key regulator involved in CML cell function as well as proliferation of both, imatinib sensitive and resistant cells. Hence, RIN9815/bcr-abl could serve as the unique preclinical model in understanding pathogenesis of CML and in drug development.
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PMID:Preclinical model for identification of therapeutic targets for CML offers clues for handling imatinib resistance. 2621 98


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