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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrosine kinase activity is associated with the transforming potential of several oncogenes. Human chronic myeloid leukemia (CML) cells and cell lines have been shown to contain an active bcr-c-abl p210 tyrosine kinase as a consequence of the Philadelphia chromosomal translocation. In the present work the activity of the c-abl and c-src oncogene-encoded tyrosine kinase was investigated during phorbol diester (TPA) induced differentiation of the K562 CML cells. The high tyrosine kinase activity of p210bcr-c-abl is strongly reduced during the initial 24 h of TPA treatment. In contrast, the activity of the c-src tyrosine kinase is not changed. No change occurs in the expression of the c-abl-specific RNAs during this period. Following the reduction of bcr-c-abl kinase activity, cell proliferation is arrested and megakaryoblastic antigens appear on the cells. Sodium butyrate caused a slight decrease in growth rate and of bcr-c-abl kinase activity during erythroid differentiation whereas no changes in c-src or c-abl tyrosine kinase activities were seen in DMSO-treated control cells.
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PMID:The bcr-c-abl tyrosine kinase activity is extinguished by TPA in K562 leukemia cells. 347 72

Tyrosine kinase inhibitors have drawn the most attention in recent years as molecular target agents for cancer treatment. The reason for this can only be the dramatic antitumor effects shown in early clinical trials against small cell cancer and chronic myeloid leukemia by the EGFR tyrosine kinase inhibitor, ZD1839, and the BCR-Abl tyrosine kinase inhibitor, STI-571, respectively. Various hypotheses were advanced in the preliminary stages of the clinical development of such molecular target agents: "They only prevent cancer cell proliferation and have no killer cell activity; they are extremely weak, and can not be expected to reduce tumors at the clinical level. "Or:" A long time is required before their physiological activity will be expressed in an antitumor effect." However, with non-small cell lung cancer, the most difficult tumor among solid cancers for an anticancer agent to be effective, not only was ZD1839 effective, but showed clear effectiveness in combination chemotherapy in the pretreatment stage. Moreover, the time for the expression of its tumor reduction effect was virtually the same as with conventional anticancer drugs, and its effectiveness proved to last longer after its initial expression. ZD1839 has succeeded in remaking the very image of molecular target agents for cancer treatment. In what follows, we focus mainly on the EGFR tyrosine kinase inhibitor, ZD1839.
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PMID:[Tyrosine kinase inhibitors--solid cancers]. 1138 8

Myeloid leukaemias are frequently associated with translocations and mutations of tyrosine kinase genes. The products of these oncogenes, including BCR-ABL, TEL-PDGFR, Flt3 and c-Kit, have elevated tyrosine kinase activity and transform haematopoietic cells, mainly by augmentation of proliferation and enhanced viability. Activated ABL kinases are associated with chronic myeloid leukaemia. Mutations in platelet-derived growth factor receptor beta are associated with chronic myelomonocytic leukaemia. Flt3 or c-Kit cooperate with other types of oncogenes to create fully transformed acute leukaemias. Elevated activity of these tyrosine kinases is crucial for transformation, thus making the kinase domain an ideal target for therapeutic intervention. Tyrosine kinase inhibitors for various kinases are currently being evaluated in clinical trials and are potentially useful therapeutic agents in myeloid leukaemias. Here, the authors review the signalling activities, mechanism of transformation and therapeutic targeting of several tyrosine kinase oncogenes important in myeloid leukaemias.
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PMID:Targeting mutated tyrosine kinases in the therapy of myeloid leukaemias. 1516 29

In chronic myeloid leukaemia (CML) expression of the chimeric tyrosine kinase, Bcr-Abl, promotes the inappropriate survival of haemopoietic stem cells by a nonautocrine mechanism in the absence of IL-3. Stimulation of glucose uptake appears to play an important role in the suppression of apoptosis by this cytokine in normal haemopoietic cells. To investigate whether the cell survival mechanisms mediated by the oncoprotein and cytokine showed any similarities, we employed a haemopoietic cell line, TonB210, engineered for inducible expression of Bcr-Abl. Tyrosine kinase expression in cytokine-deprived cells was found to mimic the effect of IL-3 in maintaining a higher V(max) for hexose uptake. In both IL-3- treated cells and those expressing Bcr-Abl, high rates of hexose uptake were associated with the retention at the cell surface of approximately 80% of the total cellular content of the GLUT1 glucose transporter. In contrast, treatment of Bcr-Abl-expressing cells for 6 h with the Bcr-Abl kinase inhibitor Glivec (10 muM), in the absence of IL-3, led to internalization of approximately 90% of the cell-surface transporters and drastically decreased (4.4+/-0.9 (mean+/-s.e.m., 4)-fold) the V(max) for hexose uptake, without significant effect on the K(m) for this process or on the total cellular transporter content. These effects were not the result of any significant loss in cell viability, and preceded the onset of apoptosis caused by inhibition of Bcr-Abl. Both IL-3 treatment and expression of Bcr-Abl led to enhanced phosphorylation of Akt (protein kinase B). The stimulation of transport by IL-3 and Bcr-Abl in TonB210 cells was inhibitable by phosphatidylinositol 3-kinase inhibitors, indicating the involvement of this kinase in the signal transduction pathway. These findings suggest that inhibition of glucose transport plays an important role in the therapeutic action of Glivec, and that the signal transduction pathways involved in transport stimulation by Bcr-Abl may offer novel therapeutic targets for CML.
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PMID:Chronic myeloid leukaemia: an investigation into the role of Bcr-Abl-induced abnormalities in glucose transport regulation. 1573 28

Allogeneic stem cell transplantation (HSCT) requires the harvest of an adequate number of stem cells (SC) from a histocompatible donor and their infusion into a patient following a conditioning regimen. During the past 35 years, the role of HSCT has changed from an experimental procedure for terminally ill patients to a curative treatment. In 2003, 1170 procedures were registered in Italy (Italian Group for Blood and Marrow Transplantation). The main reported indications were as follows: leukemia, lymphoproliferative diseases, myelodysplasia, and nonmalignant diseases such as thalassemia and severe aplastic anemia. Important changes have been observed in the last 5 years: the shift from bone marrow to peripheral blood as the SC source, the increasing number of alternative donors such as unrelated, partially matched family donors and cord blood SC, and the new extra-hematological indications including solid tumors. Moreover, the development of nonmyeloablative conditioning regimens have allowed physicians to perform HSCT in patients with advanced age or important comorbidities. In contrast, the availability of the Tyrosine kinase inhibitor (STI-571) for treatment of patients affected by chronic myelogenous leukemia, which was formerly the main indication for HSCT, has produced a dramatic decrease in the number of transplantations in this setting. HSCT performed in the early phases of disease and in young patients offers more than a 50% cure rate. The transplant-related mortality still represents the greatest obstacle, ranging from 20%-30%, despite the less toxic conditioning regimens, high-resolution HLA typing, and better supportive care. GvHD and infections remain the main causes of morbidity. As regards relapses, they correlate with disease status at the time of transplantation. Promising results have been recently obtained with haploidentical and with cord blood SC transplantation also in adult patients.
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PMID:Allogeneic stem cell transplantation. 1618 79

Tyrosine kinase inhibitors (TKIs) are now standard up-front therapy for chronic myeloid leukemia (CML). Patients with newly diagnosed chronic-phase CML treated with the TKI imatinib mesylate typically experience a complete cytogenetic remission. Outcomes for patients with advanced-phase disease are distinctly worse. Unfortunately, a small proportion of chronic-phase patients experience relapse during this therapy, and most with advanced-phase disease develop resistance to imatinib mesylate after months of therapy. Hematopoietic cell transplantation remains the only curative approach for CML and can salvage patients with advanced-phase disease. Therefore, physicians must carefully monitor patients with chronic-phase CML treated with TKIs so that they can undergo hematopoietic cell transplant (or treatment with another TKI or experimental therapy) before frank progression occurs. Fortunately, monitoring CML using cytogenetic and molecular methods (i.e., quantitative polymerase chain reaction) effectively defines end points that correlate highly with outcome.
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PMID:Monitoring chronic myelogenous leukemia in the age of tyrosine kinase inhibitors. 1750 53

Tyrosine kinase inhibitors have revolutionized the treatment of chronic myeloid leukemia and are increasingly used for other indications. Fluid retention, however, including pleural effusions, are a significant side effect of imatinib, the first-line treatment for chronic myeloid leukemia. We investigated pleural and pulmonary complications in patients treated with dasatinib, a novel multitargeted tyrosine kinase inhibitor, as part of clinical trial protocols. Of 40 patients who received dasatinib (70 mg twice daily) for imatinib resistance or intolerance, 9 (22.5%) developed dyspnea, cough, and chest pain. Of these nine patients, six had pleural effusions (all were exudates) and seven had lung parenchyma changes with either ground-glass or alveolar opacities and septal thickening (four patients had both pleural effusions and lung parenchyma changes). Lymphocytic accumulations were detected in pleural and bronchoalveolar lavage fluids in all patients except for one who presented with neutrophilic alveolitis. Pleural biopsies revealed lymphocytic infiltration in one patient and myeloid infiltration in another. After dasatinib interruption, lung manifestations resolved in all cases and did not recur in three of four patients when dasatinib was reintroduced at a lower dose (40 mg twice daily). Thus, lung physicians should be aware that lung manifestations, presumably related to an immune-mediated mechanism rather than fluid retention, may occur with dasatinib treatment.
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PMID:Lung abnormalities after dasatinib treatment for chronic myeloid leukemia: a case series. 1760 Feb 77

Tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukaemia (CML) is the consummate success story for targeted therapy, yet relapse is a nearly inevitable consequence of cessation or interruption of therapy. Primitive TKI-refractory CML stem cells are the likely source of these relapses, as they provide sanctuary for the Philadelphia chromosome. In advanced disease, their progressively anaplastic progeny ultimately maintain CML independently of the CML haematopoietic stem cell (HSC). Interestingly, there are at least two distinct cell types capable of self-renewal in different phases of CML: first, a primitive HSC with BCR-ABL mutation, which maintains the more indolent chronic-phase disease and, second, a coexisting mutated progenitor cell which acquires stem cell characteristics responsible for rapid cell expansion in advanced disease.
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PMID:Getting to the stem of chronic myeloid leukaemia. 1857 66

Tyrosine kinase inhibitor (TKI) therapy has impacted the natural course of chronic myelogenous leukemia (CML), because patients diagnosed as having chronic-phase disease can experience long-lasting responses. However, for patients with advanced CML (accelerated and blast phases), the efficacy of all current therapies is reduced. For these patients, allogeneic stem cell transplantation remains the preferred treatment if a donor is available, although TKIs play a valuable role as a bridging therapy. For patients with accelerated-phase CML, imatinib, dasatinib, and nilotinib have been shown to produce meaningful rates of hematologic and cytogenetic response. Imatinib and dasatinib are also approved for blast-phase CML. Studies with the newer agents have involved heavily pretreated patients; however, response rates have been at least comparable to those achieved with imatinib in previous studies. Therefore, these newer, more potent TKIs will probably be more likely to induce a deep response in previously untreated patients. Moreover, because fewer mechanisms appear to exist for secondary resistance to dasatinib and nilotinib, reducing the potential for disease to escape TKI therapy, these agents may result in improved longer-term outcomes. However, BCR-ABL-independent pathways may also become more important, indicating that other therapeutic targets may also have a future role in managing patients with advanced CML.
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PMID:Advanced CML: therapeutic options for patients in accelerated and blast phases. 1839 79

Tyrosine kinase inhibitors (TKIs) have dramatically improved the treatment of chronic myeloid leukemia (CML). However, resistances are occasionally observed, mainly due to mutations within the BCR-ABL kinase domain. The T315I substitution confers complete resistance to TKIs commonly used in clinical practice. In the present study, we used an allele-specific quantitative-RT-PCR to perform a molecular follow-up of BCR-ABL transcripts harboring the T315I mutation. We retrospectively quantified BCR-ABL315I mRNA in five patients who acquired the T315I mutation. Our results highlight the relevance of allele-specific Q-RT-PCR experiments for the monitoring of mutated BCR-ABL transcripts and suggest that the kinetics of emergence of T315I mutant mRNA is influenced by the stage of the disease and the presence of previous BCR-ABL kinase domain mutations.
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PMID:Quantitative monitoring of the T315I mutation in patients with chronic myeloid leukemia (CML). 1882 7


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