Search results for " BCR-ABL"
showing 10 items of 70 documents
Outcome of peripheral blood stem cell mobilization in advanced phases of CML is dependent on the type of chemotherapy applied
1998
High-dose chemotherapy with autologous transplantation of in vivo purged PBSC is a novel investigational approach to treating chronic myelogenous leukemia (CML) patients not responsive to conventional therapy with interferon-alpha (IFN-alpha) and not eligible for allogeneic transplantation. PBSC mobilization using either '5+2/7+3'-type chemotherapy or 'mini-ICE/ ICE' chemotherapy was investigated in 43 patients with advanced phases of Philadelphia (Ph)-positive CML. Thirty patients were in late chronic phase (12 months post diagnosis) and 13 patients in accelerated phase (AP) or blast crisis (BC). Contamination with Ph-positive cells was evaluated in harvests from 37/43 patients. The outcom…
Current results on the use of imatinib mesylate in patients with relapsed philadelphia chromosome positive leukemia after allogeneic or syngeneic hem…
2003
Here, we describe a patient diagnosed with chronic myelogenous leukemia who relapsed after matched unrelated donor SCT. The patient was treated with imatinib mesylate and donor lymphocyte infusions, and achieved a complete molecular remission. Additionally, safety and efficacy of imatinib mesylate in a total of 134 patients from 8 centers who underwent allogeneic or syngeneic stem cell transplantation (SCT) and had a relapse of Philadelphia chromosome positive leukemia was reviewed. Data was compiled from abstracts accepted as oral or poster presentations at the ASH (American Society of Hematology) 2001 and EBMT (European Group for Blood and Marrow Transplantation) 2001 & 2002 meetings and …
Identification of Biphenyl-Based Hybrid Molecules Able To Decrease the Intracellular Level of Bcl-2 Protein in Bcl-2 Overexpressing Leukemia Cells
2009
With the aim of enhancing the structural complexity and diversity of an existing collection of bi- and terphenyl compounds, we synthesized hybrid molecules comprising of spirocyclic ketones (a complexity-bearing core) and bi/terphenyls (privileged fragments). Compounds 1, 3, 4, and 6 showed well-defined activity on apoptosis and differentiation, making them potential leads for development as new anticancer agents and chemical probes to study signaling networks in neoplastic cells.
Platelets Contribution to Thrombin Generation in Philadelphia-Negative Myeloproliferative Neoplasms: The "Circulating Wound" Model.
2021
Current cytoreductive and antithrombotic strategies in MPNs are mostly based on cell counts and on patient’s demographic and clinical history. Despite the numerous studies conducted on platelet function and on the role of plasma factors, an accurate and reliable method to dynamically quantify the hypercoagulability states of these conditions is not yet part of clinical practice. Starting from our experience, and after having sifted through the literature, we propose an in-depth narrative report on the contribution of the clonal platelets of MPNs—rich in tissue factor (TF)—in promoting a perpetual procoagulant mechanism. The whole process results in an unbalanced generation of thrombin and i…
Role of exosomes released by chronic myelogenous leukemia cells in angiogenesis
2012
The present study is designed to assess if exosomes released from Chronic Myelogenous Leukemia (CML) cells may modulate angiogenesis. We have isolated and characterized the exosomes generated from LAMA84 CML cells and demonstrated that addition of exosomes to human vascular endothelial cells (HUVEC) induces an increase of both ICAM-1 and VCAM-1 cell adhesion molecules and interleukin-8 expression. The stimulation of cell-cell adhesion molecules was paralleled by a dose-dependent increase of adhesion of CML cells to a HUVEC monolayer. We further showed that the treatment with exosomes from CML cells caused an increase in endothelial cell motility accompanied by a loss of VE-cadherin and β-ca…
Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-γ1-driven activation of mTOR/p70S6-kinase pathway
2009
In chronic myeloid leukemia, activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway is crucial for survival and proliferation of leukemic cells. Essential downstream molecules involve mammalian target of rapamycin (mTOR) and S6-kinase. Here, we present a comprehensive analysis of the molecular events involved in activation of these key signaling pathways. We provide evidence for a previously unrecognized phospholipase C-gamma1 (PLC-gamma1)-controlled mechanism of mTOR/p70S6-kinase activation, which operates in parallel to the classical Akt-dependent machinery. Short-term imatinib treatment of Bcr-Abl-positive cells caused dephosphorylation of p70S6-K and S6-protein without inactivat…
Exosomal shuttling of miR-126 in endothelial cells modulates adhesive and migratory abilities of chronic myelogenous leukemia cells.
2014
BACKGROUND: Recent findings indicate that exosomes released from cancer cells contain microRNAs (miRNAs) that may be delivered to cells of tumor microenvironment. RESULTS: To elucidate whether miRNAs secreted from chronic myelogenous leukemia cells (CML) are shuttled into endothelial cells thus affecting their phenotype, we first analysed miRNAs content in LAMA84 exosomes. Among the 124 miRNAs identified in LAMA84 exosomes, we focused our attention on miR-126 which was found to be over-overexpressed in exosomes compared with producing parental cells. Transfection of LAMA84 with Cy3-labelled miR-126 and co-culture of leukemia cells with endothelial cells (EC) confirmed that miR-126 is shuttl…
Tyrosine Kinase Inhibitors for the Treatment of Chronic Myeloid Leukemia
2009
Imatinib mesylate (Gleevec) is a drug unique for the treatment of certain forms of cancer. It works by targeting, and turning off, specific tyrosine kinase proteins that cause the uncontrolled cell growth and the inhibition of apoptosis in cancer cells. Imatinib was designed on the basis of the structure of the ATP binding site of the Abl protein kinase with the aim to stabilizes the inactive form of Bcr-Abl, an oncoprotein involved in malignant transformation in chronic myelogenous leukemia (CML). However, imatinib can also target other tyrosine kinase proteins different from Bcr-Abl such as Kit, that is the suspected cause of gastrointestinal stromal tumor (GIST). Despite successful clini…
The new iodoacetamidobenzofuran derivative TR120 decreases STAT5 expression and induces antitumor effects in imatinib-sensitive and imatinib-resistan…
2013
The identification of novel compounds modulating the expression/activity of molecular targets downstream to BCR-ABL could be a new approach in the treatment of chronic myeloid leukemias (CMLs) resistant to imatinib or other BCR-ABL-targeted molecules. Recently, we synthesized a new class of substituted 2-(3,4,5-trimethoxybenzoyl)-2-N,N-dimethylamino-benzo[b]furans, and among these 3-iodoacetylamino-6-methoxybenzofuran-2-yl(3,5-trimethoxyphenyl)methanone (TR120) showed marked cytotoxic activity in BCR-ABL-expressing cells. Interestingly, TR120 was more potent than imatinib in cell growth inhibition and apoptosis induction in both BCR-ABL-expressing K562 and KCL22 cells. Moreover, it showed a…
In BCR-ABL-positive cells, STAT-5 tyrosine-phosphorylation integrates signals induced by imatinib mesylate and Ara-C.
2003
In BCR-ABL-positive cells, the transcription factor STAT-5 is constitutively activated by tyrosine phosphorylation. STAT-5 activation results in upregulation of bcl-X(L) and increased resistance to induction of apoptosis. Here, we investigated the effects of imatinib mesylate and cytosine arabinoside (Ara-C) on STAT-5 tyrosine-phosphorylation, cellular proliferation and induction of apoptosis in cell lines and primary hematopoietic cells. Imatinib mesylate treatment strongly suppressed STAT-5 tyrosine-phosphorylation in K562 and primary CML blasts. In contrast to JAK-2 and PI-3-kinase inhibition, exposure of K562 cells to imatinib mesylate resulted in obvious suppression of proliferation. R…