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)

The protein signal transducer and activator of transcription 5 (STAT5) of the JAK/STAT pathway is constitutively activated because of its phosphorylation by tyrosine kinase activity of fusion protein BCR-ABL in chronic myelogenous leukemia (CML) cells. This study investigated the potential therapeutic effect of STAT5 decoy oligodeoxynucleotides (ODN) using leukemia K562 cells as a model. Our results showed that transfection of 21-mer-long STAT5 decoy ODN into K562 cells effectively inhibited cell proliferation and induced cell apoptosis. Further, STAT5 decoy ODN downregulated STAT5 targets bcl-xL, cyclinD1, and c-myc at both mRNA and protein levels in a sequence-specific manner. Collectively, these data demonstrate the therapeutic effect of blocking the STAT5 signal pathway by cis-element decoy for cancer characterized by constitutive STAT5 activation. Thus, our study provides support for STAT5 as a potential target downstream of BCR-ABL for CML treatment and helps establish the concept of targeting STAT5 by decoy ODN as a novel therapy approach for imatinib-resistant CML.
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PMID:Targeted blockage of signal transducer and activator of transcription 5 signaling pathway with decoy oligodeoxynucleotides suppresses leukemic K562 cell growth. 2109 Nov 89

The transcription factor STAT5 is an essential mediator of the pathogenesis of chronic myelogenous leukemia (CML). In CML, the BCR/ABL fusion kinase causes the constitutive activation of STAT5, thereby driving the expression of genes promoting survival. BCR/ABL kinase inhibitors have become the mainstay of therapy for CML, although CML cells can develop resistance through mutations in BCR/ABL. To overcome this problem, we used a cell-based screen to identify drugs that inhibit STAT-dependent gene expression. Using this approach, we identified the psychotropic drug pimozide as a STAT5 inhibitor. Pimozide decreases STAT5 tyrosine phosphorylation, although it does not inhibit BCR/ABL or other tyrosine kinases. Furthermore, pimozide decreases the expression of STAT5 target genes and induces cell cycle arrest and apoptosis in CML cell lines. Pimozide also selectively inhibits colony formation of CD34(+) bone marrow cells from CML patients. Importantly, pimozide induces similar effects in the presence of the T315I BCR/ABL mutation that renders the kinase resistant to presently available inhibitors. Simultaneously inhibiting STAT5 with pimozide and the kinase inhibitors imatinib or nilotinib shows enhanced effects in inhibiting STAT5 phosphorylation and in inducing apoptosis. Thus, targeting STAT5 may be an effective strategy for the treatment of CML and other myeloproliferative diseases.
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PMID:The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors. 2143 78

In targeted therapy using tyrosine kinase inhibitors (TKIs), measurement of TK activities could be beneficial for diagnosis, identification of potential responders, and monitoring treatment efficacy. Here we evaluated the utility of measuring circulating TK (cTK) activity directly from plasma in leukemia patients positive for the BCR-ABL1. Plasma cTK activity was measured from 46 patients with newly diagnosed chronic myelogenous leukemia (CML), 24 with multidrug-resistant CML, 24 with BCR-ABL1-positive acute lymphocytic leukemia (ALL), and 38 healthy donors. Circulating TK activity was significantly higher in CML (median 801.93 U/mL, range 18.10-3932.30 U/mL) and BCR-ABL1-positive ALL patients (median 659.55 U/mL, range 0-1626.90 U/mL) than in healthy donors (median 82.85 U/mL, range 0.63-852.80 U/mL) (P < 0.001). Plasma cTK activity was closely correlated with cellular BCR-ABL1 kinase activation as indicated by phosphorylation of the downstream signaling proteins CRKL (P < 0.001) and STAT-5 (P= 0.003). However, cTK activity was not associated with BCR-ABL1 transcript level and was independent of BCR-ABL1 mutation type. Ex vivo inhibition of imatinib and dasatinib on plasma cTK activity was severely diminished in patients harboring T315I mutation. Ex vivo testing measuring the effect of TKIs on plasma cTK activity thus hold promise as drug sensitivity tests for predicting and monitoring response to specific TKIs.
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PMID:Plasma tyrosine kinase activity as a potential biomarker in BCR-ABL1-targeted therapy. 2169 68

The BCR-ABL tyrosine kinase has been implicated in the dysregulation of oncogenes and tumor suppressor genes involved in chronic myelogenous leukemia (CML). Suppressor of activator protein-1, regulated by interferon (SARI), is a recently identified tumor suppressor gene whose expression has been reported to be suppressed in several malignant neoplasms. However, the expression of SARI in leukemia and the underlying regulatory mechanism remain elusive. In this study, we demonstrated that SARI mRNA expression was low in CML patients. In vitro, BCR-ABL kinase inhibitor imatinib mesylate or siRNA specific to BCR-ABL upregulated SARI mRNA expression in human leukemia cells. In addition, JAK/STAT signaling inhibitor AG490 and RAS/MAPK signaling inhibitor PD98059 upregulated SARI mRNA expression, but PI3K/AKT pathway inhibitor LY294002 had no such effect. Functionally, silencing of SARI in CML-derived cell line K562 partially decreased imatinib mesylate-induced apoptosis. Taken together, these data demonstrate that SARI mRNA expression is suppressed by BCR-ABL through the downstream signaling pathways, suggesting SARI as a potential therapeutic target in CML.
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PMID:Transcription suppression of SARI (suppressor of AP-1, regulated by IFN) by BCR-ABL in human leukemia cells. 2189 28

With the availability of molecular monitoring of BCR-ABL1 and the use of tyrosine kinase inhibitors, treatment in chronic myeloid leukemia (CML) is now molecularly focused. Eighty-three samples taken at different time points from 38 CML patients; were subjected to T315I mutation analysis and gene expression analysis of AHI1; a novel gene that is thought to have a role in both BCR-ABL1 mediated leukemic transformation and response to tyrosine kinase inhibitors. Only one patient (2.63%) harboured the T315I mutation. While no significant difference in AHI1 expression was observed between newly diagnosed CML samples and non-CML controls; CML samples under imatinib therapy had levels significantly higher than both newly diagnosed samples and controls. In the first 6 months of imatinib therapy, AHI1 expression was found to increase and then gradually decrease. There was no significant difference between imatinib responders and non-responders, while dasatinib caused significantly lower AHI1 levels. It is proposed that the change in AHI1 expression during CML therapy might be under the control of mechanisms independent from BCR-ABL1. AHI1 mediated signalling could be better understood by analyzing AHI1 gene expression levels in a greater number of patients and concurrently investigating JAK/STAT and Src family kinases pathways.
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PMID:AHI1 gene expression levels and BCR-ABL1 T315I mutations in chronic myeloid leukemia patients. 2218 70

Expression of the transcription repressor Gfi-1 is required for the maintenance of murine hematopoietic stem cells. In human cells, ectopic expression of Gfi-1 inhibits and RNA interference-mediated Gfi-1 downregulation enhances proliferation and colony formation of p210BCR/ABL expressing cells. To investigate the molecular mechanisms that may explain the effects of perturbing Gfi-1 expression in human cells, Gfi-1-regulated genes were identified by microarray analysis in K562 cells expressing the tamoxifen-regulated Gfi-1-ER protein. STAT 5B and Mcl-1, two genes important for the proliferation and survival of hematopoietic stem cells, were identified as direct and functionally relevant Gfi-1 targets in p210BCR/ABL-transformed cells because: (i) their expression and promoter activity was repressed by Gfi-1 and (ii) when constitutively expressed blocked the proliferation and colony formation inhibitory effects of Gfi-1. Consistent with these findings, genetic or pharmacological inhibition of STAT 5 and/or Mcl-1 markedly suppressed proliferation and colony formation of K562 and CD34+ chronic myelogenous leukemia (CML) cells. Together, these studies suggest that the Gfi-1STAT 5B/Mcl-1 regulatory pathway identified here can be modulated to suppress the proliferation and survival of p210BCR/ABL-transformed cells including CD34+ CML cells.
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PMID:Gfi-1 inhibits proliferation and colony formation of p210BCR/ABL-expressing cells via transcriptional repression of STAT 5 and Mcl-1. 2341 66

Suppressor of cytokine signaling 2 (SOCS2) is known as a feedback inhibitor of cytokine signaling and is highly expressed in primary bone marrow (BM) cells from patients with chronic myeloid leukemia (CML). However, it has not been established whether SOCS2 is involved in CML, caused by the BCR/ABL1 fusion gene, or important for normal hematopoietic stem cell (HSC) function. In this study, we demonstrate that although Socs2 was found to be preferentially expressed in long-term HSCs, Socs2-deficient HSCs were indistinguishable from wild-type HSCs when challenged in competitive BM transplantation experiments. Furthermore, by using a retroviral BCR/ABL1-induced mouse model of CML, we demonstrate that SOCS2 is dispensable for the induction and propagation of the disease, suggesting that the SOCS2-mediated feedback regulation of the JAK/STAT pathway is deficient in BCR/ABL1-induced CML.
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PMID:SOCS2 is dispensable for BCR/ABL1-induced chronic myeloid leukemia-like disease and for normal hematopoietic stem cell function. 2282 85

Ob-R receptor is encoded by db gene and belongs to class I cytokine receptors family. Its expression was observed in hematopoietic CD34+ stem cells, erythropoietic, myeloid and lymphoblastic lineages cell lines and in human leukemic blast cells in lymphomas, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML). The studies on human bone marrow cells show that JAK/STAT pathway plays a substantial role in signal transduction in young bone marrow cells. The aim of the study was to examine the relationship between leptin receptor expression and the proliferation of neoplastic hematopoietic cells in bone marrow. The study was performed in a total of 57 children of both sexes aged 3 months to 16 years. A group of 46 patients with acute leukemia involved 25 children with ALLB, 11 children with ALLT and 10 children with ANNL. The control group consisted of 11 non-obese children with non-malignant hematological disturbances. The tests were performed on bone marrow samples. The assessments of membrane expression of Ob-R and the antigens determining the phenotype of bone marrow cells were performed using a flow cytometry method. In acute lymphoblastic leukemia, a significant decrease of Ob-R expression on leukemic blasts was observed in comparison with respective populations of normal bone marrow cells. Also in progenitor cells populations a significant decrease of CD34+Ob-R+w ALLT and ALLB was observed in comparison with the cells from normal bone marrow. No statistically significant differences in the percentage of Ob-R+ cells in ANNL bone marrow and in control bone marrow were observed.
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PMID:Leptin receptor in childhood acute leukemias. 2283 31

Myeloproliferative neoplasms (MPNs) include Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) and the Ph- diseases primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET). Since FDA approval of imatinib in 2001, CML treatment has been focused on tyrosine kinase inhibitors. With these targeted therapies, imatinib-resistant CML has emerged as a major problem. Second generation tyrosine kinase inhibitors (TKIs) have allowed for effective treatment of some patients with imatinib resistance, but bcr-abl mutants such as T315I remain problematic. Additional agents are in development and are discussed here. New clinical issues with TKI treatment include premature termination of therapy due to adverse-effects, the cost of therapy, and the apparently indefinite duration of treatment in patients who have achieved complete molecular response (CMR). In contrast to Ph+ CML, targeted therapy for Ph- MPNs is novel and of less clear therapeutic potential. New insights into Ph- MPNs include alterations in the JAK-STAT signaling pathway, particularly as mediated by the JAK2 V617F mutation. The recent development of multiple JAK2 inhibitors has provided hope for the rational and effective management of these disorders. Recently, ruxolitinib was approved as therapy for PMF. Current data suggests, however, that given its vital cell signaling function, the therapeutic benefit of targeting Jak kinases in general, or JAK2 specifically may be less than that derived from ABL-directed TKI treatment of CML. This review focuses on the current treatment options for CML and Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) and limitations faced in current clinical practice.
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PMID:Tyrosine kinase targeted treatment of chronic myelogenous leukemia and other myeloproliferative neoplasms. 2328 40

In this study, we aimed to evaluate the cytotoxic and apoptotic effects of zoledronic acid on K562 chronic myeloid leukemia (CML) cells and to examine the roles of STAT genes on zoledronic acid-induced apoptosis. The results showed that zoledronic acid decreased proliferation, and induced apoptosis in K562 cells in a dose- and time-dependent manner. mRNA and protein levels of STAT3, -5A and -5B genes were significantly reduced in zoledronic acid-treated K562 cells. These data indicated that STAT inhibition by zoledronic acid may be therapeutic in CML patients following the confirmation with clinical studies.
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PMID:STAT pathway in the regulation of zoledronic acid-induced apoptosis in chronic myeloid leukemia cells. 2372 55


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