UMLS:C0023473 - FACTA Search

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

Human chronic myelogenous leukemia-blast crisis K562 cells have been demonstrated to be relatively resistant to antileukemic drug-induced apoptosis. This has been attributed to the activity of p210bcr-abl tyrosine kinase present in the K562 cells, which is known to suppress drug-induced apoptosis. Recently, K562 cells have been shown to express the antiapoptosis Bcl-xL but not Bcl-2 proteins. To investigate the contribution of Bcl-xL toward resistance to drug-induced apoptosis, we created K562/Bcl-xS and K562/neo cells by electroporating the expression plasmids pSFFVneo-Bcl-xS and pSFFVneo, containing the bcl-xS and neomycin resistance genes, respectively, into K562 cells. K562/Bcl-xS but not K562/neo cells expressed the bcl-xS mRNA and p19Bcl-xS protein. In contrast, both cell types expressed equivalent levels of Bcl-xL, Bax, Bcl-2, Myc, retinoblastoma, p21cbor-abl, and p145abl proteins. A significant increase in the hemoglobin levels was observed in the K562/Bcl-xS compared with the K562/neo cells (P < 0.05). In addition, K562/Bcl-xS cells were significantly more sensitive than K562/neo cells to undergoing erythroid differentiation induced by low-dose 1-beta-D-arabinofuranosylcytosine (ara-C) and hexamethyl bisacetamide (P < 0.05), but not by all-trans-retinoic acid. Low-dose ara-C- or hexamethyl bisacetamide-induced differentiation was not associated with apoptosis of K562/Bcl-xS or K562/neo cells. Low-dose ara-C-induced erythroid differentiation was accompanied by conversion of the retinoblastoma protein to predominantly its underphosphorylated isoform as well as by down-regulation of Myc levels in K562/Bcl-xS and K562/neo cells. Importantly, exposure to high-dose ara-C (HIDAC; 100 microM ara-C for 4 h) caused internucleosomal DNA fragmentation and the morphological features of apoptosis in K562/Bcl-xS cells. These effects were modestly enhanced by cotreatment with HIDAC plus herbimycin A. In contrast, K562/neo cells were completely resistant to HIDAC- and herbimycin A-induced apoptosis. These results indicate that the expression of Bcl-xS induces erythroid differentiation and partially sensitizes chronic myelogenous leukemia-blast crisis-derived K562 cells to ara-C-induced differentiation and apoptosis.
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PMID:Enforced expression of Bcl-XS induces differentiation and sensitizes chronic myelogenous leukemia-blast crisis K562 cells to 1-beta-D-arabinofuranosylcytosine-mediated differentiation and apoptosis. 895 29

Mice with a null mutation of the gene encoding interferon consensus sequence-binding protein (ICSBP) develop a disease with marked expansion of granulocytes and macrophages that frequently progresses to a fatal blast crisis, thus resembling human chronic myelogenous leukemia (CML). One important feature of CML is decreased responsiveness of myeloid cells to apoptotic stimuli. Here we show that myeloid cells from mice deficient in ICSBP exhibit reduced spontaneous apoptosis and a significant decrease in sensitivity to apoptosis induced by DNA damage. In contrast, apoptosis in thymocytes from ICSBP-deficient mice is unaffected. We also show that overexpression of ICSBP in the human U937 monocytic cell line enhances the rate of spontaneous apoptosis and the sensitivity to apoptosis induced by etoposide, lipopolysaccharide plus ATP, or rapamycin. Programmed cell death induced by etoposide was specifically blocked by peptides inhibitory for the caspase-1 or caspase-3 subfamilies of caspases. Studies of proapoptotic genes showed that cells overexpressing ICSBP have enhanced expression of caspase-3 precursor protein. In addition, analyses of antiapoptotic genes showed that overexpression of ICSBP results in decreased expression of Bcl-X(L). These data suggest that ICSBP modulates survival of myeloid cells by regulating expression of apoptosis-related genes.
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PMID:Regulation of apoptosis in myeloid cells by interferon consensus sequence-binding protein. 1043 Jun 29

Etoposide is a potent anticancer agent that is used to treat various tumors. We have investigated the dose-dependent effect of etoposide on apoptosis using chronic myeloid leukemia K562 cells treated with low (5 microM) or high (100 microM) concentrations of the drug. At a low concentration, etoposide induced little apoptosis at 24 h, while about 20% of the cells showed apoptosis morphologically at a high concentration. Processing of caspase-3 was slightly detected from 12 h and became obvious at 24 h with 100 microM etoposide. Caspase-3-like protease activity was detected at 24 h with a high concentration. Moreover, these changes were accompanied by cleavage of poly ADP ribose polymerase (PARP). Changes of the mRNA levels of most apoptosis-regulating genes were not prominent at both concentrations, except for the rapid induction of c-IAP-2/HIAP-1 and the down-regulation of Bcl-X(L) by 100 microM etoposide. The downregulation of Bcl-X(L) protein occurred from 6 h, while Bax protein conversely showed a slight increase from 6 h. Taken together, the present findings show that the dose-dependent apoptotic effect of etoposide is based on a change in the balance between Bcl-X(L) and Bax, which precedes the activation of caspase-3.
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PMID:Differential responses of Bcl-2 family genes to etoposide in chronic myeloid leukemia K562 cells. 1083 93

Signal transducers and activators of transcription (STATs) are a family of transcription factors that were originally identified as mediators of cytokine-induced gene expression. We and others have recently shown that STAT5 also plays a major role in cellular transformation by the Bcr-Abl oncogene. Here we show that the antiapoptotic bcl-xL gene product and the cell cycle regulator cyclin D1 are targets of STAT5 in Bcr-Abl-transformed cells. In the CML cell line K562 and in BaF3 cells ectopically expressing Bcr-Abl, both the cyclin D1 and bcl-x promoters are highly active. The activity of these promoters can be strongly repressed by cotransfection of a dominant negative (DN) mutant of STAT5. Moreover, the cyclin D1 and bcl-x promoters contain STAT binding sites to which STAT5 constitutively binds in Bcr-Abl transformed cells. These results suggest that STAT5 contributes to transformation by Bcr-Abl by induction of cyclin D1 and bcl-xL expression.
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PMID:STAT5-Dependent CyclinD1 and Bcl-xL expression in Bcr-Abl-transformed cells. 1096 54

hnRNP A1 is a nucleocytoplasmic shuttling heterogeneous nuclear ribonucleoprotein that accompanies eukaryotic mRNAs from the active site of transcription to that of translation. Although the importance of hnRNP A1 as a regulator of nuclear pre-mRNA and mRNA processing and export is well established, it is unknown whether this is relevant for the control of proliferation, survival, and differentiation of normal and transformed cells. We show here that hnRNP A1 levels are increased in myeloid progenitor cells expressing the p210(BCR/ABL) oncoprotein, in mononuclear cells from chronic myelogenous leukemia (CML) blast crisis patients, and during disease progression. In addition, in myeloid progenitor 32Dcl3 cells, BCR/ABL stabilizes hnRNP A1 by preventing its ubiquitin/proteasome-dependent degradation. To assess the potential role of hnRNP A1 nucleocytoplasmic shuttling activity in normal and leukemic myelopoiesis, a mutant defective in nuclear export was ectopically expressed in parental and BCR/ABL-transformed myeloid precursor 32Dcl3 cells, in normal murine marrow cells, and in mononuclear cells from a CML patient in accelerated phase. In normal cells, expression of this mutant enhanced the susceptibility to apoptosis induced by interleukin-3 deprivation, suppressed granulocytic differentiation, and induced massive cell death of granulocyte colony-stimulating factor-treated cultures. In BCR/ABL-transformed cells, its expression was associated with suppression of colony formation and reduced tumorigenic potential in vivo. Moreover, interference with hnRNP A1 shuttling activity resulted in downmodulation of C/EBPalpha, the major regulator of granulocytic differentiation, and Bcl-X(L), an important survival factor for hematopoietic cells. Together, these results suggest that the shuttling activity of hnRNP A1 is important for the nucleocytoplasmic trafficking of mRNAs that encode proteins influencing the phenotype of normal and BCR/ABL-transformed myeloid progenitors.
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PMID:hnRNP A1 nucleocytoplasmic shuttling activity is required for normal myelopoiesis and BCR/ABL leukemogenesis. 1188 11

The chronic myeloproliferative disorders are clonal hematopoietic stem cell disorders and include chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and agnogenic myeloid metaplasia (AMM). These diseases are characterized by clonal expansion of the myeloid compartment, increased marrow angiogenesis, and varying risks for blastic transformation. A clear molecular abnormality exists (t(9;22) leading to the fusion of BCR-Abl) only for CML, which led to effective targeted therapy (STI-571). Since no similar pathogenetic mechanism has been discovered for the t(9;22) negative chronic myeloproliferative disorders, their respective diagnosis is currently based on a variety of rather cumbersome diagnostic criteria. Polycythemia vera is distinguished from reactive erythrocytosis through erythropoietin independent growth of erythroid progenitors in vitro, suppressed levels of endogenous erythropoietin, possible overexpression of PRV-1 (polycythemia rubra vera-1), decreased c-Mpl expression on megakaryocytes, as well as overexpression of bcl-xL, and potentially aberrant activity of the Jak-Stat pathway. ET is defined by thrombocytosis and is distinguished from reactive states by decreased megakaryocyte c-Mpl expression, and a propensity for thrombosis. AMM has been associated with a variety of observations including increased concentrations of pro-fibrotic cytokines, increased angiogenesis, and myeloid expansion. AMM is often indistinguishable clinically and prognostically from the advanced phases of other CMPD (specifically post-polycythemic and post-thrombocythemia myeloid metaplasia), all of which are subentities of a diagnosis of myelofibrosis with myeloid metaplasia (MMM). The management of CMPD patients is quite varied given the broad range of disease severity and survival observed. The role of stem cell transplantation is limited by the age and comorbidities encountered in CMPD patients. Since no broadly applicable therapy effects the mortality of the CMPD, management currently focuses on the prevention/palliation of disease morbidity (i.e. vascular complications, pruritus, organomegaly, constitutional symptoms). Palliative strategies which currently focus on non-specific myelosuppresion, will hopefully be soon replaced by targeted therapies as insight into pathogenetic mechanisms of these diseases evolves.
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PMID:Clinical and scientific advances in the Philadelphia-chromosome negative chronic myeloproliferative disorders. 1243 Sep 25

Clinical studies have shown that the tyrosine kinase inhibitor STI571 effectively controls BCR-ABL-positive chronic myelogenous leukemia (CML). However, disease progression while on STI571 therapy has been reported, suggesting de novo or intrinsic resistance to BCR-ABL-targeted therapy. To investigate possible mediators of acquired STI571 resistance, K562 cells resistant to 5 microM STI571 (K562-R) were cloned and compared to the parental cell population. K562-R cells had reduced BCR-ABL expression and limited activation of BCR-ABL signaling cascades (Stat 5, CrkL, MAPK). STI571 failed to activate caspase cascades or to suppress expression of survival genes (bcl-xL) in resistant cells. Gene sequencing and tyrosine kinase activity measurements demonstrated that K562-R cells retained wild-type and active BCR-ABL tyrosine kinase that was inhibitable by in vitro incubation with STI571, suggesting that BCR-ABL was not coupled to proliferation or survival of K562-R cells. The src-related kinase LYN was highly overexpressed and activated in K562-R cells, and its inhibition reduced proliferation and survival of K562-R cells while having limited effects of K562 cells. Specimens taken from patients with advanced CML that progressed on STI571 therapy also were analyzed for LYN kinase expression, and they were found to be elevated to a level similar to that of K562-R cells. Comparison of samples from patients taken prior to and following STI571 failure suggested that expression and/or activation of LYN/HCK occurs during disease progression. Together, these results suggest that acquired STI571 resistance may be associated with BCR-ABL independence and mediated in part through overexpression of other tyrosine kinases.
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PMID:BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. 1250 83

The expression of apoptosis-related genes BCL2, BAX, BCL2L1, BCL2A1, MCL1, DAPK1 and MYC was studied by quantitative real-time polymerase chain reaction on total RNA samples from patients with acute lymphoblastic leukaemia (ALL, n = 16), acute myeloid leukaemia (AML, n = 27), chronic myeloid leukaemia (CML, n = 12), mantle cell lymphoma (MCL, n = 19) and chronic lymphoid leukaemia (CLL, n = 32). BCL2, BAX, BCL2A1, MCL1, DAPK1 and MYC were overexpressed in all patient groups. BCL2L1 was underexpressed in CLL and CML, but not in AML, ALL and MCL. MCL1 levels were significantly higher in CD13 and CD33-positive ALL, and in CD56-positive AML samples. BCL2, BCL2L1, BCL2A1 and MCL1 were overexpressed and DAPK1 was underexpressed in CLL samples with a 11q23 deletion. MYC overexpression was significantly associated with shorter overall survival in MCL (P < 0.01). AML patients with a normal karyotype showed a higher frequency of BCL2A1 overexpression (P < 0.001) than those with an abnormal karyotype.
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PMID:Abnormal expression of apoptosis-related genes in haematological malignancies: overexpression of MYC is poor prognostic sign in mantle cell lymphoma. 1258 Sep 57

To explore the effects of tetra-arsenic tetra-sulfide (As(4)S(4)) in treatment of human chronic myelogenous leukemia K562 cells and its mechanism, trypan blue staining and microculture MTS assay were used to measure the effects of As(4)S(4) on growth inhibition of K562 cells; the morphologic change was determined by Wright's staining assay. The apoptosis rate and cell cycle were detected by flow cytometry; the changes of transcript and protein level were determined by real-time quantitative RT-PCR and Western blot analysis, respectively. The results indicated that As(4)S(4) had significant cytotoxicity on K562 cells. At the concentration of 0.5 micromol/L, the cell viability decreased significantly after being cultured with As(4)S(4) for 24 hours. When the concentration was lower than 0.1 micromol/L, As(4)S(4) had a little effect on K562 cells. The effect of As(4)S(4) on K562 was time- and concentration- dependent. After being cultured with As(4)S(4) at the concentration of 1.0 micromol/L for 24 to 48 hours, K562 cells displayed typical morphological changes of apoptosis. At a concentration greater than or equal to 1.0 micromol/L, As(4)S(4) could induce apoptosis significantly. After 12 hours of incubation with 1.0 micromol/L As(4)S(4), the apoptosis rate increased from (3.47 +/- 0.42)% to (6.16 +/- 0.98%). At the same time, the percentage of cells in G(1) phase decreased from (69.65 +/- 3.24)% to (50.53 +/- 2.86)%, whereas the percentage of cells in G(2)/M phase increased from (9.56 +/- 2.51)% to (12.91 +/- 2.13)%. The mRNA level of Bcl-X(L) and the protein level of pAkt were down-regulated after the inhibition of As(4)S(4), while the mRNA expression of Bcl-2, Bad and Bax had no change. Both of the transcript and protein level of bcr-abl had no change after incubation with As(4)S(4). It is concluded that As(4)S(4) can inhibit the growth of K562 cells efficiently through inducing apoptosis and cell cycle arrest. It seems that As(4)S(4) interferes with pAkt pathway and down-regulates Bcl-X(L), which may be involved in the response of K562 to this agent.
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PMID:[Apoptosis mechanism in human chronic myelogenous leukemia K562 cells induced by tetra-arsenic tetra-sulfide]. 1627 37

Indomethacin (IN) can inhibit cyclooxygenase activity and is considered to exert antitumor action in a variety of cancer cells. In the present study, we investigated the underlying mechanism of its antiproliferative effect on chronic myeloid leukemia (CML) cells. We studied the role of signal transducer and activator of transcription 1 or 5 (STAT(1) or STAT(5)) and Bcl-X(L) proteins in IN-induced proliferative inhibition on CML cells. Both K562 cells and fresh bone marrow mononuclear cells from five CML patients were exposed to IN. Cell proliferation was determined by MTT assay. The expression of JAK(2), STAT(1), STAT(5), and Bcl-X(L) proteins was probed with Western blotting. The level of phosphorylated STAT(1) (p-STAT(1)) or STAT(5) (p-STAT(5)) proteins was determined by coimmunoprecipitation combined with Western blotting. Intracellular localizations of both STAT(1)/STAT(5) and p-STAT(1)/p-STAT(5) were observed by indirect immunofluorescence assay. Our results showed that IN could inhibit the proliferation of CML cells in a dose-dependent manner (36-288 microg/ml). The expression of STAT(1) and STAT(5) was suppressed by IN both in a concentration-dependent manner and a time-dependent (0-36 h) manner. The levels of p-STAT(1) and p-STAT(5) were down-regulated by IN. A similar result was obtained for Bcl-X(L) protein expression. The intracellular fluorescence signals representing STAT(1)/STAT(5) and p-STAT(1)/p-STAT(5) were obviously weakened by IN. In contrast with IN, granulocyte-macrophage colony-stimulating factor could significantly promote the growth of CML cells and up-regulate the expression of both STAT(1)/STAT(5) and p-STAT(1)/p-STAT(5). This data indicated that IN is able to suppress the proliferation of CML cells, and the mechanism is associated with the inhibition of STATs/ Bcl-X(L) signal transduction pathway.
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PMID:Antiproliferative effect of indomethacin on CML cells is related to the suppression of STATs/Bcl-XL signal pathway. 1657 23

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