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Myeloid Leukemia Cells (myeloid + leukemia_cell)

Distribution by Scientific Domains
Medical Sciences81%
Life Sciences18%
Distribution within Medical Sciences
Oncology & Radiotherapy77%
Hematology22%

Kinds of Myeloid Leukemia Cells

  • chronic myeloid leukemia cell
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    Selected Abstracts

    The Binding Characteristics and Intracellular Localization of Temoporfin (mTHPC) in Myeloid Leukemia Cells: Phototoxicity and Mitochondrial Damage,

    PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 4 2000
    J. Y. Chen
    ABSTRACT The state of aggregation of the photosensitizer meso -tetrahydroxyphenylchlorin (mTHPC) in both cell free and intracellular environment was elucidated by comparing its absorption and excitation spectra. In methanol, mTHPC existed as monomers and strongly fluoresced. In aqueous solutions such as phosphate-buffered saline (PBS), mTHPC formed nonfluorescent aggregates. Some portion of mTHPC monomerized in the presence of 10% fetal calf serum PBS. In murine myeloid leukemia M1 and WEHI-3B (JCS) cells, cytoplasmic mTHPC were monomeric. By using organelle-specific fluorescent probes, it was found that mTHPC localized preferentially at the mitochondria and the perinuclear region. Photodynamic treatment of mTHPC-sensitized leukemia cells caused rapid appearance of the apoptogenic protein cytochrome c in the cytosol. Results from flow cytometric analysis showed that the release of cytochrome c was especially pronounced in JCS cells, and well correlated with the extent of apoptotic cell death as reported earlier. Electron microscopy revealed the loss of integrity of the mitochondrial membrane and the appearance of chromatin condensation as early as 1 h after light irradiation. We conclude that rapid release of cytochrome c from photodamaged mitochondria is responsible for the mTHPC-induced apoptosis in the myeloid leukemia JCS and M1 cells. [source]

    The expression of cytosolic phospholipase A2 and biosynthesis of leukotriene B4 in acute myeloid leukemia cells

    EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2007
    Gudmundur Runarsson
    Abstract Leukotrienes (LT) exert stimulatory effects on myelopoiesis, beside their inflammatory and immunomodulating effects. Here, we have studied the expression and activity of the enzymes involved in the synthesis of leukotriene B4 (LTB4) in acute myeloid leukemia (AML) cells (16 clones) and G-CSF mobilized peripheral blood CD34+ cells. CD34+ cells from patients with non-myeloid malignancies expressed cytosolic phospholipase A2 (cPLA2), 5-lipoxygenase activating protein (FLAP), and leukotriene A4 (LTA4) hydrolase but not 5-lipoxygenase (5-LO). The enzyme cPLA2 was abundantly expressed in AML cells and the activity of the enzyme was high in certain AML clones. The expression of 5-LO, FLAP, and LTA4 hydrolase in AML clones was in general lower than in healthy donor polymorphonuclear leukocytes (PMNL). The calcium ionophore A23187-induced release of [14C] arachidonic acid (AA) in AML cells was low, compared with PMNL, and did not correlate with the expression of cPLA2 protein. Biosynthesis of LTB4, upon calcium ionophore A23187 activation, was only observed in five of the investigated AML clones and only three of the most differentiated clones produced similar amounts of LTB4 as PMNL. The capacity of various cell clones to produce LTs could neither be explained by the difference in [1 , 14C] AA release nor 5-LO expression. Taken together, these results indicate that LT synthesis is under development during early myelopoiesis and the capacity to produce LTs is gained upon maturation. High expression of cPLA2 in AML suggests a putative role of this enzyme in the pathophysiology of this disease. [source]

    NF-,B inhibition triggers death of imatinib-sensitive and imatinib-resistant chronic myeloid leukemia cells including T315I Bcr-Abl mutants

    INTERNATIONAL JOURNAL OF CANCER, Issue 2 2009
    Nadia Lounnas
    Abstract The Bcr-Abl inhibitor imatinib is the current first-line therapy for all newly diagnosed chronic myeloid leukemia (CML). Nevertheless, resistance to imatinib emerges as CML progresses to an acute deadly phase implying that physiopathologically relevant cellular targets should be validated to develop alternative therapeutic strategies. The NF-,B transcription factor that exerts pro-survival actions is found abnormally active in numerous hematologic malignancies. In the present study, using Bcr-Abl-transfected BaF murine cells, LAMA84 human CML cell line and primary CML, we show that NF-,B is active downstream of Bcr-Abl. Pharmacological blockade of NF-,B by the IKK2 inhibitor AS602868 prevented survival of BaF cells expressing either wild-type, M351T or T315I imatinib-resistant mutant forms of Bcr-Abl both in vitro and in vivo using a mouse xenograft model. AS602868 also affected the survival of LAMA84 cells and of an imatinib-resistant variant. Importantly, the IKK2 inhibitor strongly decreased in vitro survival and ability to form hematopoietic colonies of primary imatinib resistant CML cells including T315I cells. Our data strongly support the targeting of NF-,B as a promising new therapeutic opportunity for the treatment of imatinib resistant CML patients in particular in the case of T315I patients. The T315I mutation escapes all currently used Bcr-Abl inhibitors and is likely to become a major clinical problem as it is associated with a poor clinical outcome. © 2009 UICC [source]

    Pml and TAp73 interacting at nuclear body mediate imatinib-induced p53-independent apoptosis of chronic myeloid leukemia cells

    INTERNATIONAL JOURNAL OF CANCER, Issue 1 2009
    Jin-Hwang Liu
    Abstract 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, p53wild 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 p53mutant 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 ,-2a (IFN,), 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 p53mutant and one with p53wild. 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. © 2009 UICC [source]

    A celecoxib derivative inhibits focal adhesion signaling and induces caspase-8-dependent apoptosis in human acute myeloid leukemia cells

    INTERNATIONAL JOURNAL OF CANCER, Issue 1 2008
    Isolda Casanova
    Abstract Most acute myeloid leukemias (AMLs), including those with c-Kit or FLT3 mutations, show enhanced anchorage independent growth associated with constitutive activation of focal adhesion proteins. Moreover, these alterations increase cell survival, inhibit apoptosis and are associated with poor prognosis and resistance to chemotherapy. Therefore, the induction of apoptosis by selective inhibition of focal adhesion signaling may represent a novel anti-AML therapy. Here, we have evaluated the antitumor effect and the mechanism of action of celecoxib and E7123, a non-Cox-2 inhibitor derivative, in a panel of human AML cell lines and bone marrow mononuclear cells from AML patients. Both compounds induce cell death by inhibiting focal adhesion signaling through p130Cas, FAK and c-Src, leading to caspase-8 dependent apoptosis. This mechanism of action differs from that of classical cytotoxic drugs or of other targeted therapies, and is amenable to rational drug development. Therefore, both drugs could be developed as AML therapeutics; nevertheless, E7123 shows more activity than celecoxib against AML cells, and may not present its Cox-2 dependent cardiovascular toxicity. Finally, our results support the evaluation of celecoxib in AML patients, and the preclinical evaluation of E7123, before its possible clinical testing. © 2008 Wiley-Liss, Inc. [source]

    Tyrosine-phosphorylated STAT5 accumulates on podosomes in Hck-transformed fibroblasts and chronic myeloid leukemia cells

    JOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2007
    Renaud Poincloux
    In chronic myeloid leukemia (CML), the transforming activity of Bcr/Abl involves constitutive activation of the phagocyte specific Src-family tyrosine kinase Hck, which in turn directly activates the signal transducer and activator of transcription 5 (STAT5). The effect of Hck on STAT5 was first explored independently of Bcr/Abl by expressing the constitutively active Hck mutant (Hckca) in MEF3T3-TetOff fibroblasts. As previously reported, Hckca -expressing cells form podosomes which are actin-rich structures involved in trans-tissular cell migration and found in the few cell types able to cross anatomic boundaries. We demonstrated that in these cells, the tyrosine-phosphorylated form of STAT5 (PY-STAT5) increased and preferentially localized on podosomes together with Hck, instead of translocating to the nucleus as observed with conventional stimuli such as IFN,. To examine whether similar results were obtained in the presence of Bcr/Abl, the CML cell line K562 was used. We observed that (i) podosomal structures are present in these cells in contrast to Bcr/Abl-negative leukemic cells, (ii) podosome formation was inhibited by Bcr/Abl- and Src-kinase inhibitors, and (iii) PY-STAT5 mainly colocalized with Hck on these structures. The presence of podosomes was not sufficient to trap STAT5 since in normal macrophages which spontaneously form podosomes and express regulated Hck, PY-STAT5 is in the nucleus. In conclusion, this is the first report showing that PY-STAT5 associates to podosomes in a process dependent on constitutive activation of Hck. We propose that STAT5, previously classified as a transcription factor, could play another role outside the nucleus, elicited by the Bcr/Abl-Hck transforming pathway. J. Cell. Physiol. 213: 212,220, 2007. © 2007 Wiley-Liss, Inc. [source]

    Trisomy 8 in Philadelphia-negative cells during imatinib therapy

    AMERICAN JOURNAL OF HEMATOLOGY, Issue 1 2004
    P. Bernardeschi
    Abstract Targeted therapy with imatinib selectively suppresses Philadelphia-positive cells in chronic myeloid leukemia cells, with reappearance of apparently normal hemopoiesis in a considerable number of patients. Recently, clonal abnormalities have been observed in Philadelphia-negative cells during imatinib therapy, the biologic and prognostic significance of which is actually unknown. A case of trisomy 8 occurring in Philadelphia-negative cells, which was treated by bone marrow transplantation, is reported. Chromosomal abnormalities in Philadelphia-negative cells do not seem to herald disease transformation, but the long-term prognosis may be influenced by an increased incidence of myelodysplasia in younger patients. Am. J. Hematol. 77:88,89, 2004. © 2004 Wiley-Liss, Inc. [source]

    Overproduction of BCR-ABL induces apoptosis in imatinib mesylate-resistant cell lines

    CANCER, Issue 1 2005
    Vanessa Desplat Ph.D.
    Abstract BACKGROUND Imatinib mesylate, a BCR-ABL tyrosine kinase inhibitor, induces apoptosis in chronic myeloid leukemia cells. Resistance to imatinib is currently the most important concern of this treatment. One of the main mechanisms of this resistance is overexpression of BCR-ABL. METHODS In the current study, the authors investigated the correlation between BCR-ABL overexpression and apoptosis in BaF/BCR - ABL and LAMA84 cell lines resistant to imatinib suddenly deprived of the inhibitor, and compared with their sensitive counterpart. RESULTS Removal of imatinib from culture medium led to a decrease in Bcr-Abl protein expression by Day 5, which was sustained for , 3 weeks of imatinib deprivation. Apoptosis was observed after 3 days of imatinib deprivation in resistant lines accompanied by caspase activation, loss of membrane asymmetry (annexin V staining), and alteration of mitochondrial potential (dihexyloxacarbocyanine iodide [DiOC6]). Transient activation of the STAT5/Bcl-xL pathway and Akt kinase activity preceded these responses. CONCLUSIONS Thus, imatinib removal led to apoptosis of BCR-ABL,overexpressing leukemic cells, a phenomenon that could be exploited to sensitize imatinib-resistant cells to the cytotoxic effect of other drugs. Cancer 2005. © 2004 American Cancer Society. [source]

    Contribution of BCR,ABL-independent activation of ERK1/2 to acquired imatinib resistance in K562 chronic myeloid leukemia cells

    CANCER SCIENCE, Issue 1 2010
    Takeru Nambu
    BCR,ABL tyrosine kinase, generated from the reciprocal chromosomal translocation t(9;22), causes chronic myeloid leukemia (CML). BCR,ABL is inhibited by imatinib; however, several mechanisms of imatinib resistance have been proposed that account for loss of imatinib efficacy in patients with CML. Previously, we showed that overexpression of the efflux drug transporter P-glycoprotein partially contributed to imatinib resistance in imatinib-resistant K562 CML cells having no BCR,ABL mutations. To explain an additional mechanism of drug resistance, we established a subclone (K562/R) of the cells and examined the BCR,ABL signaling pathway in these and wild-type K562 (K562/W) cells. We found the K562/R cells were 15 times more resistant to imatinib than their wild-type counterparts. In both cell lines, BCR,ABL and its downstream signaling molecules, such as ERK1/2, ERK5, STAT5, and AKT, were phosphorylated in the absence of imatinib. In both cell lines, imatinib effectively reduced the phosphorylation of all the above, except ERK1/2, whose phosphorylation was, interestingly, only inhibited in the wild-type cells. We then observed that phospho-ERK1/2 levels decreased in the presence of siRNA targeting BCR,ABL, again, only in the K562/W cells. However, using an ERK1/2 inhibitor, U0126, we found that we could reduce phospho-ERK1/2 levels in K562/R cells and restore their sensitivity to imatinib. Taken together, we conclude that the BCR,ABL-independent activation of ERK1/2 contributes to imatinib resistance in K562/R cells, and that ERK1/2 could be a target for the treatment of CML patients whose imatinib resistance is due to this mechanism. (Cancer Sci 2009) [source]

    The oral iron chelator deferasirox represses signaling through the mTOR in myeloid leukemia cells by enhancing expression of REDD1

    CANCER SCIENCE, Issue 5 2009
    Junko H. Ohyashiki
    To evaluate the effect of deferasirox in human myeloid leukemia cells, and to identify the moleclular pathways responsible for antiproliferative effects on leukemia cells during chelation therapy, we performed gene expression profiling to focus on the pathway involved in the anticancer effect of deferasirox. The inhibitory concentration (IC50) of deferasirox was 17,50 µM in three human myeloid cell lines (K562, U937, and HL60), while those in fresh leukemia cells obtained from four patients it varied from 88 to 172 µM. Gene expression profiling using Affymerix GeneChips (U133 Plus 2.0) revealed up-regulation of cyclin-dependent kinase inhibitor 1A (CDKN1A) encoding p21CIP, genes regulating interferon (i.e. IFIT1). Pathways related to iron metabolism and hypoxia such as growth differentiation factor 15 (GDF-15) and Regulated in development and DNA damage response (REDD1) were also prominent. Based on the results obtained from gene expression profiling, we particularly focused on the REDD1/mTOR (mammalian target of rapamycin) pathway in deferasirox-treated K562 cells, and found an enhanced expression of REDD1 and its down-stream protein, tuberin (TSC2). Notably, S6 ribosomal protein as well as phosphorylated S6, which is known to be a target of mTOR, was significantly repressed in deferasirox-treated K562 cells, and REDD1 small interfering RNA restored phosphorylation of S6. Although iron chelation may affect multiple signaling pathways related to cell survival, our data support the conclusion that REDD1 functions up-stream of tuberin to down-regulate the mTOR pathway in response to deferasirox. Deferasirox might not only have benefit for iron chelation but also may be an antiproliferative agent in some myeloid leukemias, especially patients who need both iron chelation and reduction of leukemia cells. (Cancer Sci 2009; 100: 970,977) [source]