Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

B cell chronic lymphocytic leukemia (B-CLL) cannot be cured with conventional chemotherapy. This clinical enigma appears to be at least partially due to the fact that B-CLL cells are resistant to programmed cell death (apoptosis) and that they are arrested in G0/G1 phase of the cell cycle. The reasons for the dysregulation of these two key cellular events in B-CLL are unclear. The present study aimed at determining correlations between the expression levels of proteins regulating apoptosis, cell cycle and DNA repair in B-CLL cells and normal B cells. In addition, the differential sensitivity of B-CLL cells to drug-induced apoptosis was quantified. We show that in B-CLL cells levels of the death-suppressor Bcl-2 correlated positively with those of the pro-apoptotic protein Bax and of the cyclin-dependent kinase (cdk) inhibitor p27Kip1. In B-CLL cells levels of the anti-apoptotic Bcl-xL showed a positive correlation with levels of the 80 kDa regulatory component (Ku80) of the DNA-dependent protein kinase that is involved in DNA double-stranded break repair. These correlations were not detected in normal B cells. The sensitivity of leukemic cells to FLUD but not to ADM, CPM or to DEX was reduced in pre-treated patients. These data support the hypothesis that in B-CLL cells death-modulators and molecules modulating cell cycle and DNA repair are regulated in a coordinated manner. Leukemia (2000) 14, 40-46.
Leukemia 2000 Jan
PMID:Chemosensitivity of B cell chronic lymphocytic leukemia and correlated expression of proteins regulating apoptosis, cell cycle and DNA repair. 1063 75

Glucocorticoid-induced apoptosis is preceded by G1 arrest and supposed to be up-regulated by polyamine-depletion, which also induces G1, arrest. In CEM leukemia cells, dexamethasone showed an antileukemic effect by inducing G1 arrest and apoptosis. DFMO, which depleted cellular polyamines by inhibiting ornithine decarboxylase, induced G1 arrest but without apoptosis, though it enhanced dexamethasone-induced G1 arrest and apoptosis. The G1 arrest was associated with hypophosphorylation of pRb. Dexamethasone inhibited the increase of mutated p53 expression but had little effect on p2Wafl/Cip1 expression. The p27Kip1, level was increased by dexamethasone or and DFMO in line with the kinetics of G1 arrest. Therefore, the up-regulation of dexamethasone-induced apoptosis by polyamine-depletion may be associated with additive down-regulation of G1 progression via the p27Kip1-pRb pathtway.
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PMID:Polyamine-depletion induces p27Kip1 and enhances dexamethasone-induced G1 arrest and apoptosis in human T lymphoblastic leukemia cells. 1065 47

The process of terminal differentiation is associated with exit from the cell cycle and loss of the proliferative potential of cells. The cyclin-dependent kinase inhibitors (CDIs) play critical roles in check-point functions during the cell cycle and as inhibitors of cell proliferation. Loss of their activities can impair development and differentiation and contribute to the uncontrolled proliferation characteristic of cancer cells. When the promyelocytic leukemia cell line HL60 is induced to differentiate in vitro, by a variety of agents, cellular levels of the CD1 proteins p21Cip1 and p27Kip1 are increased. To further address the roles of these two proteins in differentiation, we have overexpressed either a human p21Cip1 or p27Kip1 construct in HL60 cells. The overexpression of p21Cip1 accelerated both the monocytic and granulocytic differentiation of HL60 cells triggered by TPA or DMSO, respectively. The accelerated and more dramatic induction of differentiation seen in the p21Cip1 overexpressors was associated with a more rapid reduction of CDK2 kinase-associated activity, increased levels and more rapid dephosphorylation of the Rb protein, and increased levels of the cyclin D3 protein. Stable overexpression of p27Kip1 also enhanced TPA-induced differentiation of HL60 cells. These studies provide direct evidence that the increased expression of p21Cip1 and p27Kip1 play a causal role in the process of terminal differentiation of HL60 cells. Therefore, agents that enhance the expression of one or both of these proteins might be useful in therapy by enhancing the terminal differentiation of leukemia cells.
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PMID:Overexpression of p21Cip1 or p27Kip1 in the promyelocytic leukemia cell line HL60 accelerates its lineage-specific differentiation. 1069 93

In the present study, we analysed 34 de novo diffuse large B cell lymphoma (DLCL) from a population-based lymphoma registry for alterations of the RB1 pathway at the genetic (RB1 and CDK4) and protein (pRb, cyclin D1, cyclin D3, CDK4, and E2F-1) level. The results were correlated with the data from our previous studies of CDKN2A deletion and hypermethylation, other p53 pathway components, p27Kip1 expression, and proliferation, as well as with clinical outcome, including prognosis. We found aberrant pRb expression in four (12%) of 34 DLCLs. One of these had a point mutation in intron 3 10 bp downstream of exon 3 generating a novel splice signal. Seven tumours (21%) showed cyclin D3 overexpression, including all three thyroid lymphomas (P = 0.006). Cyclin D3 overexpression and p16INK4A/pRb aberrations were mutually exclusive, supporting an oncogenic role for cyclin D3 in DLCL. p16INK4A inactivation, cyclin D3 overexpression, or aberrant pRb expression was identified in 18 of 34 DLCLs (53%). Combining these results with our previous p53 pathway studies showed that 82% of the de novo DLCLs had alterations of these pathways, and that both pathways were altered in 13 cases (38%). Low E2F-1 expression was associated with treatment failure (P = 0.020), and multivariate analysis of overall survival identified both low E2F-1 expression (relative risk = 6.9; P = 0.0037) and p16INK4A inactivation (relative risk = 3.3; P = 0.0247) as independent prognostic markers. These data support a role of E2F-1 as tumour suppressor gene in lymphoma and strongly suggest that the RB1 and p53 pathways are important in the development of de novo DLCL. Furthermore, low E2F-1 expression and p16INK4A inactivation may serve as prognostic markers for patients with this type of lymphoma.
Leukemia 2000 May
PMID:Frequent disruption of the RB1 pathway in diffuse large B cell lymphoma: prognostic significance of E2F-1 and p16INK4A. 1080 23

Primary effusion lymphoma (PEL) represents a peculiar type of B cell lymphoma which associates with HHV-8 infection and preferentially grows in liquid phase in the serous body cavities. In this report, we provide the detailed characterization of a newly established PEL cell line, termed CRO-AP/6. The cell line was obtained from the pleural effusion of a HIV-positive patient with PEL. Its derivation from the tumor clone was established by immunogenotypic analysis. Detailed phenotypic investigations defined that CRO-AP/6 reflects pre-terminally differentiated B cells expressing the CD138/syndecan-1 antigen. Karyotypic studies of CRO-AP/6 identified several chromosomal abnormalities, whereas genotypic studies ruled out the involvement of molecular lesions associated with other types of B cell lymphoma. Both CRO-AP/6 and the parental tumor sample harbored infection by HHV-8. Conversely, EBV infection was present in the parental tumor sample although not in CROAP/6, indicating that CRO-AP/6 originated from the selection of an EBV-negative tumor subclone. The pattern of viral (HHV-8 v-cyclin) and cellular (p27Kip1) regulators of cell cycle expressed by CRO-AP/6, together with the results of growth fraction analysis, point to abrogation of the physiological inverse relationship between proliferation and p27Kip1 expression. Also, both CRO-AP/6 and the parental tumor sample display biallelic inactivation of the DNA repair enzyme gene O6-methylguanine-DNA methyltransferase (MGMT) by promoter methylation. Overall, the CRO-AP/6 cell line may help understand cell cycle control of PEL cells, may clarify the relative contribution of HHV-8 and EBV to the disease growth and development and may facilitate the identification of recurrent cytogenetic abnormalities highlighting putative novel cancer related loci relevant to PEL.
Leukemia 2000 Jul
PMID:Characterization of a novel HHV-8-positive cell line reveals implications for the pathogenesis and cell cycle control of primary effusion lymphoma. 1091 56

Hydroxyurea, a differentiation-inducing agent of human erythroleukemia K562 cells, is commonly used to treat some types of leukemia. However, the mechanism for its therapeutic effect is not clearly understood yet. In this study, we have observed an interesting effect of hydroxyurea on tumor cells: an induction of senescence-like changes. Human erythroleukemia K562 cells, when treated with hydroxyurea for 7 days or more, underwent a change into phenotypically senescent cells together with a reduction of hemoglobin generation, a differentiation marker. The hydroxyurea-treated cells showed positive senescence associated-beta-galactosidase staining, a senescence index, and the accumulation of cdk (cyclin dependent kinase) inhibitors, such as p16INK4a, p21Waf1, and p27Kip1, implicated in cellular senescence. Nonetheless, these changes were not accompanied by DNA fragmentation. Taken together, we summarize that the long-term treatment of cancer cells with hydroxyurea can induce cellular senescence different from differentiation or programmed cell death.
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PMID:Hydroxyurea induces a senescence-like change of K562 human erythroleukemia cell. 1096 88

The functional role of the cyclin-dependent kinase inhibitor (CDKI) p21CIP1 in differentiation of human myelomonocytic leukemia cells (U937) exposed to low concentrations of the antimetabolite 1-beta-D-arabino-furanosylcytosine (ara-C) was examined utilizing a cell line stably expressing a p21CIP1 antisense construct. Continuous exposure to 50 nM ara-C led to marked induction of p21CIP1 at 48-72 h in empty-vector control cells but not in their antisense-expressing counterparts (p21AS/F4 and B8). Such treatment induced expression of the myelomonocytic differentiation marker CD11b in approximately 35% of control cells, but no evidence of maturation was noted in antisense-expressing lines. However, antisense-expressing cells exposed to low concentrations of ara-C exhibited a reciprocal increase in apoptosis, manifested by the appearance of cells with classic morphologic features and hypodiploid quantities of DNA, reduced mitochondrial membrane potential (deltapsim), an increase in cytochrome c release into the cytosol, cleavage/activation of procaspases-9 and -3, and degradation of PARP and p27Kip1. Whereas empty-vector control cells exposed to 50 nM ara-C exhibited a decline in Bcl-2 expression, dephosphorylation of pRb, and an initial accumulation in S-phase, antisense-expressing cells did not. However, c-Myc down-regulation induced by low concentrations of ara-C was, if anything, more complete in antisense-expressing cells. Exposure of control but not antisense-expressing cells to ara-C led to phosphorylation/activation of MAP kinase at 24 h; moreover, the specific MEK/MAP kinase inhibitor PD98059 enhanced low-dose ara-C-mediated apoptosis only in wild-type cells. Lastly, exposure to 50 nM ara-C for 72 h resulted in detectable levels of cytoplasmic p21CIP1, a phenomenon associated with resistance to apoptosis, only in empty vector controls. Collectively, these findings demonstrate a functional role for p21CIP1 in leukemic cell maturation induced by low concentrations of ara-C. They also indicate that, as in the case of more conventional differentiation-inducers such as phorbol esters, disruption of the p21CIP1 response after exposure to low concentrations of the cytotoxic drug ara-C prevents leukemic cells from engaging a maturation program, but instead directs them along an apoptotic pathway.
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PMID:Evidence of a functional role for the cyclin-dependent kinase inhibitor p21CIP1 in leukemic cell (U937) differentiation induced by low concentrations of 1-beta-D-arabinofuranosylcytosine. 1099 87

Characteristics of treatment-induced cell cycle arrest are important for in vitro and in vivo sensitivity of acute myeloid leukemia (AML) cells to cytotoxic drugs. We analyzed the expression of the major G1 cell cycle regulators (p21Cip1, p27Kip1, cyclins D, cyclin E and pRb) in 41 fresh AML cell samples. The level of p27 expression was the only factor correlated with the response to chemotherapy, a high level of p27 expression being predictive of complete remission. There was a close relation between expression of pRb, cyclin D2 and FAB subtype, illustrated by the absence of both proteins in most samples having a monocytic component (M4, M5). We also assessed the expressions of pRb, cyclin E, p21 and p27 and the activity of cdk2, the major regulator of S-phase entry, after exposure to cytosine-arabinoside (AraC) and daunorubicin (DNR), and found these proteins could characterize time- and dose-dependent cellular response to each drug. We observed hyperphosphorylated pRb, increased levels of cyclin E and a high cdk2 activity, but no p21 induction, in AML cells exposed to 10(-6) M AraC. After exposure to 10(-5) M AraC, corresponding to the serum concentration reached in high-dose AraC regimens (HDAraC), a strong p21 induction was observed, associated with similarly overexpressed cyclin E and even higher cdk2 activity than after 10(-6) M AraC, while apoptosis was significantly increased. These data suggest that cdk2 activity is likely to play a role in AraC-induced apoptosis in AML cells. This mechanism may account for high efficacy of HDAraC in cells showing little sensitivity to conventional AraC doses.
Leukemia 2001 Apr
PMID:Cell cycle regulatory protein expression in fresh acute myeloid leukemia cells and after drug exposure. 1136 57

Animal studies have demonstrated that a dietary polyphenol known as tannic acid (TA) exhibits anticarcinogenic activity in chemically induced cancers. Most recently, we have reported that TA and ester-bond containing green tea polyphenols are potent proteasome inhibitors in vitro and in vivo. We hypothesize that CellQuest, a patented formula which contains high level of TA obtained from a musaceas (plantain) plant extract, will inhibit the tumor cell proteasome activity. Here, we report that a partially purified CellQuest fraction, S3, potently inhibits the proteasomal chymotrypsin-like activity of Jurkat T cell extracts in a concentration-dependent manner. Inhibition of the proteasome by S3 in leukemia Jurkat T, simian virus 40-transformed and prostate cancer LNCaP cells results in accumulation of ubiquitinated proteins and the natural proteasome substrate p27Kip1, followed by induction of apoptosis. In contrast, non-transformed, immortalized human natural killer cells and normal human fibroblasts are resistant to S3-mediated proteasome inhibition and apoptosis induction. Our present study suggests that CellQuest targets and inhibits the proteasome selectively in tumor cells, which may contribute to the claimed anticancer activity.
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PMID:A natural musaceas plant extract inhibits proteasome activity and induces apoptosis selectively in human tumor and transformed, but not normal and non-transformed, cells. 1461 61

Adult T-cell leukemia (ATL) is a peripheral T-cell neoplasm caused by human T-cell leukemia virus type-I (HTLV-I). Since ATL cells often require IL-2 for their proliferation and survival, we examined the effect of IL-2 deprivation on the IL-2-dependent ATL cells established from ATL patients. After IL-2 withdrawal, these cells were arrested in the G1 phase and then underwent apoptosis. p27Kip1 was observed to act as a cell cycle inhibitor. A decrease in the amount of Bcl-xL was more distinct than that of Bcl-2, while Bax increased slightly during IL-2 withdrawal. The activation of caspase-3 and the loss of mitochondrial membrane potential were also observed. An overexpression of Bcl-xL protein in the KK1, one of the ATL cell lines, suppressed apoptosis by the 3rd day, however, apoptosis could not be prevented completely. Thereafter, a decrease in Bcl-xL and an activation of caspase-3 were observed even under the overexpression of Bcl-xL. The mitochondrial membrane potential and the intra-cellular levels of reactive oxygen species (ROS) also changed due to IL-2 deprivation. From these results, the IL-2 signals are considered to be essential for the survival of ATL cells, and the interruption of IL-2 signaling might thus be useful as a potentially new treatment for ATL.
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PMID:Growth arrest and apoptosis in adult T cell leukemia cell lines following IL-2 deprivation. 1525 42


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