Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596978 (Leukemia)
 15,069 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor-beta (TGF-beta) has been found to block the progression of the cell-cycle by up-regulating a Cdk inhibitor, p15, only in epithelial cells; on the other hand, wild-type p53 was shown to activate transcriptionally the gene for another Cdk inhibitor, p21. The regulatory effects of TGF-beta on hematopoietic tissues is poorly understood. Hence, we investigated the effect of TGF-beta on hematopoietic progenitor cells in p53-deficient mice to determine whether an inhibitory signal from TGF-beta is linked to p53 in hematopoietic regulation. We found that the proliferation of megakaryocyte-progenitors (CFU-Mk) in our wild-type mice was markedly inhibited by TGF-beta. Contrary to an earlier report, an erythroid and a granulocyte-macrophage progenitor, stimulated by IL-3, were not significantly inhibited, whereas TGF-beta also completely inhibited the growth of high-proliferative potential progenitor cells (HPP-CFC) in the marrow of mice with 5-fluorouracil (5FU), as reported. It is interesting that in the p53-deficient mice, the inhibitory action of TGF-beta on the HPP-CFC was incompletely abolished. The response curve we obtained for graded doses of TGF-beta suggests that there is, at least, a subpopulation of HPP-CFC which is less sensitive to the regulation by TGF-beta. In contrast to HPP-CFC, the CFU-Mk, which TGF-beta inhibited only in wild-type mice not treated with 5FU, remained inhibited in the p53-deficient strain. Thus, HPP-CFC might be regulated by TGF-beta through their signal pathways which are linked to p53.
Leukemia 1997 Feb
PMID:A fraction unresponsive to growth inhibition by TGF-beta among the high-proliferative potential progenitor cells in bone marrow of p53-deficient mice. 900 87

The p21MDA6 gene product induces cell cycle arrest in p53-null human leukemic cells exposed to differentiation stimuli. We employed an HL-60 cell line stably transfected with a p21MDA6 antisense construct to compare the effects of p21MDA6 dysregulation on the response of myeloid leukemia cells to differentiating and cytotoxic agents. Antisense-expressing cells (HL-60/AS5) treated with 5 nM PMA for 24 h exhibited attenuated induction of p21MDA6 compared to empty vector controls (HL-60/V2). This phenomenon was accompanied by a reduction in the percentage of cells undergoing G1 arrest (67.6 +/- 4.7 vs 82.9 +/- 1.3; P < or = 0.01) and expressing the monocytic maturation marker cd11b (35.5 +/- 2.8 vs 50.5 +/- 2.4; P < or = 0.005). Although HL-AS5 and HL-60/V2 cells did not exhibit obvious differences in the phosphorylation status of the retinoblastoma protein (pRB), in E2F complex formation, or in p27klp1 induction following PMA exposure, inhibition of activity of cyclin-dependent kinase-2 was attenuated in the antisense-expressing line. A 24-h exposure to 5 nM PMA also reduced the cloning efficiency of HL-60/V2 cells to a significantly greater extent than HL-60/AS5 cells (ie to 30.1 +/- 7.0 vs 57.2 +/- 5.6 of controls; P < or = 0.01). In contrast to the disparate responses to PMA, HL-60/AS5 and HL-60/V2 cells treated with the antimetabolite 1-beta-D-arabinofurano-sylcytosine (Ara-C; 10 microM for 6 h) displayed equal susceptibility to G1 arrest, apoptosis, and inhibition of clonogenicity, phenomena unaccompanied by p21MDA6 and p27klp1 induction, or pRB dephosphorylation. These observations indicate that dysregulation of p21MDA6 in p53-null human myeloid leukemia cells interferes with PMA-related G1 arrest, CDK-2 inhibition, differentiation, and loss of clonogenic survival in the absence of obvious alterations in pRB phosphorylation status or E2F complex formation. They also provide functional evidence that p21MDA6 induction does not appear to be required for Ara-C-induced apoptosis, G1 arrest, or the resulting reduction in the self-renewal capacity of HL-60 cells.
Leukemia 1997 Apr
PMID:Effects of antisense p21 (WAF1/CIP1/MDA6) expression on the induction of differentiation and drug-mediated apoptosis in human myeloid leukemia cells (HL-60). 909 90

Leukemia cell proliferation is dependent upon cytokines produced by the leukemia cells or by the microenvironment under stimulation by leukemia cells. Abnormal expression of the p53, rb, and ras genes is associated with cytokine production, suggesting that abnormal expression can affect leukemia cells by affecting intracellular growth controls and by stimulating cytokine production. While these observations suggest that cytokines can be used to stimulate leukemia proliferation during cytotoxic therapy increasing the sensitivity to treatment, they also suggest that inhibition of cytokine affects could increase clinical responses by reducing leukemia cell regrowth between courses of therapy.
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PMID:Cytokines, molecular biological abnormalities, and acute myelogenous leukemia. 915 Mar 47

Leukemia in the soft-shell clam, Mya arenaria, is characterized by tumor cells which are detected initially in the hemolymph. This disease is much more common in clams inhabiting polluted waters, suggesting an environmental component to its pathogenesis. In this study, leukemia cells were identified using a murine monoclonal antibody, 1E10, which recognizes a leukemia-specific protein expressed by tumor cells. Mutant p53 protein was detected using a murine monoclonal antibody (PAb 240) which reacts with mutant p53. Using immunofluorescence, the reactivity of clam cells to the 1E10 antibody was evaluated along with mutant p53 protein reactivity. Reverse transcriptase-polymerase chain reactions followed by sequence analyses were utilized to examine clams with hemocytes reacting with the p53 antibody for possible p53 gene mutations. Mutant p53 protein was expressed by tumor cells from five animals with advanced disease (in which greater than 90% of cells reacted with 1E10). A C-->G transversion was detected at the end of exon 6 from two of the five animals that reacted with both the mutant p53 antibody and 1E10. This substitution changes the amino acid of this codon from proline to alanine. Overall, our results suggest that environmentally induced alterations in p53 can contribute to the pathogenesis of leukemia in soft-shell clams inhabiting polluted water and/or sediment.
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PMID:Detection of mutant p53 in clam leukemia cells. 916 98

Mutations of the N-ras oncogene and p53 tumor suppressor gene were simultaneously investigated in bone marrow cells from 44 patients with myelodysplastic syndrome (MDS) or MDS-derived leukemia by single-strand conformation polymorphism (SSCP) analysis followed by direct sequencing. The mutations of the N-ras gene were detected only in two cases with MDS-derived leukemia. Three patients with MDS-derived leukemia and one with refractory anemia with excess of blasts exhibited five mutations of the p53 gene. No concomitant mutations of both genes were observed in our study, suggesting that alterations of both genes could play an important role in the progression of MDS in a non-cooperative manner.
Leukemia 1997 Jun
PMID:No concomitant occurrence of the N-ras and p53 gene mutations in myelodysplastic syndromes. 917 41

The most frequent chromosome aberrations in B cell chronic lymphocytic leukemia (B-CLL) detected by conventional chromosome banding analysis are trisomy 12 followed by structural abnormalities of the long arms of chromosomes 13, 14, and 11. Complex karyotypes, trisomy 12, and a '14q+' abnormality have been associated with inferior prognosis, whereas aberrations of 13q have been found in patients with a favorable outcome. However, the cytogenetic analysis of B-CLL by conventional banding techniques has remained a difficult task mainly due to the low in vitro mitotic activity of the tumor cells. Although B cell mitogens are used for cell culture, clonal chromosome aberrations are detected in only half of the B-CLL tumors. 'Interphase cytogenetics' by means of fluorescence in situ hybridization (FISH) circumvents this problem, because there is no need to induce the malignant cells to proliferate in vitro. Numerical and structural chromosome aberrations can be detected in non-dividing interphase cells as well as in metaphase spreads. By FISH, the most common chromosome abnormalities are deletions of 13q followed by deletions of 11q, trisomy 12, and deletions of 17p. Except for the TP53 gene at 17p13, no candidate gene affected by these aberrations has so far been identified. FISH will be instrumental for the identification of such genes because the recurrent aberrations, especially deletions, can be systematically delineated to the resolution level of several kb. Furthermore, based on the sensitive detection of chromosome abnormalities by FISH, more accurate correlations between chromosome abnormalities and prognosis can be performed. Deletion of the TP53 gene at 17p13 have already been shown to be one of the most important independent prognostic factors for survival. Other specific aberrations of clinical significance will likely be identified by the systematic application of interphase cytogenetics on a large series of patients.
Leukemia 1997 Apr
PMID:Cytogenetic and molecular cytogenetic analysis of B cell chronic lymphocytic leukemia: specific chromosome aberrations identify prognostic subgroups of patients and point to loci of candidate genes. 917 33

A new cell line (LR10.6) with pre-B cell phenotype has been established from bone marrow cells obtained from a child with B lineage acute lymphoblastic leukemia in complete clinical remission. The line expresses nuclear TdT enzyme, cytoplasmic Ig lambda-chain and membrane mu-chain and other B but no T or myeloid markers. The cells also show activation antigens CD69 and CD71, adhesion molecules CD54, CD50 and CD56 and the tyrosine kinase receptor CD117. No expression of multidrug resistance phenotype MDR-1 is observed on these cells which nevertheless express the transcriptional factor p53 protein in a mutant form. Cytogenetic study shows a translocation t(5;12)(q31;p13) involving breakpoints which contain the growth factor interleukin 3 gene (5q31) and the recently identified TEL/ETV6 gene (12p13). Activation of the cells with phorbol-12 myristate 13-acetate (PMA) up-regulates the expression of the CD69 activation antigen and down-regulates the CD117 molecule. In addition, PMA fails to induce the CD20 B cell antigen.
Leukemia 1997 Jul
PMID:A new human cell line with pre-B cell phenotype and t(5;12). 920 88

Friend leukemia virus complex (FLV) consists of replication-defective, Friend spleen focus-forming virus (F-SFFV) and replication-competent, Friend murine leukemia virus (F-MuLV). We produced transgenic mice possessing F-SFFV gp55 gene and clarified that the gp55 glycoprotein encoded by F-SFFV env-related gene is, by itself, responsible for the initiation of erythroleukemia. The occurrence of erythroleukemia, however, is sporadic in these mice. Erythroleukemia cell lines established from these mice possessed mutations in the p53 allele. One had a temperature-sensitive mutant p53 allele, p53Val-135 and showed induction of apoptosis by expressing a wild-type p53 protein at 32 degrees C. Superinfection of the mice with Moloney murine leukemia virus (Mo-MuLV) conferred 100% induction of erythroleukemia, mutating p53 gene or activating Spfi-1 gene by insertional events. Activation of the JAK/STAT pathway, which is involved in cytokine signaling, was investigated in the gp55 signaling mediated by the erythropoietin receptor. JAK1 and STAT5 were constitutively tyrosine-phosphorylated but the DNA binding activity of STAT5 was not induced.
Leukemia 1997 Apr
PMID:Pathogenesis of Friend leukemia virus. 920 27

We have generated a series of murine erythroleukemia clones that ectopically express a temperature sensitive mutant p53 allele. In many clones, activation of p53 at low temperature resulted in the accumulation of cells in G1 and in apoptosis. Several cytokines including erythropoietin, IL-3 and the ligand for the Kit receptor blocked p53-dependent apoptosis in p53ts-expressing cells at 32 degrees C. Cytokine-treated cells were reversibly arrested in G1 and resumed growth upon return to 37 degrees C. Certain clones exhibited only a G1 arrest in response to p53 activation at 32 degrees C. One of the these clones secreted erythropoietin and another secreted IL-3. We tested the possibility that autocrine secretion of IL-3 played a role in preventing apoptosis and showed that disruption of the autocrine loop by cell dilution or with neutralizing antibodies to IL-3 restored p53-dependent apoptosis at 32 degrees C. Thus, two properties of p53 protein, namely, its ability to arrest cells in G1 and its ability to promote apoptosis could be uncoupled by cytokines acting as survival factors.
Leukemia 1997 Apr
PMID:p53-mediated cell cycle arrest and apoptosis. 920 79

The observation that wild type p53 may induce cells to undergo either apoptosis or differentiation raises the question of whether these two events share similar p53-dependent pathways. To evaluate the interrelationship between these two p53-dependent processes, our study focused on the human HL-60, a pro-myelocytic p53 non-producer cell line in which p53 expression was introduced and the induction of apoptosis and differentiation was followed under controlled conditions. p53 expression was induced in the HL-60 cell line by infection with the recombinant wild type p53 (p53WT) vaccinia virus. Viral infection gave rise to cells expressing various levels of wild type p53 protein. High levels of p53 protein induced cells to undergo rapid apoptosis, whereas lower levels of p53 protein induced cells to undergo cell differentiation at a more moderate rate of kinetics. These results suggest that p53 protein levels may determine whether a given cell should prefer one pathway over the other to exit the cell cycle.
Leukemia 1997 Apr
PMID:Expression of p53 in differentiation and apoptosis and its deregulation in tumor cell. 920 80


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