Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The complement receptor 1 (CR1), also called CD35, is a polymorphic glycoprotein which mediates a variety of neutrophil functions, including phagocytosis and, probably, tumor cell cytotoxicity. The role played by this molecule in chronic myeloid leukemia (CML) is not yet well understood. CML frequently shows a marked decrease of CR1 antigens on both the neutrophil population and myeloid precursors. This reduced expression appears to be related to disease activity, since patients at more advanced clinical stages, as well as those who develop blastic crisis, have been found to express the lowest levels of CR1 antigens. At the onset of the disease low CR1 expression on CML neutrophils seems to be associated with a higher risk of blastic transformation. Furthermore, CML neutrophils deficient in CR1 lack the ability to respond to PMA stimulation, suggesting a failure in CR1 granular storage. In patients lacking CR1, the number of receptors increased to normal levels following exposure of CML cells to therapeutic concentrations of recombinant alpha interferon. The role played by the CR1 molecule in sustaining neutrophil-mediated tumor cell cytotoxicity has yet to be definitively proved; studies performed by our group are relevant here, since complete suppression of tumor lysis following receptor neutralization by anti CR1 monoclonal antibodies was demonstrated in a large number of normal and CML individuals. In CML patients, the evidence of a direct relationship between lytic activity and antigen receptor levels seems to further support the involvement of CR1 molecules in tumor cell lysis, function.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Complement receptor 1 (CR1) expression in chronic myeloid leukemia. 149 69

Chronic myeloproliferative diseases, such as chronic myeloid leukemia and polycythemia vera, are associated with neutrophil dysfunction. Very little data is available on essential thrombocythemia (ET). In the current study we evaluated 21 patients with ET. All patients were studied at least 16 weeks after any cytostatic therapy and 10 days after any other therapy. Neutrophil functions were investigated as follows: flow cytometric evaluation of whole blood phagocytosis of opsonized FITC-conjugated E. coli; whole blood chemiluminescence after stimulation with opsonized zymosan and evaluation by an automated, computer-assisted luminometer (LB 950, Berthold); and chemiluminescence and superoxide anion generation by purified neutrophils after f-MLP and PMA stimulation. Chemiluminescence and superoxide anion generation after f-MLP stimulation were found to be significantly lower than in normal subjects, whereas values within the normal ranges were registered after PMA stimulation. Phagocytosis-associated chemiluminescence was found to be impaired both by using zymosan opsonized with autologous plasma and zymosan opsonized with normal plasma, despite a normal phagocytic activity. These data show the presence in ET of a complex neutrophil dysfunction that may be related to an impaired signal transduction during both the phagocytic process and f-MLP stimulation.
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PMID:Neutrophil functions in essential thrombocythemia. 762 97

Our group recently cloned the cDNA-encoding bomapin, a member of the serine protease inhibitor (serpin) superfamily, from a human bone marrow cDNA library (J Biol Chem 270:2675, 1995). To understand its expression within the hematopoietic compartment, RNA extracted from bone marrow or peripheral blood from normal donors and patients with leukemia was reverse transcribed and analyzed by polymerase chain reaction (PCR). Bomapin PCR products were readily detected in normal bone marrow, which was designated as a medium mRNA level. In peripheral blood, bomapin expression was low or undetectable in normal donors (n = 6) and patients with chronic lymphocytic leukemia (n = 6). Blood from patients with chronic myeloid leukemia (n = 6), chronic myelomonocytic leukemia (n = 6), acute myeloid leukemia (n = 5), and acute lymphocytic leukemia (n = 5) exhibited low to medium levels of bomapin expression. Furthermore, a high level of bomapin expression was detected in one individual with acute monocytic leukemia. These data suggest that bomapin expression may be elevated in hematopoietic cells of monocytic lineage. Therefore, we analyzed the expression of bomapin within cell lines that exhibited characteristics of the monocytic lineage. Bomapin PCR products were detected in the monocytic THP-1 and AML-193 cell lines but not in CRL 7607, CRL 7541, KG-1, or K562 cells. Induction of bomapin transcripts was not detected in the latter series of cell lines following a 24-hour treatment with phorbol myristate acetate (PMA, 10(-8) mol/L) or tumor necrosis factor-alpha (TNF-alpha, 30 U/mL), whereas treatment of THP-1 or AML-193 cells with these agents reduced the intensity of the bomapin PCR products. Northern blotting confirmed these results and showed that the expression of bomapin in THP-1 cells was downregulated over a 4-day period by PMA and, to a lesser extent, TNF-alpha. Immunoblotting was used to show the presence of a 40-kD protein in THP-1 cytosol preparations. Bomapin antigen levels were correspondingly reduced after treatment with PMA. Because PMA and TNF-alpha induce monocytic differentiation in THP-1 and AML-193 cells, these data increase the possibility that bomapin may play a role in the regulation of protease activities specifically in early stages of cellular differentiation.
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PMID:Expression of bomapin, a novel human serpin, in normal/malignant hematopoiesis and in the monocytic cell lines THP-1 and AML-193. 945 55

Thirty-seven patients with chronic phase chronic myeloid leukaemia and fourteen healthy controls have been evaluated for lineage differentiation with immunological markers on purified bone marrow CD34 positive cells by multiparameter flow cytometry. The myeloid-associated antigen CD33 and the stem cell factor receptor (CD117, c-kit) was expressed by 82.3% and 73.5% on CP-CML patients and by 57% and 57.5% on healthy donors, respectively (P < 0.005). CD34+/CD19+ or CD34+/CD10+ B-lymphoid cell population represented 9. 1% and 10.7% of the CD34+ cells in CML whereas in normal controls this subpopulation was expressed by 27.9% and 30.4% of the CD34+ cells, respectively (P< 0.005). The T-lineage associated markers (CD7 and CD2) were detected on a minor population of CD34+ BM cells of healthy controls (mean, 3.6% and 4.6%, respectively). The CD2 positive cells represented 1.5% of the CD34+ cells in CML patients. CP-CML patients co-expressed the CD7 antigen on a mean of 32.6% of the CD34+ BM cells. Moreover, 93% of this CD34/CD7 double positive subpopulation co-expressed CD33 antigen in CML patients. Co-expression of CD7 on CD34+ cells was induced to decrease significantly after short-term in vitro culture with the differentiation-inducing agent phorbol ester (PMA) and with a combination of cytokines (stem-cell factor, interleukin-3 and granulocyte colony-stimulating factor). In conclusion, a high co-expression of CD7 antigen is demonstrated on CD34+ cells of chronic phase-chronic myeloid leukaemia patients. The loss of CD7 marker following incubation with PMA and cytokines suggests that this antigen is expressed transiently in early myeloid leukaemic CML haemopoiesis.
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PMID:CD7 expression on CD34+ cells from chronic myeloid leukaemia in chronic phase. 1039 10

abl and bcr genes play an important role in the diagnostics of chronic myelogenous leukemia (CML). The translocation of these genes results in an abnormal chromosome 22 called the Philadelphia chromosome (Ph). The chimeric bcr-abl gene is a fundamental phenomenon in the pathogenesis of CML. Malignant transformation of hematopoietic cells is also accompanied by the c-myc gene changes (translocation, amplification). Nuclear topology of the abl, bcr and c-myc genes was determined in differentiated as well as in irradiated HL-60 cells using dual-colour fluorescence in situ hybridisation and image analysis by means of a high resolution cytometer. After the induction of the granulocytic differentiation of HL-60 cells with all trans retinoic acid (ATRA) or dimethylsulfoxide (DMSO), the abl and bcr homologous genes were repositioned closer to the nuclear periphery and the average distances between homologous abl-abl and bcr-bcr genes as well as between heterologous abl-bcr genes were elongated as compared with untreated human leukemic promyelocytic HL-60 cells. Elongated gene-to-gene and centre-to-gene distances were also found for the c-myc gene during granulocytic differentiation. In the case of the monocytic maturation of HL-60 cells treated with phorbol esters (PMA), the abl and bcr homologous genes were repositioned closer to each other and closer to the nuclear centre. The position of the c-myc gene did not change significantly after the PMA stimulus. The proximity of the abl and bcr genes was also found after gamma irradiation using 60Co (5 Gy). Immediately after the gamma irradiation c-myc was repositioned closer to the nuclear centre, but 24 h after radiation exposure the c-myc position returned back to the pretreatment level. The c-myc gene topology after gamma irradiation (when the cells are blocked in G2 phase) was different from that detected in the G2 sorted control population. We suggest that changes in the abl, bcr and c-myc topology in the case of gamma irradiation are not the effects of the cell cycle. It is possible, that differences in the cell cycle of hematopoietic cells after the gamma irradiation and concurrent proximity of the abl, bcr and c-myc genes could be important from the point of view of contingent gene translocations, that are responsible for malignant transformation of cells.
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PMID:The influence of the cell cycle, differentiation and irradiation on the nuclear location of the abl, bcr and c-myc genes in human leukemic cells. 1073 5

Although differentiation of leukemic blasts to dendritic cells (DC) has promise in vaccine strategies, the mechanisms underlying this differentiation and the differences between leukemia and normal progenitor-derived DC are largely undescribed. In the case of chronic myeloid leukemia (CML), understanding the relationship between the induction of DC differentiation and the expression of the BCR-ABL oncogene has direct relevance to CML biology as well as the development of new therapeutic approaches. We now report that direct activation of protein kinase C (PKC) by the phorbol ester PMA in the BCR-ABL(+) CML cell line K562 and primary CML blasts induced nonterminal differentiation into cells with typical DC morphology (cytoplasmic dendrites), characteristic surface markers (MHC class I, MHC class II, CD86, CD40), chemokine and transcription factor expression, and ability to stimulate T cell proliferation (equivalent to normal monocyte-derived DC). PKC-induced differentiation was associated with down-regulation of BCR-ABL mRNA expression, protein levels, and kinase activity. This down-regulation appeared to be signaled through the mitogen-activated protein kinase pathway. Therefore, PKC-driven differentiation of CML blasts into DC-like cells suggests a potentially novel strategy to down-regulate BCR-ABL activity, yet raises the possibility that CML-derived DC vaccines will be less effective in presenting leukemia-specific Ags.
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PMID:Induced dendritic cell differentiation of chronic myeloid leukemia blasts is associated with down-regulation of BCR-ABL. 1290 78

Fibromodulin is an extracellular matrix protein normally produced by collagen-rich tissues; the fibromodulin gene has been found to be the most overexpressed gene in B-cell chronic lymphocytic leukemia. In this study, fibromodulin was expressed at the gene level (reverse transcription-polymerase chain reaction [RT-PCR]) in all patients with B-CLL (n = 75) and in most (5 of 7) patients with mantle cell lymphoma (MCL). No mutations in the fibromodulin gene were detected. Fibromodulin was also detected at the protein level in the cytoplasm of the B-CLL cells and in the supernatant after in vitro cultivation, but not at the cell surface. Fibromodulin was not found in patients with T-cell chronic lymphocytic leukemia (T-CLL), B-cell prolymphocytic leukemia (B-PLL), T-cell prolymphocytic leukemia (T-PLL), hairy cell leukemia, follicular lymphoma, lymphoplasmacytic lymphoma, multiple myeloma, acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), or chronic myelogenous leukemia (CML) or in 36 hematologic cell lines. Normal blood mononuclear cells (T and B lymphocytes, monocytes), tonsil B cells, and granulocytes did not express fibromodulin. Activation (phorbol 12-myristate 13-acetate [PMA]/ionomycin) of normal T and B lymphocytes induced weak fibromodulin gene expression, but not to the extent seen in freshly isolated B-CLL cells. The reason for the exclusive ectopic expression of fibromodulin in B-CLL and MCL is unknown. However, its unique protein expression makes it likely that fibromodulin is involved in the pathobiology of B-CLL and MCL.
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PMID:Fibromodulin, an extracellular matrix protein: characterization of its unique gene and protein expression in B-cell chronic lymphocytic leukemia and mantle cell lymphoma. 1574 Dec 14

Nuclear topography, expression of the BCR/ABL fusion gene and its protein level/cellular pattern were studied in CML cell line K562 stimulated to differentiation, apoptosis and influenced by ABL-RNA interference (ABL-RNAi). Phorbol ester-induced maturation of K562 cells was accompanied by repositioning of down-regulated BCR/ABL genes closer to the nuclear membrane. This nuclear rearrangement could be connected with differentiation-related heterochromatinization of the amplified BCR-ABL locus, as demonstrated by increased histone H3(K9) dimethylation and decreased H3(K9) acetylation of B3A2 breakpoint. Topography of BCR/ABL in differentiated K562 cells was compared with other leukemic cell types: PMA-maturation of HL60 cells did not influence the nuclear positioning of individual BCR and ABL genes. Moreover, BCR and ABL genes in non-stimulated HL60 as well as in the bone marrow cells of CML patients, i.e. also BCR/ABL fusion genes, were positioned more interiorly in comparison with BCR/ABL multiple loci of K562 cells. Decreased expression of BCR/ABL gene was also found after cell stimulation by selectively pro-apoptotic agent etoposide and by ABL-RNAi leading to apoptosis. In order to compare the efficiency of selected experimental strategies, levels of Bcr/Abl and c-Abl proteins were determined and in all cases tested were reduced. In K562 cells the Bcr/Abl and c-Abl proteins were distributed homogeneously in both the cell nucleus and cytoplasm, while differentiation of K562 cells was characterized by a distinct pattern of Bcr/Abl and c-Abl proteins that were focally distributed rather in the cytoplasm while apoptotic population was completely absent of Bcr/Abl and c-Abl signals.
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PMID:Nuclear topography and expression of the BCR/ABL fusion gene and its protein level influenced by cell differentiation and RNA interference. 1597 41

Trichosanthin (TCS), a type I ribosome-inactivating protein, induces cell death in various cell types including several tumor cell lines. However, the mechanism remains largely uncharacterized. In this study, we investigated the possible mechanism underlying its cytotoxicity by using human chronic myeloid leukemia cell line K562. We found that TCS induced apoptosis in K562 cells in a time- and concentration-dependent manner and can be blocked by caspase-3 inhibitors. Interestingly, TCS treatment induced a transient elevation in intracellular calcium concentration and a slow increase in reactive oxygen species production, while calcium chelators and antioxidants had no obvious effect on TCS-induced apoptosis, suggesting that calcium changes and reactive oxygen species may not be involved in TCS-mediated apoptosis in K562 cells. Instead we found that TCS partly inhibited PKC activity. Indeed, the PKC activator, PMA, inhibited while the PKC inhibitor, calphostin c, enhanced TCS-induced apoptosis. These PKC modulators had similar effects on TCS-induced cleavage of caspase-3, and caspase-3 inhibitors prevented calphostin c-enhanced apoptosis induced by TCS. In summary, we conclude that TCS induces apoptosis in K562 cells partly via PKC inhibition and caspase-3 activation.
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PMID:PKC inhibition is involved in trichosanthin-induced apoptosis in human chronic myeloid leukemia cell line K562. 1694 56

In chronic myeloid leukemia K562 cells, differentiation is also blocked because of low levels of ganglioside GM3, derived by the high expression of sialidase Neu3 active on GM3. In this article, we studied the effects of Neu3 silencing (40-70% and 63-93% decrease in protein content and activity, respectively) in these cells. The effects were as follows: (a) gangliosides GM3, GM1, and sialosylnorhexaosylceramide increased markedly; (b) cell growth and [(3)H]thymidine incorporation diminished relevantly; (c) as mRNA, cyclin D2, and Myc were much less expressed, whereas cyclin D1 was expressed more like its inhibitor p21; (d) as mRNA, pro-apoptotic proteins Bax and Bad increased with concurrent decrease and increase in the anti-apoptotic proteins Bcl-2 and Bcl-XL, respectively; (e) the apoptosis inducers etoposide and staurosporine were active on Neu3 silencing cells but not on mock cells; (f) as mRNA, the megakaryocytic markers CD10, CD44, CD41, and CD61 increased similar to the case of mock cells stimulated with PMA; (g) the signaling cascades mediated by PLC-beta2, PKC, RAF, ERK1/2, RSK90, and JNK were largely activated. The induction of a GM3-rich ganglioside pattern in K562 cells by treatment with brefeldin A elicited a phenotype similar to that of Neu3 silencing cells. In conclusion, upon Neu3 silencing, K562 cells show a decrease in proliferation, propensity to undergo apoptosis, and megakaryocytic differentiation.
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PMID:Silencing of membrane-associated sialidase Neu3 diminishes apoptosis resistance and triggers megakaryocytic differentiation of chronic myeloid leukemic cells K562 through the increase of ganglioside GM3. 1882 Jun 43


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