Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have adapted the alkaline phosphatase-anti alkaline phosphatase (APAAP) technique to demonstrate cell antigen distributions in intact agar culture. The method facilitates batch processing and is no less convenient to perform than standard APAAP procedures. Myeloid and lymphoid antigens generally demonstrated strong staining intensity. However, staining at day 0 consistently produced no antigen expression for two monoclonals (CD11c and CD34) in contrast to positivity in parallel cytospins. CD11c showed rapidly increasing antigen expression over subsequent days of culture whereas the expression of CD34 could not be shown in conventional agar culture at any time from day 0 to day 14. Positivity was only restored in CD34-positive leukaemic cells using a modified culture technique in which cells were cultured as pre-formed small aggregates. Assessment of these aggregates extended to cell cycle analysis using anti-bromodeoxyuridine. CD71 positivity in normal culture samples correlated with colony configuration (whether clones were 'spread' or 'tight' in appearance). CD38 staining of normal bone marrow culture at day 7 showed asymmetrical staining of cells in a small number of micro-groups. The clonal detection of aberrant antigens (CD7, CD2) for assessment of minimal residual disease in AML was a disappointment due to the relative frequency of positive clones in normal culture.
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PMID:Immunostaining of whole agar cultures by APAAP. 762 32

In a panel of acute myeloblastic leukemia (AML) cell lines, representative of distinct differentiation stages, we investigated the possible correlation between drug-resistance and both expression and function of the multidrug resistance (MDR)-related P-glycoprotein (P-gp). The AML cell lines were KG1a, KG1, TF1, HEL, ML1, and two non drug-selected P-gp positive subclones originating from HL-60 (HL-60JD) and U937 (U937AQ). All these cells overexpressed the mdr1 gene (analyzed by RT-PCR) and displayed variable levels of P-gp expression. Flow cytometric semi-quantitative evaluation of P-gp with two P-gp specific monoclonal antibodies (MRK16 and UIC2) showed the following P-gp expression hierarchy: TF1 < KG1a < HEL < KG1 < HL-60JD < ML1 < U937AQ; the latter expressing 13 times more P-gp than TF1. When P-gp function was assessed by Rhodamine 123 (Rh123) efflux kinetics, we found that only KG1a and KG1 cells, which have an early (immature) CD34+ CD33- CD38- phenotype, and to a lesser extent TF1, with an intermediate (CD34+ CD33+ CD38+) phenotype, displayed significant P-gp activity which could be inhibited by both verapamil and SDZ PSC 833. In contrast, the other more mature CD33+ CD34- AML cell lines presented no Rh123 efflux capacity although they expressed higher P-gp levels. Daunorubicin (DNR) accumulation studies showed that inhibitors of P-gp increased DNR accumulation only in the immature AML cells whereas they had no impact on the mature AML cell lines. MTT drug cytotoxicity assay confirmed that the immature AML cells were 10-15-fold more resistant to DNR than the mature AML cells. Although P-gp inhibitors were able to increase the cytotoxicity of DNR in AML cells which displayed functional P-gp, they could not increase DNR cytotoxicity to levels comparable to that of the CD34- CD33+ cells, suggesting that DNR resistance of immature AML cells may not solely be related to P-gp. With drug-selection, AML subclones displayed higher levels of P-gp expression and higher extruding capacities, and therefore chemoresistance, and this independently of their initial differentiation phenotype. Finally, this study provides evidence for a lack of correlation between expression and function of P-gp in AML cells; this relationship being dependent upon leukemic cell differentiation in unselected myeloid leukemic cells.
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PMID:Lack of correlation between expression and function of P-glycoprotein in acute myeloid leukemia cell lines. 776 42

Bone marrow blast cells of 174 child and 188 adult patients with AML were examined and characterized in terms of their FAB type, immunological phenotype (102 children, 123 adults) and karyotype (69 children, 95 adults). The incidence of FAB variants of AML proved similar in children and adults. In patients under 15 and over 60, peroxidase activity in myeloblasts was lower than in middle-aged patients. Similar rates of HLA-Dr. Thy-1, CD11a, T-cell antigens, CD19, Gly-A and Eb antigens were found in cells of child and adult patients. The frequency of CD11b, CD38 and CD10 antigen expression on blast cells was higher in children than in adults. Abnormal blast karyotype was noted in 81.8% of children and 73.7% of adults. Translocation (8;21) was usually found in cases of M2 type (82%), significantly more frequently in children. predominantly in the group aged 6-10. t(15;17) was detected in all age groups only in M3 type of cells (86%). t(9;22) occurred more frequently in adults than in children; t(11q23) incidence rates were somewhat higher in children than in adults. Three cases of AML in children are described with deletion of chromosome 5 in their leukaemic cells. The data obtained indicate different biological characteristics of blast cells in children and adults. It is likely that haemopoietic cell involvement in children under 2 years and adult patients over 60 occurs at earlier stages than in middle-aged patients.
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PMID:Blast cells in child and adult AML: comparative study of morphocytochemical, immunological and cytogenetic characteristics. 798 10

In 72 patients with blood malignancies (leukemias), the expression and distribution of the "B-lineage" antigen CD38, was analyzed, individually and in combination with CD19, CD10, HLA-DR, CD13, CD14, CD33, CDw65, CD2 and CD7. The expression of CD38 on the surface of leukemic cells was totally different from its expression on normal hematopoietic cells. Its positivity in myeloid malignancies was as follows: In patients with acute myeloid leukemia in 21/28 cases-75% (probability of expression 0.68 +/- 0.2, p < 0.05) and in patients with chronic myeloid leukemia in 4/6 cases-66%. In lymphoproliferative malignancies the CD38 antigen was expressed as follows: In patients with acute non-T lymphoblastic leukemia in 12/16 cases-75% (probability of expression 0.7 +/- 0.2, p < 0.05) and in patients with chronic B lymphocytic leukemia in 6/8 cases-75%. CD38 was also found positive in patients with acute mixed lineage leukemia.
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PMID:Immunophenotypic significance of the "lymphoid" CD38 antigen in myeloid blood malignancies. 828 67

Despite the usual uniform and primitive appearance of cells derived from the leukemic clone in most patients with acute myeloid leukemia (AML), there is considerable heterogeneity among leukemic blasts, particularly with respect to their capacity to proliferate and/or self renew. We have assessed whether these differences in proliferative potential are correlated with the phenotypic changes that characterize normal hematopoiesis, which might suggest an analogous hierarchy of AML progenitors. We have used the ability of primitive AML cells to persist or produce blast colony forming cells (CFU-blast) detected after 2 to 8 weeks in the presence of growth factors in suspension cultures (SC) termed SC-initiating cells (IC), or with stroma in long-term cultures (LTC-IC) as a quantitative assay for a cell that may have primitive characteristics. This SC assay is linear, cell concentration independent, and the frequency of SC-IC by limiting dilution analysis is lower than primary CFU-blast. The average output of CFU-blast after 2 to 8 weeks by individual SC-IC varied between 2 and more than 100 in individual patients. Leukemic blasts were sorted based on their expression of antigens previously found useful to characterize normal progenitor differentiation, and analyzed for the percentage of CFU-blast SC-IC, and leukemic LTC-IC within each fraction. All of these progenitor types were heterogeneous in their expression of CD45RA and CD33, but expressed uniformly low levels of CD15 and differed from normal primitive progenitors in their high expression of HLA-DR. CFU-blast had a significantly higher expression of CD71 and CD38 as compared with SC-IC or leukemic LTC-IC. In patients with CD34+ blasts, the majority of their SC-IC at 4 weeks were CD34+/CD38-; however, patients with CD34- blasts had at least some CD34- progenitors. These results show that while heterogeneity exists between patients, it is possible to physically separate subpopulations of AML cells with different proliferative potentials. It also provides some support for the concept that quantitation of leukemic cells capable of producing CFU-blast for 4 weeks or more in vitro measures a less frequent leukemic progenitor with higher proliferative potential that may be the only relevant cell for maintaining the leukemic clone in vivo.
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PMID:Characterization of a hierarchy in human acute myeloid leukemia progenitor cells. 863 46

A review of recent information on the expression and the ATRA-driven modulation of cell surface adhesion molecules of acute myelogenous leukemia blast cells is presented. Cytofluorometric studies on fresh blast cells have demonstrated that CD11a, CD11b CD11c, CD15, CD45RO and CD54 expression is significantly lower in acute promyelocytic leukemia (APL) than is acute myeloid leukemia of other subtypes (AML). In vitro treatment with ATRA dramatically modifies the adhesion phenotype of APL blast cells, promoting a consistently striking up-regulation of CD11b, CD11c, CD15, CD65, CD54, and CD38. Which is in general, poorly demonstrable in AML. The behaviour of CD15s is variable and fully independent from CD15 and CD65 in induction experiments, suggesting a differential enzyme regulation within the selectin ligand system. ATRA is capable, in both APL and AML, of producing a switch from the high- (RA) to the low- (RO) molecular weight isoform of CD54, Moreover, treatment with this retinoid exerts a negative regulation of the membrane expression of CD49e, CD58 and CD11a in APL as well as in AML. Of particular interest is the fact that the negative effect on CD1 1a expression generates an asynchronous phenotype in APL (CD11a-, CD11b+, CD15+), undetectable on normal maturing myeloid cells. In the last part of this review the possible implications of adhesion molecule modulation in the pathogenesis of ATRA syndrome are discussed.
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PMID:All-trans retinoic acid (ATRA) and the regulation of adhesion molecules in acute myeloid leukemia. 872

The active form of vitamin D3 [1 alpha, 25-dihydroxyvitamin-D3 (1 alpha, 25(OH)2D3)] modulates the proliferation and differentiation of hematopoietic cells. Analogs of 1 alpha, 25(OH)2D3 that have greater potency may have the potential as adjuvant therapy for high-risk patients in remission for acute myelogenous leukemia (AML) and myelodysplastic syndromes. A new generation of 11 analogs of 1 alpha, 25(OH)2D3 has been synthesized, and we examined their effects on the human leukemic cell line HL-60. This cell line provides a sensitive monitor of activity of the 1 alpha, 25(OH)2D3 analogs. All the compounds were potent, producing a 50% clonal inhibition (ED50) in the range of 10(-8) to 10(-11) mol/L; nine of the 11 analogs had ED50s at concentrations that were at least 10-fold lower than those for the parental 1,25(OH)2D3. The most active compound [cmpd LA, (22R)-1 alpha, 25-(OH)2-16,22,23-triene-D3] had an ED50 of 2 x 10(-11) mol/L; it was also tested on clonogenic cells from patients with AML, and it achieved an ED50 of approximately 6 x 10(-11) mol/L, while 1 alpha, 25(OH)2D3 produced an ED50 of approximately 10(-8) mol/L on the same population of cells. Five different cell surface markers were examined on HL-60 cells exposed to the 1 alpha, 25(OH)2D3 analogs: HLA-DR and CD11b were induced by all of the compounds; CD13 was induced by six of the 12 compounds, including 1,25(OH)2D3; CD14 was strongly induced by all compounds; and CD38 was induced rather weakly by nine of 12 analogs. WAF1/CIP1/p21, a cyclin-dependent kinase inhibitor (CDKI), which is important in blocking the cell cycle, was examined by Western blot and was found to be induced by all of the compounds, suggesting a possible mechanism by which these analogs inhibit leukemic growth. The induction of WAF1 occurred at concentrations of vitamin D analogs as low as 10(-10) mol/L. This structure-function study showed that a new series of 1 alpha, 25(OH)2D3 analogs was active in clonal inhibition, as well as induction of differentiation and WAF1 expression of HL-60 cells. The key structural motifs included C-16 double bond, double and/or triple bonds in the side chain, lengthening of the side chain, 20-epi-conformation of the side chain, replacement of six hydrogens at the end of the side chain with fluorines, and the removal of C-19. Consideration should be given to further in vivo testing of toxicity and efficacy to move toward a clinical trial, especially in a setting of minimal residual disease.
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PMID:A new series of vitamin D analogs is highly active for clonal inhibition, differentiation, and induction of WAF1 in myeloid leukemia. 882 40

We previously demonstrated that the mitochondrial NADH dehydrogenase subunit 2 (ND2) gene was overexpressed in human acute myelogenous leukemia (AML) cells. Since this finding suggested that ND2 gene expression was related to myeloid differentiation, we here investigated the effects of rotenone, a specific NADH dehydrogenase inhibitor, on HL-60 cell growth, differentiation and death. Fifty nM rotenone inhibited the growth of HL-60 cells and caused an increase in the cell population in the G(2) +M phase. In the quantitative comparison of myeloid antigen, the expression of CD13 and CD38 were relatively increased in the rotenone-treated cells. These findings suggest that the inhibition of NADH dehydrogenase changes the cell cycle and induces some specific surface antigens of HL-60 cells. On the other hand, the expression of ND2 gene remained unchanged after the rotenone treatment, suggesting the rotenone-mediated mitochondrial inhibition did not affect the mitochondrial gene expression. Five mu M rotenone strongly inhibited the cellular proliferation. Electron microscopy and an electrophoretic analysis of DNA showed that the majority of the HL-60 cells were induced into typical apoptosis within 24-48 hours. On the basis of this and other studies, we believe that mitochondrial function is directly involved in both cellular differentiation and apoptotic cell death.
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PMID:Rotenone, a mitochondrial NADH dehydrogenase inhibitor, induces cell surface expression of CD13 and CD38 and apoptosis in HL-60 cells. 883 8

Resistance to chemotherapy in multiple myeloma (MM) and acute myeloid leukemia (AML) is frequently caused by multiple drug resistance (MDR), characterized by a decreased intracellular drug accumulation. MDR is associated with expression of P-glycoprotein (P-gp). GF120918, an acridine derivative, enhances doxorubicin cell kill in resistant cell lines. In this study, the effect of GF120918 on MDR cell lines and fresh human leukemia and myeloma cells was investigated. The reduced net intracellular rhodamine-123 (Rh-123) accumulation in the MDR cell lines RPMI 8226/Dox1, /Dox4, /Dox6 and /Dox40 as compared with wild-type 8226/S was reversed by GF120918 (0.5-1.0 microM), and complete inhibition of rhodamine efflux was achieved at 1-2 microM. This effect could be maintained in drug-free medium for at least 5 h. GF120918 reversal activity was significantly reduced with a maximum of 70% in cells incubated with up to 100% serum. GF120918 significantly augmented Rh-123 accumulation in vitro in CD34-positive acute leukemia (AML) blasts and CD38-positive myeloma (MM) plasma cells obtained from 11/27 de novo AML and 2/12 refractory MM patients. A significant correlation was observed between a high P-gp expression and GF120918 induced Rh-123 reversal (P=0.0001). Using a MRK16/IgG2a ratio > or = 1.1, samples could be identified with a high probability of GF120918 reversal of Rh-123 accumulation. In conclusion, GF120918 is a promising MDR reversal agent which is active at clinically achievable serum concentrations.
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PMID:In vitro effect of GF120918, a novel reversal agent of multidrug resistance, on acute leukemia and multiple myeloma cells. 894 33

It has been supposed in de novo AML that malignant transformation occurs at the level of committed progenitors. Recent data of our group and others provide evidence that in AML malignant transformation may regularly occur at the level of stem cells. These cells can be discriminated by function and specific surface molecules. CD34, a glycophosphoprotein, is a cellular surface antigen characteristically expressed by stem cells. CD34+ stem cells can be further subdivided by the expression of additional surface molecules like CD38 and CD117. In this article we present results from cytogenetic examinations of FACS-isolated stem cell subpopulations in eight patients (four AML and four MDS). Six of them displayed clonal karyotype abnormalities at the time of first diagnoses in the native bone marrow (5q-; 5q- and complex abnormalities; +8; inv(16) and +8; i(17q) and -21; i(21q)). We used CD117, the receptor for the stem cell factor (also KIT oncogene) as a new cellular surface marker. CD34+/CD117+/- stem cell subpopulations were examined in two patients with AML and three patients with MDS. We found leukemic stem cells in every type of stem cell subpopulation examined (CD34+/CD38-, CD34+/CD38+, CD34+/CD117-, CD34+/CD117+). Secondary, progression-associated chromosome abnormalities likewise were demonstrable in CD34+ cells. In three patients a mosaic of normal and abnormal metaphases was found in the highly purified stem cell subpopulations. We conclude that in AML and MDS stem cells are the target of leukemogenic genetic defects. CD117 as a new marker to isolate different CD34+ subpopulations was not sufficient to discriminate between normal and leukemic stem cells. Our findings have implications for autologous stem cell transplantation, high-dose chemotherapy and the pathogenetic concept of leukemogenesis.
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PMID:Cytogenetic analysis of CD34+ subpopulations in AML and MDS characterized by the expression of CD38 and CD117. 918 Feb 91


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