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)

The capabilities of 1alpha, 25-dihydroxyvitamin D3 (1,25(OH)2D3), and two novel vitamin D analogues, EB1089 and KH1060, to induce the differentiation of two established leukaemia cell lines, U937 and HL-60, were assessed alone or in combination with the retinoid compounds, 9-cis retinoic acid (9-cis RA) and all-trans retinoic acid (ATRA). The vitamin D derivatives acted to increase the differentiation of U937 and HL-60 cell cultures in a dose-dependent manner, as determined by nitroblue tetrazolium (NBT) reduction, with EB1089 and KH1060 being more effective than the native hormone. As an additional index of leukaemic cell differentiation, induction of expression of the phenotypic cell surface antigen, CD14, and the beta2-integrins, CD11b and CD18 by the vitamin D and retinoid compounds were monitored using fluorescence activated cell sorting (FACS) analyses. Following 96-hr treatment of U937 and HL-60 cells with 5 x 10(-10) M of the vitamin D derivatives, a striking increase in CD14 antigen expression was apparent, indicating the promotion by these compounds of a monocyte/macrophage lineage of cells. CD11b and CD18 antigen expression were also raised above control levels. In contrast, both retinoid compounds used at the higher concentration of 1 x 10(-8) M were not effective inducers of CD14 antigen expression. However, CD11b and CD18 were both readily increased in U937 and HL-60 cell cultures. Treatment of U937 cell cultures with the vitamin D compounds and the retinoids resulted in cooperative effects on induction of differentiation, with correlation by both NBT reduction and FACS analyses of CD14 antigen expression. The presence of 9-cis RA or ATRA appeared to contribute to the further increase of CD14 in these cells. HL-60 cell cotreatment with these compounds also displayed enhanced cooperative effects in phagocytic function by NBT reduction. However, analysis of CD14 revealed a dramatic diminution in HL-60 cells treated with the combinations of the vitamin D derivatives and the retinoids. Assessment of HL-60 cell morphology treated with these combinations demonstrated the presence of a mixed population of monocytes and granulocytes. CD11b and CD18 antigen expression was also enhanced in both cell lines with cotreatment. The ability of EB1089 and KH1060 to induce leukaemic cell differentiation may provide an additional option for therapeutic use alone or together with other differentiation agents such as 9-cis RA or ATRA.
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PMID:The role of vitamin D derivatives and retinoids in the differentiation of human leukaemia cells. 933 80

Although retinoic acid (RA) has been known for many years to be a modulating agent that plays a role in generating both granulocytes and monocytes, the molecular mechanism underlying this role has not been defined in the monoblast lineage. In particular, the part played by the retinoid X receptors (RXRs), which are members of the steroid/thyroid hormone nuclear receptor family, has not been explored. In this study, therefore, the human monoblastic leukemia cell line U937 has been used as a model system to investigate the role of one of the RXRs, RXR-alpha, in monoblast differentiation. RXR-alpha mRNA was present in untreated U937 cells, and levels increased after induction of differentiation with phorbol ester. The same was found for RXR-beta mRNA. Using plasmids containing sense or antisense RXR-alpha sequences under the control of an inducible promoter, we generated stably transfected cell lines which expressed either increased or decreased levels of RXR-alpha, respectively. The sense cell lines (U alpha S and its clonal derivative alpha G2S) showed increased sensitivity to RA, while the antisense cell lines (U alpha A and its clonal derivative alpha B5A) showed decreased sensitivity to RA, as demonstrated by growth inhibition and by regulation of an RA-responsive reporter gene. Both U alpha A and alpha B5A also failed to respond to another modulating agent, 1 alpha,25-dihydroxycholecalciferol (DHCC), but only U alpha S and not alpha G2S showed an enhanced response to DHCC. The combination of RA and DHCC together inhibited growth of both sense and antisense cell lines. In addition, alpha G2S exhibited increased expression of CD11b and CD54, while alpha B5A cells showed increased expression of CD102, suggesting that RXR-alpha has a role in regulating expression of cell adhesion molecules in U937 cells. These results demonstrate that RXR-alpha has a role in mediating growth inhibition and cell adhesion during myelomonocytic differentiation, and suggest that different species of heterodimers involving RXR-alpha may control the acquisition of different features of mature monocyte/macrophage function.
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PMID:Stable transfection of U937 cells with sense or antisense RXR-alpha cDNA suggests a role for RXR-alpha in the control of monoblastic differentiation induced by retinoic acid and vitamin D. 934 89

We report a case of a 70-year-old man with a hybrid leukemia treated successfully with granulocyte-colony stimulating factor (G-CSF) combined with a cytocine arabinoside regimen through the induction of differentiation of leukemic cells into monocytoid cells resulting in apoptosis. The leukemic cells demonstrated a TCR-gamma rearrangement, and expressed CD2, CD7, CD33 and G-CSF receptors but not CD11b on the cell surface nor non-specific esterase in cytoplasm. Several days following the administration of G-CSF, the cells with monocytoid characteristics such as CD11b and cytoplasmic non-specific esterase appeared in the peripheral blood replacing the blastic cells. The cells were shown to be derived from the same clone of the leukemic cell because of the identical TCR-gamma gene rearrangement. The short-term culture of leukemic cells with G-CSF induced the differentiation into a monocyte lineage, resulting in apoptosis. Although there is no denying the possibility that cytosine arabinoside is partly responsible, our results strongly suggest that G-CSF plays the main role in differentiation of leukemic cells into a monocyte lineage inducing apoptosis in vivo in this patient.
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PMID:Granulocyte-colony stimulating factor induces differentiation and apoptosis of CD2, CD7 positive hybrid leukemia cells in vivo and ex vivo. 937 81

We have investigated a case of acute myelocytic leukaemia derived from myelodysplastic syndrome (MDS-AML) with an 8;21 translocation. In this case the AML1/MTG8 (ETO) fusion transcript was not detected by reverse transcriptase-polymerase chain reaction (RT-PCR), and the rearrangement of the AML1 gene locus was not detected by Southern blot nor pulse field gel electrophoresis (PFGE) analyses using specific probes for the AML1 gene. Fluorescence in-situ hybridization (FISH) study using cosmid probes for 21q22 revealed that the breakpoint of 21q22 was telomeric to the AML1 gene locus and centromeric from D21S259, 351, 3421 loci. This is the first report concerning the t(8;21)(q22;q22) carrying AMLs (de novo AML, MDS-AML and therapy-related AML) to show that the breakpoint at 21q22 is located outside the AML1 gene locus. It is also noteworthy that the cell-surface antigen expression pattern of the bone marrow (BM) blasts was changed from CD7+ CD2+ CD13+ CD33+ CD19- CD11b+ CD14+ CD36+ to CD7- CD2- CD13+ CD19+ CD11b- CD14- CD33+ CD34+ CD36- CD56+ during leukaemic progression, and the pattern in leukaemic phase was similar to the characteristic phenotype of de novo AML cases with t(8;21), when the AML1/MTG8 fusion transcripts are always detected by RT-PCR.
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PMID:Genetic analysis of 8;21 chromosomal translocation without AML1 gene involvement in MDS-AML. 940 Oct 77

In 227 of 495 (45.9%) Japanese adult patients with acute myelocytic leukemia (AML), leukemic cells expressed CD4. Incidence of CD4 expression in each FAB subtype was as follows: M1 37.4%, M2 33.7%, M3 35.4%, M4 65.0%, and M5 78.3%. The typical expression pattern of myelomonocytic differentiation antigens and cytokine receptors in CD4+ AML was CD34lowCD33high CD11bhighGM-CSFRhigh. AML cases with 11q23 abnormalities and with inv(16) were frequently CD4-positive. These data collectively indicate that CD4 expression in AML cells is associated with monocytic characteristics. However, CD4+CD34high AML cases appear to have unique immature characteristics including low expression of myelomonocytic differentiation antigens (ie CD33 and CD11b), and accumulation of chromosome abnormalities (ie t(8;21) in CD4lowCD34high AML and chromosome 7 abnormalities in CD4highCD34high AML). We speculate that these leukemia subsets originate from CD4+ hematopoietic precursor cells, therefore then should be considered separately from most of the CD4+ AML as represented by CD34lowCD33high CD11bhighGM-CSFRhigh. Overall survival of patients with CD4+ AML in our series was worse than that of those with CD4 AML (P = 0.0202).
Leukemia 1998 Jan
PMID:Biphasic expression of CD4 in acute myelocytic leukemia (AML) cells: AML of monocyte origin and hematopoietic precursor cell origin. 943 19

The active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), is a potent inducer of differentiation in myeloid leukaemia cells, but its clinical use is limited because of its hypercalcaemic activity. We examined the ability of 1,25(OH)2D3 in combination with several anti-cancer drugs to inhibit the proliferation of, and induce differentiation in, human monoblastic leukaemia U937 cells. Hydroxyurea (HU), cytarabine and camptothecin showed effective synergism with 1,25(OH)2D3 with regard to growth inhibition, while daunorubicin and etoposide had only modest synergistic effects. HU and cytarabine effectively enhanced nitroblue tetrazolium-reducing activity induced by 1,25(OH)2D3. HU also enhanced the morphological maturation and expression of CD11b and CD14 in cells treated with 1,25(OH)2D3. Among the anti-cancer drugs examined, HU had the greatest synergistic effects with 1,25(OH)2D3 with regard to growth inhibition and differentiation induction in U937 cells. HU also enhanced the differentiation of other myeloid leukaemia HL-60, ML-1, THP-1, P39/TSU, P31/FUJ and NB4 cells induced by 1,25(OH)2D3 and that of U937 cells induced by 24-epi-1,25(OH)2D2 and 1,25(OH)2D7. Interestingly, 1alpha(OH)D derivatives (1alpha-hydroxyvitamin D3, D2, D4 and D7) effectively induced the differentiation of monoblastic leukaemia U937, P39/TSU and P31/FUJ cells. HU also enhanced the growth inhibition and differentiation of U937 cells induced by 1alpha(OH)D derivatives. As 1alpha(OH)D derivatives preferentially act on monocytic cells, they may be useful in the treatment of acute monocytic leukaemia, both alone and in combination with HU.
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PMID:Growth inhibition and differentiation induction in human monoblastic leukaemia cells by 1alpha-hydroxyvitamin D derivatives and their enhancement by combination with hydroxyurea. 945 43

While assessing the prognostic implications of immunophenotyping in 382 patients enrolled in treatment protocols of the Eastern Cooperative Oncology Group (ECOG) for de novo adult acute myeloid leukaemia, we identified 95 patients with a unique antigen profile characterized by high expression of the leucocyte integrin CD11b (CD11b+ AML). High expression of CD11b was defined as > or = 32% positive blasts based on the retrospectively established prognostic cut-off point for this antigen. Although CD11b is normally expressed by mature monocytes, natural killer cells and granulocytes, leukaemic blasts in CD11b+ AML lacked other immunologic monocytic features (e.g. CD14 and CD122, the interleukin-2 receptor beta chain) and demonstrated a high degree of immaturity, as reflected by a high incidence of blasts expressing the stem cell factor receptor, CD117, and few blasts positive for the myeloid differentiation antigen CD15. Furthermore, by FAB criteria, only 41% of CD11b+ AML cases were classified as M4/M5. Patients with CD11b+ AML had a low response rate (54%) when compared with acute monocytic leukaemia (AMOL; 82%, P = 0.006) or AML overall (68%, P = 0.031), independent of age, cytogenetic abnormalities and P-glycoprotein expression. Because of its poor prognosis, recognition of CD11b+ AML is clinically warranted and, given its morphologic and cytogenetic ambiguity, must be based on the unique antigen profile.
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PMID:Acute myeloid leukaemia expressing the leucocyte integrin CD11b-a new leukaemic syndrome with poor prognosis: result of an ECOG database analysis. Eastern Cooperative Oncology Group. 948 12

11q23 translocations (t(11q23)) are recurring cytogenetic abnormalities in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia, involving the same gene, ALL1 (or MLL). Mixed lineage antigen expression has been reported in these leukemias, but its frequency and clinical significance are unknown. We immunophenotyped leukemia cells from 19 adult de novo AML patients with t(11q23) by multiparameter flow cytometry. Translocations included t(6;11)(q27;q23), t(9;11)(p22;q23), t(9;11;19)(p22;q23;q13.3), t(2;11)(11;17)(q37;q11q23;q11), t(11;17)(q23;q25), t(11;19)(q23;p13.1), t(11;19)(q23;p13.3) and t(11;22)(q23;q11). FAB types were M4 and M5. The committed stem cell and myeloid antigens HLADr, CD4dim, CD11b, CD13, CD15, CD32, CD33, CD38 and CD64 were each expressed in 80-100% of cases, and the early stem cell and lymphoid antigens CD34, CD56, CD3, CD2 and CD7 in 42, 39, 16, 5 and 5%, respectively. Antigen expression frequencies did not differ from those in 443 adequately karyotyped M4 and M5 cases without t(11q23). Fifteen patients (79%) attained complete remission (CR); median CR duration and survival were 10.0 and 15.1 months. CR duration and survival did not correlate with antigen expression. In particular, patients with t(9;11) survived longer than those with other t(11q23) (median not reached vs 7.6 months; P = 0.048), but antigen expression did not differ in the two groups. Thus frequencies of lymphoid antigen expression are similar in AML with t(11q23) and in other FAB M4 and M5 cases, treatment outcome does not differ in t(11q23) cases with and without lymphoid antigen expression, and better outcome of patients with t(9;11) compared to other t(11q23) does not correlate with differences in antigen expression. Mixed lineage antigen expression is not a distinctive feature of AML with t(11q23).
Leukemia 1998 Mar
PMID:Acute myeloid leukemia with 11q23 translocations: myelomonocytic immunophenotype by multiparameter flow cytometry. 952 25

Phorbol esters exert a dual function in human leukemia cells, induction of differentiation and activation of integrin-mediated functions. Here we have shown that the plastic adherence of phorbol ester-treated U937 cells is mediated by expression of integrin Mac-1 (CD11b/CD18) on the cell surface and that these adherent cells exhibit anoikis (apoptosis when adherent cells are detached or adherence is inhibited). We used U937-derived clones overexpressing either antisense RNAs antisense to CD11b and CD18 mRNAs or mRNA from a truncated mutant CD11b gene. We have also shown that apoptosis in non-adherent cells or anoikis was mediated by sphingosine and that survival of adherent cells was achieved by a shift of the dynamic balance between sphingosine and sphingosine 1-phosphate toward the latter by adherence-activated sphingosine 1-kinase.
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PMID:Involvement of Mac-1-mediated adherence and sphingosine 1-phosphate in survival of phorbol ester-treated U937 cells. 953 36

We have demonstrated previously that a phosphorothioate antisense oligonucleotide to the p65 subunit of the inducible transcription factor NF-kappaB produced rapid changes in the expression of leukocyte integrin CD11b (Mo 1) and in the adhesion of dimethylsulfoxide (DMSO)-differentiated HL-60 cells stimulated by 12-O-tetradecanoylphorbol 13-acetate. We have also shown that a variety of agents which inhibit NF-kappaB, including vitamin E and related antioxidants, curcumin and several non-steroidal anti-inflammatory agents, significantly enhanced the differentiation of HL-60 leukemia cells when combined with low levels of 1,25-dihydroxyvitamin D3 (vitamin D3). To provide further evidence that interference with the activation of NF-kappaB affects the maturation of HL-60 leukemia cells by creating an environment conducive to terminal differentiation, we measured the effects of phosphorothioate antisense oligonucleotides to the various subunits of NF-kappaB on the differentiation of HL-60 cells produced by low levels of vitamin D3. When used alone these oligonucleotides had no significant effect on the differentiation of HL-60 cells. However, the antisense oligomer to the Rel A subunit of NF-kappaB markedly increased the extent of differentiation produced by low levels of vitamin D3. An enhancement of the differentiation of HL-60 cells induced by vitamin D3 was also obtained by several transcription factor decoys designed to mimic the consensus sequences of genes activated by Rel A. The findings provide additional support for the concept that inhibition of the activation of NF-kappaB may be involved in regulating the entry of promyelocytic leukemia cells into a differentiation pathway.
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PMID:Enhancement by antisense oligonucleotides to NF-kappaB of the differentiation of HL-60 promyelocytic leukemia cells induced by vitamin D3. 956 10


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