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)

Hematopoietic cell differentiation takes place in phenotypically recognizable stages characterized by morphology as well as by the expression of enzymes and surface markers. It is recognized that differentiation results from an interaction of environmental cues, such as cytokines and hormones, with internal cellular programs, but the precise mechanisms are not entirely clear. HL60 cells, a human acute myeloid leukemia (AML) cell line with promyelocytic features, provide a model for such studies because they behave like stem cells, which can differentiate into two different lineages, granulocytic or monocytic/macrophage, depending on the inducer. Protein levels and kinase activity of cyclin-dependent kinase 5 (Cdk5) were reported [F. Chen and G. P. Studzinski (1999) Exp. Cell Res. 249, 422, 1999] to increase in HL60 cells induced to monocytic differentiation by 1alpha,25-dihydroxyvitamin D3 (1,25D3), but the specificity of the association of Cdk5 with the monocytic phenotype has not been established. We show here that up-regulation of Cdk5 does not occur in granulocytic differentiation, whereas inhibition of Cdk5 activity by olomoucine, or its expression by a plasmid construct expressing antisense Cdk5, switches the 1,25D3-induced monocytic phenotype (a combination of positive nonspecific esterase reaction, expression of the CD14 marker, and morphology) to general myeloid phenotype (positive nitro-blue tetrazolium reaction, CD11b marker and morphology). The transcriptional up-regulation of Cdk5 by 1,25D3 was not inhibited by olomoucine. These findings show that in human myeloid cells up-regulation of Cdk5 is specifically associated with the monocytic phenotype.
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PMID:Specific association of increased cyclin-dependent kinase 5 expression with monocytic lineage of differentiation of human leukemia HL60 cells. 1077 Feb 90

The differentiation and apoptosis-sensitizing effects of the Bcr-Abl-specific tyrosine kinase inhibitor CGP57148B, also known as STI-571, were determined in human Bcr-Abl-positive HL-60/Bcr-Abl and K562 cells. First, the results demonstrate that the ectopic expression of the p185 Bcr-Abl fusion protein induced hemoglobin in the acute myeloid leukemia (AML) HL-60 cells. Exposure to low-dose cytosine arabinoside (Ara-C; 10 nmol/L) increased hemoglobin levels in HL-60/Bcr-Abl and in the chronic myeloid leukemia (CML) blast crisis K562 cells, which express the p210 Bcr-Abl protein. As compared with HL-60/neo, HL-60/Bcr-Abl and K562 cells were resistant to apoptosis induced by Ara-C, doxorubicin, or tumor necrosis factor-alpha (TNF-alpha), which was associated with reduced processing of caspase-8 and Bid protein and decreased cytosolic accumulation of cytochrome c (cyt c). Exposure to CGP57148B alone increased hemoglobin levels and CD11b expression and induced apoptosis of HL-60/Bcr-Abl and K562 cells. CGP57148B treatment down-regulated antiapoptotic XIAP, cIAP1, and Bcl-x(L), without affecting Bcl-2, Bax, Apaf-1, Fas (CD95), Fas ligand, Abl, and Bcr-Abl levels. CGP57148B also inhibited constitutively active Akt kinase and NFkappaB in Bcr-Abl-positive cells. Attenuation of NFkappaB activity by ectopic expression of transdominant repressor of IkappaB sensitized HL-60/Bcr-Abl and K562 cells to TNF-alpha but not to apoptosis induced by Ara-C or doxorubicin. Importantly, cotreatment with CGP57148B significantly increased Ara-C- or doxorubicin-induced apoptosis of HL-60/Bcr-Abl and K562 cells. This was associated with greater cytosolic accumulation of cyt c and PARP cleavage activity of caspase-3. These in vitro data indicate that combinations of CGP57148B and antileukemic drugs such as Ara-C may have improved in vivo efficacy against Bcr-Abl-positive acute leukemia.
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PMID:CGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl-positive human leukemia cells to apoptosis due to antileukemic drugs. 1097 73

The neural cell adhesion molecule, CD56, is expressed on acute myelogenous leukemia (AML) cells in 17-20% of the patients. However, the clinical and biological significance of its expression in AML has not been well analyzed from the standpoint of CD56 expression and its association with differentiation to a natural killer (NK) cell lineage. Here we present a 78-year-old patient with chronic myelomonocytic leukemia (CMML) whose leukemic cells had features of both monocytes and NK cells. We demonstrated that the leukemic cells were positive for CD4, CD56 and interleukin-2 (IL-2) receptor beta chain (CD112) in addition to myelomonocytic markers such as CD33, CD11b and CD11c. These leukemic cells proliferated well in vitro in response to 10-100 U/ml of IL-2, and functionally showed significant cytotoxicity against K562 target cells in a 4-hour (51) Cr release assay. All the above data indicate that these cells possessed at least some of the biological features of NK cells. Accordingly, we speculate that the leukemic cells in this patient may have been derived from a possible common progenitor of monocytes and NK cells.
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PMID:Chronic myelomonocytic leukemia derived from a possible common progenitor of monocytes and natural killer cells. 1104 23

The seco-steroid hormone, 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] inhibits proliferation and induces differentiation of malignant cells including those of the hematopoietic system. The 24-oxo metabolite of 1,25(OH)(2)D(3) also has prominent antiproliferative activities against various cancer cells. We chemically synthesized five novel 24-oxo vitamin D(3) analogues and evaluated their abilities both to inhibit clonal growth and induce differentiation of myeloid leukemia cells and to cause hypercalcemia. The 1alpha,25-dihydroxy-16-ene-D(3) [1,25(OH)(2)-16-ene-D(3)] and 1alpha,25-dihydroxy-16-ene-19-nor-D(3) [1,25(OH)(2)-16-ene-19-nor-D(3)] and their 24-oxo metabolites showed greater potency than 1,25(OH)(2)D(3) in their abilities to inhibit clonal proliferation of HL-60, NB4, and U937 leukemic cell lines as measured by methylcellulose soft-gel assay. Their inhibition of clonal growth was irreversible as analyzed by pulse exposure studies. The synthetic analogues also had greater potency than 1,25(OH)(2)D(3) to induce differentiation of HL-60 and NB4 cells as measured by generation of superoxide, nonspecific esterase production, and induction of CD11b and CD14 cell surface antigens and to increase the proportion of these cells in the G(0)-G(1) phase of the cell cycle. For most assays, the 24-oxo metabolite was slightly more potent than the unmodified analogue, and 50% activity was usually found in the nanomolar range. These analogues and their 24-oxo metabolites also inhibited fresh leukemic cell clonal proliferation. Expression of p27(KIP1), a cyclin-dependent kinase inhibitor that plays an important role in blocking the cell cycle, was found by Western blot analysis to be induced by the analogues and their 24-oxo metabolites in both HL-60 and U937 cells, suggesting a possible mechanism by which these analogues inhibit leukemic growth. Notably, the calcemic activity tested by injections of 1alpha,25-dihydroxy-16-ene-24-oxo-19-nor-D(3) in mice was at least 12-fold less than 1alpha,25(OH)(2)-16-ene-19-nor-D(3). Taken together, chemically synthesized 24-oxo metabolites of 1alpha,25(OH)(2)-16-ene-D(3) and 1alpha,25(OH)(2)-16-ene-19-nor-D(3) irreversibly inhibited proliferation and induced differentiation of acute myeloid leukemia cells with minimal toxicity; these compounds may have a role in the maintenance phase of therapy for acute myeloid leukemia.
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PMID:24-Oxo metabolites of vitamin D3 analogues: disassociation of their prominent antileukemic effects from their lack of calcium modulation. 1130 93

Acute myelogenous leukemia (AML) can be separated by whether the presentation was proceeded by a myelodysplastic (MDS related AML) or developed de novo (dAML). Clinically, MDS related AML (mAML) has been considered to have a worse prognosis that dAML. The objective of this literature review was to identify unique biologic features of mAML. Compared to dAML, mAML is characterized by an altered immunophenotype (increased frequency of CD34, CD11b and CD25), lack of leukemic progenitor cell suppression due to TGFbeta1, increased bcl-2 expression, presence of inducible nitric oxide synthase, lower levels or mrp transcripts and increased expression of p53. Possible interpretations of these differences between mAML and dAML are presented. Implications for mAML directed therapy are discussed.
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PMID:Is myelodysplastic related acute myelogenous leukemia a distinct entity from de novo acute myelogenous leukemia? Potential for targeted therapies. 1137 67

We recently identified HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, as a potential therapeutic target of various retinoic acid responsive cancers. Lovastatin, a competitive inhibitor of HMG-CoA reductase, induced a retinoic acid-like differentiation response followed by extensive apoptosis in neuroblastoma cell lines at relatively low concentrations (<20 microM) of this agent. More recently, we demonstrated that acute myeloid leukemias but not acute lymphocytic leukemias also displayed increased sensitivity to lovastatin-induced apoptosis. In this study, we examined the ability of lovastatin to induce differentiation of acute myeloid leukemic cells and to evaluate the role differentiation may hold in the anti-leukemic properties of this agent. Increased expression of the leukocyte integrins CD11b and CD18 as well as down-regulation of the anti-apoptotic gene bcl-2 are associated with late stage differentiation of the myeloid lineage and retinoic acid induced maturation of acute myeloid leukemic cells. Lovastatin exposure induced increased expression of CD11b and CD18 markers similar to retinoic acid treatment. Following 24 hrs exposure to 20 microM lovastatin, all 7 acute myeloid leukemia cell lines tested showed a decrease in bcl-2 mRNA expression while only 1/5 acute lymphocytic leukemia cell lines showed a similar response. A role for bcl-2 in the apoptotic response of acute myeloid leukemia cells to lovastatin was demonstrated as exogenous constitutive expression of bcl-2 in the AML-5 cell line inhibited apoptosis in a time and dose dependent manner. Thus, lovastatin exposure of acute myeloid leukemia cells induced a differentiation response that may contribute to the therapeutic potential of this agent in the treatment of this disease.
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PMID:Lovastatin induces a pronounced differentiation response in acute myeloid leukemias. 1142 18

Immunophenotypic analysis of transient myeloproliferative disorder (TMD) and acute myeloid leukemia (AML) using multiparameter flow cytometry might provide insight into their relationship. We retrospectively analyzed the expression of multiple lymphoid, myelomonocytic, and megakaryocytic antigens on blast proliferations in 18 patients with Down syndrome (DS; AML, 9; TMD, 9). The AMLs and TMDs shared several immunophenotypic characteristics. Blasts in all expressed CD45, CD38, and CD33; most AMLs and all TMDs were CD36+; and the majority expressed CD41 and CD61, suggesting megakaryocytic differentiation. The majority of cases were CD34+, CD14-, and CD64-. There was aberrant expression of the T-cell-associated antigen CD7 in most AMLs and TMDs. CD56 was expressed aberrantly in 5 AMLs and 7 TMDs. The major difference between the disorders was the pattern of expression of myeloid markers CD11b and CD13; each was expressed in 8 AMLs but only 2 TMDs. Blasts were HLA-DR-positive in 3 AMLs vs 7 TMDs. Blasts in TMD and AML in DS have a characteristic immunophenotype distinct from AML in other settings. The immunophenotypic similarities suggest a biologic relationship between the disorders; however, distinct immunophenotypic differences also were observed.
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PMID:Transient myeloproliferative disorder and acute myeloid leukemia in Down syndrome. An immunophenotypic analysis. 1148 66

The expression of several myeloid and non-lineage associated surface antigens in 70 patients with acute myeloblastic leukemia was investigated in relation to patient and disease characteristics, response to therapy, and prognosis. A leukocyte integrin, CD11b, was the only antigen that showed a significant association with complete remission (CR) duration and survival (P < .025). The mean survival for CD11b+ patients was longer than for CD11b- patients (578 +/- 76 versus 397 +/- 7 days, respectively). CR duration was 897 +/- 84 for CD11b+ patients and 366 +/- 71 for CD11b- patients. Multivariate analysis confirmed the predictive value of CD11b expression for longer survival (relative risk, 3.2; P = .02) and CR duration (relative risk, 3.2; P = .03). CR rate was also significantly higher in CD11b+ patients (77.3%) than in CD11b- patients (46.1%) (P = .01). Survival and remission duration were not influenced by expression of other surface markers including CD13, CD14, CD33, CD34, CD71, CD38, and HLA-DR or by other variables including French-American-British subtype, age, and leukocyte count. Extramedullary disease (EXD) was associated with the presence of both CD13 and CD14 expression (P < .04) but occurred less frequently in CD13+ cases. CD13 expression occurred more frequently in female patients (P = .03). CD38 expression was associated with lower platelet count and an increase in the number of blasts (P < .02).
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PMID:Significant association between expression of the CD11b surface molecule and favorable outcome for patients with acute myeloblastic leukemia. 1150 66

The Wilms tumor gene (WT1) encodes a zinc-finger containing transcription factor present in primitive hematopoietic progenitor cells. WT1 is also highly expressed in most cases of acute myeloid leukemia. Moreover, WT1 can interfere with induced differentiation of leukemic cell lines. These data suggest a function of WT1 in the maintenance of a primitive phenotype and a role in leukemogenesis by interfering with differentiation, prompting us to investigate its function in human hematopoietic progenitor cells. By retroviral transfer, human CD34(+) cord blood progenitor cells were transduced with a vector encoding either of two splicing variants of WT1, with or without the KTS insert in the zinc-finger domain, linked to expression of green fluorescent protein (GFP) via an internal ribosomal entry site. When compared to cells transduced with vector containing GFP only, WT1 expressing cells showed strongly reduced colony formation in methylcellulose and inhibited proliferation in suspension culture, with no apparent reduction in viability. Cell cycle phase distribution was not affected by WT1 expression. No signs of impaired differentiation, as judged by the surface markers CD11b, CD14 and glycophorin were detected. In contrast to the results with human CD34(+) progenitor cells, the proliferation of murine bone marrow cells was not significantly affected by WT1, consistent with previous data. We conclude that forced expression of WT1 in highly enriched human hematopoietic progenitor cells leads to strong anti-proliferative effects but is compatible with induced maturation of these cells.
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PMID:Forced expression of the Wilms tumor 1 (WT1) gene inhibits proliferation of human hematopoietic CD34(+) progenitor cells. 1175 13

Recently, it has been clarified that interaction between hematopoietic cells and endothelial cells is important in normal hematopoiesis and leukemogenesis. In this study, we examined the relationship between AML cells and endothelial cells by analyzing the expression profile of angiogenic factors, angiopoietin-1 (Ang-1), Ang-2, Tie-2 (a receptor for angiopoietins) and vascular endothelial growth factor (VEGF). Our results demonstrated that CD7(+)AML expressed Ang-2 mRNA frequently and integrin-family adhesion molecules (CD11c and CD18) intensively, suggesting the close correlation with endothelial cells. On the other hand, in t(8;21) AML cells, expression of Ang-2 was infrequent and expression of integrin-family adhesion molecules (CD11b, CD11c and CD18) was weak, suggesting the sparse association with endothelial cells. As for CD7(+)AML cells, despite the frequent and intense expression of endothelial cell-associated molecules (such as Ang-2, CD11c and CD18), intensity of Tie-2 expression was quite low (P < 0.05). Ang-2 expressed in CD7(+)AML cells is not considered to act in an autocrine fashion, but to work on endothelial cells to "feed" leukemic cells. Although Ang-2 is recognized as a natural antagonist for Tie-2, our data presented here suggested the alternative role of Ang-2 in the relationship between endothelial cells and leukemia cells, at least in a subset of leukemia such as CD7(+)AML. These results were supported by the study using AML cell lines, KG-1 (CD7 negative) and its subline KG-1a (CD7 positive); KG-1 had mRNA expression profile of Ang-1(+)Ang-2(-)Tie-2(+), while KG-1a showed Ang-1(+)Ang-2(+)Tie-2(-). These difference in the expression profile of angiogenic factors between CD7(+)AML and t(8;21)AML may explain the characteristic morphological features of these leukemias (CD7(+)AML as blastic type and t(8;21)AML as differentiative type).
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PMID:Expression of endothelial cell-associated molecules in AML cells. 1184 Feb 70


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