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

We have previously shown that protein phosphatase-1 (PP1) is the most abundant Ser/Thr phosphatase in human adult primary leukemic cells. To determine the clinical importance of PP1 expression, we compared PP1 activity of leukemic blasts with other putative prognostic factors in 46 patients with acute myelogenous leukemia (AML) who were treated with remission induction chemotherapy. PP1 was ubiquitously but differently expressed in various FAB subtypes (M1-M5), although PP1 activity was significantly higher in blasts of AML-M4 than in AML-M2. PP1 activity was significantly lower in elderly patients > or =55 years (P=0.005), and in those with high white cell counts > or =100,000/microl (P=0.039) at initial diagnosis. Correlation was observed between PP1 activity (<0.15 vs > or =0.15 nmol/min/10(8) cells) and prognosis of AML patients. Eleven of 46 patients with less than 0.15 nmol/min/10(8) cells (low PP1 activity group) had significantly lower overall survival than those with > or =0.15 nmol/min/10(8) cells (high PP1 activity group). The median overall survival was 8 months for patients with low PP1 activity compared to 27 months for those with high PP1 activity in their AML cells. Multivariate analysis using Cox's proportional hazard model showed that low PP1 activity significantly contributed to prognosis. This preliminary study suggests that low PP1 activity may be associated with shortened survival time for AML patients with high white cell counts.
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PMID:Clinical significance of low protein phosphatase-1 activity of blasts in acute myelogenous leukemia with high white cell counts. 1117 87

NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme that detoxifies quinones and reduces oxidative stress. A cysteine-to-threonine (C --> T) substitution polymorphism at nucleotide 609 of the NQO1 complementary DNA (NQO1 C609T) results in a lowering of NQO1 activity. Individuals homozygous for this mutation have no NQO1 activity, and heterozygotes have low to intermediate activity compared with people with wild type. DNA samples from 493 adult de novo acute leukemia patients and 838 matched controls were genotyped for NQO1 C609T. The majority of cases were diagnosed as acute myeloid leukemia (AML) (n = 420); 67 as acute lymphoblastic leukemia (ALL); and 6 as other forms of acute leukemia. The frequency of cases with low or null NQO1 activity (heterozygote + homozygous mutant) was significantly higher among total acute leukemia case subjects compared with their matched controls (odds ratio [OR] = 1.49; 95% confidence interval [CI], 1.17-1.89). Both ALL (OR = 1.93; 95% CI, 0.96-3.87) and AML case subjects (OR = 1.47; 95% CI, 1.13-1.90) exhibited a higher frequency of low or null NQO1 genotypes than controls. For de novo AML, the most significant effect of low or null NQO1 activity was observed among the 88 cases harboring translocations and inversions (OR = 2.39; 95% CI, 1.34-4.27) and was especially high for those harboring inv(16) (OR = 8.13; 95% CI, 1.43-46.42). These findings were confirmed in a second group of 217 de novo AML cases with known cytogenetics. Thus, inheritance of NQO1 C609T confers an increased risk of de novo acute leukemia in adults, implicating quinones and related compounds that generate oxidative stress in producing acute leukemia.
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PMID:Low NAD(P)H:quinone oxidoreductase 1 activity is associated with increased risk of acute leukemia in adults. 1122 89

Cyclin A1 is tissue-specifically expressed during spermatogenesis, but it is also highly expressed in acute myeloid leukemia (AML). Its pathogenetic role in AML and in the cell cycle of leukemic blasts is unknown. B-myb is essential for G1/S transition and has been shown to be phosphorylated by the cyclin A2/cdk2 complex. Here it is demonstrated that cyclin A1 interacts with the C-terminal portion of B-myb as shown by glutathione S-transferase (GST) precipitation. This interaction is confined to cyclin A1 because binding could not be detected between cyclin A2 and B-myb. Also, cdk2 was not pulled down by GST-B-myb from U937 lysates. In addition, co-immunoprecipitation of cyclin A1 and B-myb in leukemic cells evidenced protein interaction in vivo. Baculovirus-expressed cyclin A1/cdk2 complexes were able to phosphorylate human as well as murine B-myb in vitro. Tryptic phosphopeptide mapping revealed that cyclin A1/cdk2 complexes phosphorylated the C-terminal part of B-myb at several sites including threonine 447, 490, and 497 and serine 581. These phosphorylation sites have been demonstrated to be important for the enhancement of B-myb transcriptional activity. Further studies showed that cyclin A1 cooperated with B-myb to transactivate myb binding site containing promoters including the promoter of the human cyclin A1 gene. Taken together, the data suggest that cyclin A1 is a tissue-specific regulator of B-myb function and activates B-myb in leukemic blasts. (Blood. 2001;97:2091-2097)
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PMID:Cyclin A1 directly interacts with B-myb and cyclin A1/cdk2 phosphorylate B-myb at functionally important serine and threonine residues: tissue-specific regulation of B-myb function. 1126 76

Interstitial deletion or loss of chromosome 5, del(5q) or -5, is a frequent finding in myeloid leukemias and myelodysplasias, suggesting the presence of a tumor suppressor gene within the deleted region. In our search for this gene, we identified a candidate, 5qNCA (LOC51780), which lies within a consistently-deleted segment of 5q31. 5qNCA expresses a 7.2-kb transcript with a 5286-bp open reading frame which is present at high levels in heart, skeletal muscle, kidney, placenta, and liver as well as CD34+ cells and AML cell lines. 5qNCA encodes a 191-kD nuclear protein which contains a highly-conserved C-terminus containing a zinc finger with the unique spacing Cys-X2-Cys-X7-His-X2-Cys-X2-Cys-X4-Cys-X2-Cys and a jmjC domain, which is often found in proteins that regulate chromatin remodeling. Expression of 5qNCA in a del(5q) cell line results in suppression of clonogenic growth. Preliminary sequence results in AML and MDS samples and cell lines has revealed a possible mutation in the KG-1 cell line resulting in a THR to ALA substitution that has not been found in over 100 normal alleles to date. We propose 5qNCA is a good candidate for the del(5q) tumor suppressor gene based on its predicted function and growth suppressive activities, and suggest that further mutational and functional study of this interesting gene is warranted.
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PMID:A novel nuclear protein, 5qNCA (LOC51780) is a candidate for the myeloid leukemia tumor suppressor gene on chromosome 5 band q31. 1168 74

Certain cell lines like HL 60 and K 562 are utilised as leukemic cell models for leukemogenesis research, which differentiate along the granulocytic and/or monocytic pathway when treated with certain inducer molecules. High dose methylprednisolone treatment has been shown to induce in vivo and in vitro differentiation of myeloid leukemia cells to mature granulocytes in patients with acute promyelocytic leukemia (APL) and other subtypes of acute myeloid leukemia (AML). Arsenic trioxide (As(2)O(3)) has been confirmed to have remission induction effects on APL. However, there are conflicting results on the effects with other AML subtypes. Also, it has been well established that the reversible phosphorylation of proteins is a major regulatory mechanism in the signal transduction pathways that control cell growth and differentiation. Serine/threonine protein phosphatases (PP) are major components of phosphorylation. In this study, we investigated the effect of As(2)O(3) on HL 60 and K 562 myeloid leukemic differentiation and compared the signalling cascades of the two inducers with respect to serine/threonine PP 1 and 2A. We utilised PP1 and PP2A inhibitors okadaic acid and calyculin A. In contrast to methylprednisolone, there was no effect of phosphatase inhibitors on As(2)O(3)-induced leukemic differentiation. Incomplete leukemic differentiation occurred with lower As(2)O(3) concentration as 10(-6)M. Unlike As(2)O(3), methylprednisolone induced complete granulocytic and/or monocytic differentiation of HL 60 and K 562 cells via upregulation of PP2A regulatory subunits. Therefore, As(2)O(3) and methylprednisolone are promising agents that have the potential to be used together in myeloid leukemic differentiation therapy.
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PMID:Arsenic trioxide and methylprednisolone use different signal transduction pathways in leukemic differentiation. 1183 83

Up to 30% of acute myelogenous leukemia (AML) patients harbor an activating internal tandem duplication (ITD) within the juxtamembrane domain of the FLT3 receptor, suggesting that it may be a target for kinase inhibitor therapy. For this purpose we have developed CT53518, a potent antagonist that inhibits FLT3, platelet-derived growth factor receptor (PDGFR), and c-Kit (IC(50) approximately 200 nM), while other tyrosine or serine/threonine kinases were not significantly inhibited. In Ba/F3 cells expressing different FLT3-ITD mutants, CT53518 inhibited IL-3-independent cell growth and FLT3-ITD autophosphorylation with an IC(50) of 10-100 nM. In human FLT3-ITD-positive AML cell lines, CT53518 induced apoptosis and inhibited FLT3-ITD phosphorylation, cellular proliferation, and signaling through the MAP kinase and PI3 kinase pathways. Therapeutic efficacy of CT53518 was demonstrated both in a nude mouse model and in a murine bone marrow transplant model of FLT3-ITD-induced disease.
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PMID:CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). 1212 72

In a previous study we used gene expression arrays to identify genes that are more highly expressed by leukemic than by non-leukemic leukocytes from acute myelogenous leukemia patients. One of such genes was Phosphorylates tyrosine serine threonine 2 (PYST2), a dual-specificity Mitogen-activated protein (MAP) kinase (MAPK) phosphatase. In the present study, high levels of PYST2 mRNA were detected by RT-PCR and by Northern blotting in bone marrow (BM) leukocytes and in peripheral blood mononuclear cells from additional eight AML patients. No PYST2 mRNA was detected in nine out of twelve samples of Peripheral blood mononuclear cells (PBMC) from healthy blood bank donors and very low levels were detected by the same techniques in the other three PBMC samples from the healthy donors. Relatively high levels of PYST2 were detected in a variety of myeloid leukemia and other cancer cell lines. In view of the potential role played by PYST2 in MAPK signaling cascades we propose that an over expression of PYST2 in malignant cells may reflect a disrupted or an altered MAPK signaling pathway in malignancy processes.
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PMID:Overexpression of the dual-specificity MAPK phosphatase PYST2 in acute leukemia. 1296 91

The Ets1 proto-oncoprotein is a member of the Ets family of transcription factors that share a unique DNA binding domain, the Ets domain. The DNA binding activity of Ets1 is controlled by kinases and transcription factors. Some transcription factors, such as AML-1, regulate Ets1 by targeting its autoinhibitory module. Others, such as Pax-5, alter Ets1 DNA binding properties. Ets1 harbors two phosphorylation sites, threonine-38 and an array of serines within the exon VII domain. Phosphorylation of threonine-38 by ERK1/2 activates Ets1, whereas phosphorylation of the exon VII domain by CaMKII or MLCK inhibits Ets1 DNA binding activity. Ets1 is expressed by numerous cell types. In haemotopoietic cells, it contributes to the regulation of cellular differentiation. In a variety of other cells, including endothelial cells, vascular smooth muscle cells and epithelial cancer cells, Ets1 promotes invasive behavior. Regulation of MMP1, MMP3, MMP9 and uPA as well as of VEGF and VEGF receptor gene expression has been ascribed to Ets1. In tumors, Ets1 expression is indicative of poorer prognosis.
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PMID:The biology of the Ets1 proto-oncogene. 1297 29

Two hereditary human leukemia syndromes are severe congenital neutropenia (SCN), caused by mutations in the gene ELA2, encoding the protease neutrophil elastase, and familial platelet disorder with acute myelogenous leukemia (AML), caused by mutations in the gene AML1, encoding the transcription factor core-binding factor alpha (CBFalpha). In mice, CBFalpha regulates the expression of ELA2, suggesting a common link for both diseases. However, gene-targeted mouse models have failed to reproduce either human disease, thus prohibiting further in vivo studies in mice. Here we investigate CBFalpha regulation of the human ELA2 promoter, taking advantage of bone marrow obtained from patients with either illness. In particular, we have identified novel ELA2 promoter substitutions (-199 C to A) within a potential motif for lymphoid enhancer factor-1 (LEF-1), a transcriptional mediator of Wnt/beta-catenin signaling, in SCN patients. The LEF-1 motif lies adjacent to a potential CBFalpha binding site that is in a different position in human compared with mouse ELA2. We find that LEF-1 and CBFalpha co-activate ELA2 expression. In vitro, the high mobility group domain of LEF-1 interacts with the runt DNA binding and proline-, serine-, threonine-rich activation domains of CBFalpha. ELA2 transcript levels are up-regulated in bone marrow of an SCN patient with the -199 C to A substitution. Conversely, a mutation of the CBFalpha activation domain, found in a patient with familial platelet disorder with AML, fails to stimulate the ELA2 promoter in vitro, and bone marrow correspondingly demonstrates reduced ELA2 transcript. Observations in these complementary patients indicate that LEF-1 cooperates with CBFalpha to activate ELA2 in vivo and also suggest the possibility that up-regulating promoter mutations can contribute to SCN. Two hereditary AML predisposition syndromes may therefore intersect via LEF-1, potentially linking them to more generalized cancer mechanisms.
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PMID:Lymphoid enhancer factor-1 links two hereditary leukemia syndromes through core-binding factor alpha regulation of ELA2. 1459 2

The hematopoietic class III receptor tyrosine kinase (RTK) Flt3 (Flk2, STK1) has recently received much attention as a potential drug target. Activation of Flt3 by different types of mutations plays an important role for proliferation, resistance to apoptosis, and prevention of differentiation of leukemic blasts in acute myeloid leukemia (AML). At least one type of such mutations - an internal tandem duplication in the Flt3 juxtamembrane domain (Flt3-ITD) - has been associated with an unfavorable prognosis. Signal transduction of Flt3 involves activation of several conserved pathways, including the RAS/MAP-Kinase and the phosphoinositide-3-kinase/Akt signaling cascades. Transforming versions of Flt3 exhibit altered signaling, for example a very pronounced activation of STAT5, ultimately resulting in alternate profiles of gene expression and cell transformation. Selective inhibitors of Flt3 tyrosine kinase activity have the potential to suppress aberrant Flt3 signaling. Although highly homologous to other class III RTKs, Flt3 is resistant to the phenylaminopyrimidine STI571 (Gleevec, Imatinib), a potent inhibitor of other RTKs in the family, such as the PDGFbeta-receptor or c-Kit. STI571 binding to Flt3 is prevented by the phenylalanine 691 side-chain in the ATP binding center and mutating this site to threonine renders the corresponding Flt3 mutant sensitive to STI571. Compounds of several other structural families, including the quinoxaline AG1296, the bis(1H-2-indolyl)-1-methanone D-65476, the indolinones SU5416 and SU11248, the indolocarbazoles PKC412 and CEP-701, and the piperazonyl quinazoline CT53518, are potent inhibitors of Flt3 kinase. They exhibit different selectivity profiles, both with respect to other kinases and among wildtype Flt3 and its activated versions. These compounds hold promise as novel drugs against AML and as probes for understanding activation mechanisms and signaling pathways in the class III RTK family.
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PMID:Flt3 receptor tyrosine kinase as a drug target in leukemia. 1518 May 25


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