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)

The effect of morphine and cocaine on the transport of hydrolyzed nitrogen mustard (NH2-OH) and choline by peripheral blood cells of normal subjects and patients with chronic lymphocytic leukemia, acute lymphoblastic leukemia, and acute myeloblastic leukemia was determined. Transport of HN2-OH by lymphocytes from normal individuals and patients with chronic lymphocytic leukemia was stimulated by morphine and cocaine and, in each case, the effect was statistically significant (P less than 0.05 or greater). However, choline transport by normal lymphocytes was not altered by cocaine and was only slightly stimulated by morphine; choline transport by lymphocytes from patients with chronic lymphocytic leukemia was not stimulated by either morphine or cocaine. HN2-OH and choline transport by cells from patients with either acute lymphoblastic or myeloblastic leukemia was stimulated to a comparable degree by both drugs. Stimulation of HN2-OH transport by morphine and cocaine was greater in normal lymphocytes than in acute leukemic cells and the differences were highly significant (p less than 0.001). Conversely, stimulation of choline transport was more marked in acute leukemic cells than in normal lymphocytes, and these differences were also highly significant (p less than 0.001). It was previously shown that transport of nitrogen mustard by normal and leukemic human cells was biphasic in nature, consisting of a choline-independent component at "high" drug concentrations and a choline-dependent system at "low" substrate concentrations. The preferential stimulation of the low-dose, choline-dependent system by morphine and cocaine in acute leukemic cells relative to that observed in normal lymphocytes suggests a possible mechanism of increasing the therapeutic index of nitrogen mustard.
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PMID:Drug-induced stimulation of transport of hydrolyzed nitrogen mustard and choline by normal and leukemic human cells in vitro. 106 33

Bcr-Abl, the product of the protooncogene bcr-abl, is a constitutively active protein-tyrosine kinase that is highly expressed in chronic myelogenous leukemia and in acute myeloid leukemia cells. Because Bcr-Abl is known to provide mitogenic signals through suppression of apoptosis, we investigated the effect of this oncogene product on signaling by tumor necrosis factor (TNF), a proapoptotic cytokine. We used a bcr-abl-deficient human megakaryocytic leukemia cell line MO7E and an isogenic MBA cell line stably transfected with bcr-abl. Electrophoretic mobility shift assay revealed that TNF activated the nuclear transcription factor NF-kappaB in MO7E cells but not in MBA cells. The impaired NF-kappaB activation in Bcr-Abl-expressing cells was not due to absence of the NF-kappaB proteins p65, p50, or p100 or of IkappaBalpha or IkappaBbeta. Okadaic acid-induced NF-kappaB activation was unaffected by Bcr-Abl expression. TNF induced IkappaBalpha phosphorylation and degradation in MO7E cells but not in MBA cells. The suppression of TNF-induced NF-kappaB activation by Bcr-Abl was not restricted to MBA cells, because ectopic expression of Bcr-Abl in human acute myeloid leukemia HL-60 cells also blocked TNF-induced NF-kappaB activation. When examined for the TNF receptors by the radioreceptor assay, flow cytometry, or Western blot analysis, we found that Bcr-Abl expression down-regulated the expression of the TNF receptors. The RNase protection assay and Northern blot analysis revealed the transcriptional down-regulation of the TNF receptor by Bcr-Abl protein. Overall, these results indicate that ectopic expression of Bcr-Abl interferes with the TNF signaling pathway through the down-regulation of TNF receptors.
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PMID:Ectopic expression of protein-tyrosine kinase Bcr-Abl suppresses tumor necrosis factor (TNF)-induced NF-kappa B activation and IkappaBalpha phosphorylation. Relationship with down-regulation of TNF receptors. 1206 Jun 65

We have used the single and dual color fluorescence in situ hybridization (FISH) technique combined with a new detection system, tyramide signal amplification (TSA), by using the multiple endocrine neoplasm type 1 (MEN1) gene and chromosome 11 specific alpha satellite DNA probes for the study of the allelic deletion of the MEN1 gene. The MEN1 gene is a new tumor suppressor gene and has been recently cloned on chromosome 11q13. FISH combined with the TSA detection system was performed on bone marrow interphase nuclei of 22 patients with acute myeloid leukemia (AML). The FISH-TSA analysis revealed the mono allelic deletion of the MEN1 gene in 4 out of 22 patients (18.18%), 2 of 9 AML-M2 patients (22.2%), 1 of 6 AML-M4 patients (16.6%), and 1 of 4 AML-M5 patients (25.0%). Our study indicates that allelic deletion of the MEN1 gene is not a major cause or a primary event in tumorigenesis of AML, although the long arm (q13 region) of chromosome 11 involves a chromosomal rearrangement in AML.
Teratog Carcinog Mutagen 2002
PMID:Determination of allelic deletion of multiple endocrine neoplasm type 1 (MEN1) gene in acute myeloid leukemia (AML) by application of FISH-TSA technique. 1221 May

Hydroquinone is a myelotoxin that is found in many foods and is also formed through the metabolism of benzene. Human exposure to benzene is associated with the development of myelodysplastic syndrome and acute myelogenous leukemia. Hydroquinone is genotoxic in several in vitro and in vivo test systems, inducing micronuclei (MN), sister-chromatid exchange (SCE), and chromosomal aberrations. Glutathione S-transferases (GSTs) are a superfamily of polymorphic enzymes involved in the conjugation of reactive chemical intermediates to soluble forms. These enzymes play a key role in the detoxification of endogenous and exogenous compounds, and the polymorphic genes GSTM1, GSTT1, and GSTP1 have been associated with the differential metabolism of several genotoxicants. In the present study, we have evaluated the effect of GSTM1, GSTT1, and GSTP1 polymorphisms on the frequency of MN and SCE induced by hydroquinone in human lymphocytes. Lymphocytes were obtained from 15 healthy non-smoking donors, and their GSTM1, GSTT1, and GSTP1 genotypes determined. Treatment of cultures of the lymphocytes with hydroquinone significantly increased the overall frequencies of MN and SCE (P<0.0001). Individuals with the GSTM1 null genotype had a significantly higher frequency of MN compared with GSTM1-present individuals (P=0.013); in contrast, the GSTM1 genotype had no effect on hydroquinone-induced SCE frequency. The other polymorphisms did not significantly affect the frequencies of MN or SCE. These results suggest that GSTM1 is involved in the metabolic fate of hydroquinone and that polymorphisms in GSTM1 could be related to inter-individual differences in DNA damage arising from the exposure to this compound.
Environ Mol Mutagen 2004
PMID:GSTM1, GSTT1, and GSTP1 genotypes and the genotoxicity of hydroquinone in human lymphocytes. 1514 65

The loss and gain of whole chromosomes (aneuploidy) is common in the development of leukemia and other cancers. In acute myeloid leukemia, the loss (monosomy) of chromosomes 5 and 7 and the gain (trisomy) of chromosome 8 are common clonal chromosomal abnormalities. Here, we have tested the hypothesis that metabolites of the human leukemogen benzene cause a higher rate of gain and loss among the chromosomes involved in leukemogenesis and, as such, are nonrandom and selective in their effects. Human peripheral blood was exposed to two metabolites of benzene, namely, hydroquinone (HQ) and benzenetriol (BT), and the ploidy status of nine different chromosomes (1, 5, 6, 7, 8, 9, 11, 12, and 21) was examined using fluorescence in situ hybridization of metaphase spreads. Poisson regression was used to provide interpretable incidence rate ratios and corresponding P values for all nine chromosomes. Statistically significant differences were found between the sensitivity of the nine chromosomes to gain or loss. Chromosomes 5 and 7 were highly sensitive to loss following HQ and BT exposure, whereas chromosomes 7, 8, and 21 were highly sensitive to gain in comparison to other chromosomes. Significant support for the a priori hypothesis that chromosomes 5 and 7 are more sensitive to loss induced by HQ and BT than the other seven chromosomes was also obtained. These data support the notion that benzene metabolites affect the ploidy status of specific chromosomes more than others and may initiate or promote leukemia induction through these specific effects.
Environ Mol Mutagen 2005 May
PMID:Nonrandom aneuploidy of chromosomes 1, 5, 6, 7, 8, 9, 11, 12, and 21 induced by the benzene metabolites hydroquinone and benzenetriol. 1566 17

The effectiveness of bifunctional alkylating nitrogen mustard compounds in chemotherapy is related to their ability to form DNA inter-strand crosslinks. Patients exposed to DNA inter-strand crosslinking (ICL) agents subsequently experience an elevated incidence of myelodysplastic syndromes (MDS) and MDS related acute myeloid leukemia. Fanconi's anemia (FA) patients are deficient in the repair of crosslink DNA damage and they experience a high incidence of MDS. These observations indicate that hematopoietic cells are specific target for the transforming effects of DNA crosslinking damage. Changes in transcript levels were characterized in human hematopoietic cells occurring in response to the nitrogen mustard, mechlorethamine (HN2), but not in response to monofunctional analogs. Only modest changes in a few gene transcripts were detected in HL60 cells exposed to levels of HN2 tittered to maximal dose that caused growth suppression with minimal cell death and allowed eventual resumption of normal cell growth. Under conditions of transient growth suppression, a subset of glutathione-S-transferase (GST) isoenzyme genes was consistently upregulated three to fourfold by HN2, but not by monofunctional analogs. Subsequent efforts to confirm the changes detected by microarray analyses revealed an unexpected dependence on treatment conditions. The GST alpha class A2 subfamily member transcripts were upregulated 24 h after a 1 h exposure to HN2 that caused an extensive, but transient block in late S/G2 cell cycle phase, but were minimally altered with continuous exposure. The 1-h exposure to HN2 caused a transient late S/G2 cell cycle arrest in both the HL-60 cell line and the Colo 320HSR human colon cancer cell line. Overexpression of GSTA2 by transient transfection protected Colo 320HSR cells against both cycle arrest and apoptosis following exposure to HN2. Overexpression of GSTA2 in Colo 320HSR cells induced after exposure to HN2 did not alter cycle arrest or apoptosis. The results indicate that human GSTA2 facilitates the protection of cells from HN2 damage and not repair. Our results are consistent with the possibility that GSTA2 polymorphisms, variable isoenzyme expression, and variable induced expression may be factors in the pathogenesis of MDS.
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PMID:Overexpression of GSTA2 protects against cell cycle arrest and apoptosis induced by the DNA inter-strand crosslinking nitrogen mustard, mechlorethamine. 1577 98

Bifunctional alkylating agents that cross-link DNA are implicated in the pathogenesis of therapy related myelodysplastic syndromes (MDS) and MDS related acute myeloid leukemia (MDR-AML). We exposed HL60 cells to the highest level of bifunctional alkylating nitrogen mustard mechlorethamine (HN2) that was consistent with recovery following suppressed growth. Microarray analyses showed minor changes in transcripts in HN2 treated cells. A moderate up-regulation of S100P mRNA was consistently observed after 1 day of exposure to bifunctional alkylating agents and expression was not induced with monofunctional agents. Elevated S100P protein/antigen was not detected until days later in a subset of non-mitotic G2 cells. Elevated S100P protein persisted over the course of a delayed recovery phase. The results confirm recent reports indicating that S100P is a survival factor. In addition, our results indicate that S100P has a specific role in G2 cell function associated with a prolonged phase of recovery after exposure to bifunctional alkylating agents.
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PMID:S100P is selectively upregulated in tumor cell lines challenged with DNA cross-linking agents. 1593 73

Polymorphisms in xenobiotic metabolizing genes are associated with altered metabolism of carcinogens in acute leukemia (AL). This study applied two data mining approaches to explore potential interactions among P53 and xenobiotic metabolizing genes in 230 AL patients [131 acute myeloid leukemia (AML) and 99 acute lymphoblastic leukemia (ALL)] and 199 controls. Individually, none of the genotypes showed significant associations with AML risk. However, in ALL the CYP1A12A TC genotype was associated with increased risk (OR = 2.02; 95% CI = 1.14-3.58; P = 0.01), whereas the GSTM1 null genotype imparted reduced risk (OR = 0.55; 95% CI = 0.31-0.96; P = 0.03). In classification and regression tree analysis, combinations of GSTM1 present, CYP1A12C AA or GG, EPHX1 exon3 TC, and EPHX1 exon4 AA or GG genotype strongly enhanced the risk of AML (OR = 5.89; 95% CI = 1.40-26.62; P = 0.01). In ALL, combinations of CYP1A12A TT, P53 GG or CC and GSTP1 AG genotypes conferred the highest risk (OR = 4.19; 95% CI = 1.45-12.25; P = 0.004). In multifactor dimensionality reduction analysis, a four locus model (GSTP1, P53, EPHX1 exon3, and CYP1A12A) was the best predictor model for ALL risk. The association between this model and ALL risk remained true even at low prior probabilities of 0.01% (false positive report probability = 0.05). Interaction entropy interpretations of the best model of ALL revealed that two-way interactions were mostly synergistic. These results suggest that high order gene-gene interactions play an important role in AL risk.
Environ Mol Mutagen 2012 Oct
PMID:High order interactions of xenobiotic metabolizing genes and P53 codon 72 polymorphisms in acute leukemia. 2293 May 68

Susan Love, MD, MBA, has dedicated her professional life to the eradication of breast cancer. Author of the bestselling Dr. Susan Love's Breast Book, Dr. Susan Love's Menopause and Hormone Book, and Live a Little, Susan is Chief Visionary Officer of the Dr. Susan Love Research Foundation where she oversees an active research program centered on breast cancer cause and prevention. Susan co-founded the National Breast Cancer Coalition in the early 1990s, and she served on President Clinton's National Cancer Advisory Board from 1998-2004. Her recent projects include recruiting 377,000 women for the Love Army of Women, an Internet program that partners women and scientists to accelerate breast cancer research; and the online Health of Women Study designed to identify the cause of breast cancer. A recipient of six honorary doctorate degrees, Susan is Clinical Professor of Surgery at the David Geffen School of Medicine at the University of California, Los Angeles. In June of 2012, Susan was diagnosed with acute myelogenous leukemia and was treated with an allogenic stem cell transplant.
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PMID:Live your life out loud. 2440 Jun 25

Benzene and formaldehyde (FA) are important industrial chemicals and environmental pollutants that cause leukemia by inducing DNA damage and chromosome aberrations in hematopoietic stem cells (HSC), the target cells for leukemia. Our previous studies showed that workers exposed to benzene and FA exhibit increased levels of aneuploidy in their blood cells. As centrosome amplification is a common phenomenon in human cancers, including leukemia, and is associated with aneuploidy in carcinogenesis, we hypothesized that benzene and FA would induce centrosome amplification in vitro. We treated human lymphoblastoid TK6 cells with a range of concentrations of hydroquinone (HQ, a benzene metabolite) or FA for 24 h, allowed the cells to recover in fresh medium for 24 h, and examined centrosome amplification; chromosomal gain, loss, and breakage; and cytotoxicity. We included melphalan and etoposide, chemotherapeutic drugs that cause therapy-related acute myeloid leukemia and that have been shown to induce centrosome amplification as well as chromosomal aneuploidy and breakage, as positive controls. Melphalan and etoposide induced centrosome amplification and chromosome gain and breakage in a dose-dependent manner, at cytotoxic concentrations. HQ, though cytotoxic, did not induce centrosome amplification or any chromosomal aberration. FA-induced centrosome amplification and cytotoxicity, but did not induce chromosomal aberrations. Our data suggest, for the first time, that centrosome amplification is a potential mechanism underlying FA-induced leukemogenesis, but not benzene-induced leukemogenesis, as mediated through HQ. Future studies are needed to delineate the mechanisms of centrosome amplification and its association with DNA damage, chromosomal aneuploidy and carcinogenesis, following exposure to FA.
Environ Mol Mutagen 2015 Jul
PMID:Induction of centrosome amplification by formaldehyde, but not hydroquinone, in human lymphoblastoid TK6 cells. 2582 Nov 86


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