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)

Background: Expression of the myeloperoxidase (MPO) gene is specific for myeloid precursors and their leukemic counterparts. Unlike the enzyme, MPO mRNA is found only in early myeloid precursors; this makes MPO mRNA a good marker for myeloid lineage of leukemic blasts. A reverse transcriptase-polymerase chain reaction (RT-PCR) method for MPO mRNA detection was developed and used in the diagnosis of acute myelogenous leukemia (AML). In this study, we investigated the use of MPO mRNA for early detection of circulating blasts in patients with AML during and after chemotherapy. Methods and Results: MPO mRNA detection by RT-PCR was performed on cellular material from archival smears of preipheral blood (PB) and bone marrow aspirate from 16 patients previously diagnosed with AML, types MO-M5. MPO mRNA findings were correlated with morphology and flow-cytometric data. A group of six patients diagnosed with adult de novo acute lymphoblastic leukemia served as a negative patient control group for this retrospective study. MPO mRNA findings in PB appear to follow two patterns in patients with complete remission: (1) sustained positivity throughout the clinical course, correlated with relapse; and (2) initial positivity followed by sustained negativity, correlated with long complete remissions. For the only patient in this study found in partial remission, MP mRNA positivity in PB was seen throughout the clinical course. No MPO mRNA positivity was detected in the PB of acute lymphoblastic leukemia cases. Conclusions: A highly sensitive method for detection of MPO mRNA, such as RT-PCR, is useful in monitoring patients with AML for confirming or ruling out complete remission at the molecular level. The pattern of MPO mRNA positivity over time appears to be important and to correlate with clinical course, with sustained positivity being associated wtih impending relapse, while a switch from initial positivity to sustained negativity appears to be associated with long complete remssion. Studies of larger patient groups are necessary to confirm these initial findings.
Mol Diagn 1996 Dec
PMID:Use of Myeloperoxidase mRNA in Monitoring Patients With Acute Myelogenous Leukemia for Early Detection of Circulating Blasts. 1046 78

Some widely used antidepressants such as imipramine, clomipramine, and citalopram have been found to possess antineoplastic effects. In the present study, these compounds were found to induce apoptotic cell death in human acute myeloid leukemia HL-60 cells. Apoptosis induced by the antidepressants was identified by electron microscopy and conventional agarose gel electrophoresis and was quantitated by propodium iodide staining and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) via flow cytometry. Treatment with apoptosis-inducing concentrations of the antidepressants (80 microM imipramine, 35 microM clomipramine, or 220 microM citalopram) caused induction of caspase-3/caspase-3-like activity, which was monitored by the cleavage of poly(ADP-ribose) polymerase (PARP), the loss of the 32 kD caspase-3 (CPP32) precursor, and the cleavage of the fluorescent CPP32-like substrate PhiPhiLux. Pretreatment with a potent caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl-ketone (zVAD-fmk) inhibited antidepressant-induced CPP32/CPP32-like activity and apoptosis. Furthermore, activation of caspase induced by the antidepressants was preceded by the hypergeneration of intracellular reactive oxygen species (ROS). These results suggested that the antidepressants may induce apoptosis via a caspase-3-dependent pathway, and induction of apoptosis by the antidepressants may provide a clue for the mechanism of their antineoplastic effects.
J Biochem Mol Toxicol 1999
PMID:The antidepressants imipramine, clomipramine, and citalopram induce apoptosis in human acute myeloid leukemia HL-60 cells via caspase-3 activation. 1048 22

Interferon-alpha (IFN-alpha) is established as part of the treatment for chronic myeloid leukaemia, although its precise mode of action remains largely unknown. Its use in acute myeloid leukaemia (AML) has been limited. We have previously documented autologous cytolytic activity against AML blasts in patients after autologous bone marrow transplantation. Here we present a patient with poor-risk AML who relapsed from first complete remission (CR) and was unwilling to undergo high-dose chemotherapy with stem cell rescue. In second chemotherapy-induced CR, the patient had no evidence of antileukaemia cytolytic activity in an in vitro assay, and she commenced IFN-alpha (Roferon). She subsequently developed high levels of leukaemia-specific cytotoxicity, and has remained in second CR for two years. These findings support the use of IFN-alpha in patients with poor-risk AML, and suggest that one mechanism of action may be immunological.
Cytokines Cell Mol Ther 1999 Jun
PMID:Generation of autologous immunity to acute myeloid leukaemia and maintenance of complete remission following interferon-alpha treatment. 1051 84

The FUS (TLS)-ERG chimeric protein associated with t(16;21)(p11;q22) acute myeloid leukemia is structurally similar to the Ewing's sarcoma chimeric transcription factor EWS-ERG. We found that both FUS-ERG and EWS-ERG could induce anchorage-independent proliferation of the mouse fibroblast cell line NIH 3T3. However, only FUS-ERG was able to inhibit the differentiation into neutrophils of a mouse myeloid precursor cell line L-G and induce its granulocyte colony-stimulating factor-dependent growth. We constructed several deletion mutants of FUS-ERG lacking a part of the N-terminal FUS region. A deletion mutant lacking the region between amino acids 1 and 173 (exons 1 to 5) lost the NIH 3T3-transforming activity but retained the L-G-transforming activity. On the other hand, a mutant lacking the region between amino acids 174 and 265 (exons 6 and 7) lost the L-G-transforming activity but retained the NIH 3T3-transforming activity. These results indicate that the N-terminal region of FUS contains two independent functional domains required for the NIH 3T3 and L-G transformation, which we named TR1 and TR2, respectively. Although EWS intrinsically possessed the TR2 domain, the EWS-ERG construct employed lacked the EWS sequence containing this domain. Since the TR2 domain is always found in chimeric proteins identified from t(16;21) leukemia patients but not in chimeric proteins from Ewing's sarcoma patients, it seems that the TR2 function is required only for the leukemogenic potential. In addition, we identified three cellular genes whose expression was altered by ectopic expression of FUS-ERG and found that these are regulated in either a TR1-dependent or a TR2-dependent manner. These results suggest that FUS-ERG may activate two independent oncogenic pathways during the leukemogenic process by modulating the expression of two different groups of genes simultaneously.
Mol Cell Biol 1999 Nov
PMID:Dual transforming activities of the FUS (TLS)-ERG leukemia fusion protein conferred by two N-terminal domains of FUS (TLS). 1052 52

The Philadelphia chromosome is present in a heterogeneous group of leukemias. It is most commonly associated with chronic myelogenous leukemia (CML) and B-lineage acute lymphoblastic leukemia (ALL) being found in more than 95% and 15-25% of cases respectively. We undertook a study to determine the morphologic, phenotypic and molecular diversity of Philadelphia positive de novo acute leukemia patients seen at our institution over the past 3 1/2 years. Twenty-one patients with de novo acute leukemia were found to have the Philadelphia chromosome by cytogenetic studies. They consisted of 3 patients with acute myelogenous leukemia (AML), 1 biphenotypic leukemia and 17 ALL patients. Of the patients with ALL, 16 were of B-lineage while 1 had a T-cell phenotype. Ten patients expressed the p210 BCR-ABL transcript alone and 10 expressed only the p190 BCR-ABL transcript. One patient had co-expression of p190 and p210 b3a2 BCR-ABL transcripts. Thus the Philadelphia chromosome can be found in a diverse cohort of morphologic and immunologic subtypes of de novo acute leukemia reflecting the heterogeneity of lineage involvement in this disease.
Int J Mol Med 1999 Dec
PMID:Molecular and phenotypic spectrum of de novo Philadelphia positive acute leukemia. 1056 81

Using polymerase chain reaction (PCR), we examined a panel of 10 microsatellite markers (BAT26, BAT40, D2S123, D4S171, D8S87, D10S197, D12S89, Tp53, D18S58, PLCpr) covering nine chromosomal arms for microsatellite instability (MSI) in 29 patients with primary MDS. Bone marrow DNA was compared with corresponding constitutional DNA derived from buccal epithelial cells. Apart from BAT26 and BAT40 that were mononucleotide (poly A) repeats, the others were dinucleotide (CA) repeats. The patients comprised 10 cases of refractory anemia (RA), three cases of refractory anemia with ringed sideroblasts (RARS), nine cases of refractory anemia with excess of blasts (RAEB), four cases of refractory anemia with excess of blasts in transformation (RAEBt), and three cases of chronic myelomonocytic leukemia (CMML). Serial samples were available in seven patients, in which four showed transformation into higher disease grade or acute myeloid leukemia (AML). Genetic alterations at one locus (three at D2S123, one at D4S171) were evident in four cases, and loss of heterozygosity at Tp53 was detected in one case. Accordingly, none of the 29 patients with primary MDS nor the seven with disease progression in this study exhibited MSI. This shows that MSI may not be important in the pathogenesis or progression of MDS in contrast to other genetic mechanisms, notably recurrent chromosomal abnormalities that dysregulate the expression or function of genes controlling cell growth, differentiation and apoptosis.
Int J Mol Med 2000 Feb
PMID:Absence of microsatellite instability in primary myelodysplastic syndrome. 1063 95

While numerical and structural chromosomal abnormalities characterize many hematopoietic and nonhematopoietic malignancies, the occurrence of polyploidy is by and large rare. We report here an interesting patient with small cell carcinoma (SCC) and hypotetraploidy initially referred to us because of a question of acute nonlymphocytic leukemia, M3 subtype, with a question of a 15;17 translocation characteristic of acute promyelocytic leukemia. However, the patient did not have a 15;17 translocation and the final hematopathologic analysis of the bone marrow aspirates and immunohistochemistry studies subsequently revealed the patient to have SCC. Small cell carcinoma is a highly malignant and a very aggressive neoplasm. A review of the literature, using Medline, Cancerlit, and the Science Citation Index, revealed that in most, if not all, reports, the presence of polyploidy is noted as a rare entity. In leukemia, reports of polyploidy point to a distinct category of patients with a poor risk for which more intensive treatment is needed. Limited information is currently available to assess the risk of polyploidy in small cell carcinoma. Our case is important not only because of the relative rarity of polyploidy, but also because insights gained from the study of this and other similar patients may help shed additional light on the mechanism of carcinogenesis, which is not fully known to date. As polyploidization is a manifestation of genetic instability and as genetic instability has been implicated in the genesis and progression of many cancers, it is perhaps not too surprising that polyploidy in our case was associated with a poor disease outcome. The patient has since expired.
Exp Mol Pathol 2000 Feb
PMID:Hypotetraploidy in a patient with small cell carcinoma. 1064 Apr 56

We have shown that the TARDIS assay (trapped in agarose DNA immunostaining) can be used to detect DNA-topoisomerase I (topo I) cleavable complexes in situ in individual cells following treatment with topo I-targeting drugs. This assay is a modification of the assay for DNA-topoisomerase II (topo II) cleavable complexes (Willmore et al., Mol Pharmacol 53: 78-85, 1998). Drug-stabilised topo I-DNA complexes were detected in situ by topo I-specific primary antibodies and then visualised using fluorescein isothiocyanate conjugated second antibodies. Immunofluorescence was then quantified using a cooled slow-scan coupled device camera and image analysis procedures. Camptothecin (CPT) was shown to stabilise topo I-DNA cleavable complexes in whole cells in a dose-dependent manner in both CCRF-CEM and K562 cells and in lymphoblasts from an adult with newly diagnosed acute myeloid leukaemia treated ex vivo with CPT. In K562 cells, cleavable complexes were found to be maximal between 30 and 90 minutes continuous exposure of CPT, and approximately 78% of cleavable complexes formed in these cells were found to be reversed within 5 minutes of drug removal. It has also been shown that the immunofluorescence detected by the TARDIS assay was specific for topo I-targeting agents. Hence, the TARDIS assay provides a powerful tool to determine the levels of drug-stabilised cleavable complexes in whole cells and thereby aid in the understanding of the mechanism of interaction between topo I-targeting drugs and their target.
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PMID:Camptothecin-stabilised topoisomerase I-DNA complexes in leukaemia cells visualised and quantified in situ by the TARDIS assay (trapped in agarose DNA immunostaining). 1067 79

The ETO protein was originally identified by its fusion to the AML-1 transcription factor in translocation (8;21) associated with the M2 form of acute myeloid leukemia (AML). The resulting AML-1-ETO fusion is an aberrant transcriptional regulator due to the ability of ETO, which does not bind DNA itself, to recruit the transcriptional corepressors N-CoR, SMRT, and Sin3A and histone deacetylases. The promyelocytic leukemia zinc finger (PLZF) protein is a sequence-specific DNA-binding transcriptional factor fused to retinoic acid receptor alpha in acute promyelocytic leukemia associated with the (11;17)(q23;q21) translocation. PLZF also mediates transcriptional repression through the actions of corepressors and histone deacetylases. We found that ETO is one of the corepressors recruited by PLZF. The PLZF and ETO proteins associate in vivo and in vitro, and ETO can potentiate transcriptional repression by PLZF. The N-terminal portion of ETO forms complexes with PLZF, while the C-terminal region, which was shown to bind to N-CoR and SMRT, is required for the ability of ETO to augment transcriptional repression by PLZF. The second repression domain (RD2) of PLZF, not the POZ/BTB domain, is necessary to bind to ETO. Corepression by ETO was completely abrogated by histone deacetylase inhibitors. This identifies ETO as a cofactor for a sequence-specific transcription factor and indicates that, like other corepressors, it functions through the action of histone deactylase.
Mol Cell Biol 2000 Mar
PMID:The ETO protein disrupted in t(8;21)-associated acute myeloid leukemia is a corepressor for the promyelocytic leukemia zinc finger protein. 1068 54

Chromosome 2 (chr 2) deletions are recurrent abnormalities in acute myeloid leukemia (AML) induced by ionizing radiation in the mouse. The localization of deletion sites has proven extremely useful in providing information on the molecular mechanisms of leukemogenesis. The models available for the study of AML are mostly represented by inbred mouse strains, in which the molecular resolution of breakpoints is problematic. In this study, we have examined five leukemic cell lines exhibiting hemizygous chr 2 loss, derived from CBA, C3H, or (C57BLxCBA/H) F1 mice in which AML had been induced by a whole-body dose of radiation. By application of a somatic cell hybridization technique, we have generated interspecific cell hybrids retaining the deleted murine chr 2 homologue. This strategy permitted a very detailed genetic analysis allowing the utilization of any genetic marker on chr 2 without a requirement for polymorphism. Somatic cell hybrid clones were subjected to a high-density polymerase chain reaction-based microsatellite screening using 62-106 informative markers for each cell line. Detailed maps accurately defining chr 2 breakpoints were obtained. The identification of critical breakpoint markers allowed the construction of partial yeast artificial chromosome contigs across chr 2 breakpoints. These maps represent an essential resource for cloning of the breakpoint regions.
Mol Carcinog 2000 Mar
PMID:Somatic cell hybrids for high-density mapping of chromosome 2 breakpoints in radiation-induced myeloid leukemia cell lines from inbred mice. 1070 84


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