UMLS:C0023467 - FACTA Search

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Query: UMLS:C0023467 (acute myeloid leukemia)
35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined a t(9;11)(p22;q23) chromosome translocation in an acute myeloid leukemia of an infant. The breakpoints on the two chromosomes occurred within introns of the involved genes: AF-9 on chromosome 9, and ALL-1 on chromosome 11. Sequence analysis identified heptamers flanking the breakpoints on both chromosomes 9 and 11, suggesting that the V-D-J recombinase was involved in the translocation. The presence of an N-region between the two chromosomes supports the hypothesis that a mistake in V-D-J joining was involved in the genesis of the translocation and indicates that terminal deoxynucleotidyl transferase was expressed in the cells from which this acute myeloid leukemia originated. In addition, potential topoisomerase II DNA-binding sites were found near the breakpoints of both chromosomes, suggesting the involvement of altered topoisomerase II activity in this translocation. Altered topoisomerase II activity in the presence of an active V-D-J recombinase may be a pathogenetic mechanism of acute myeloid leukemia with rearrangements at 11q23.
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PMID:Potential topoisomerase II DNA-binding sites at the breakpoints of a t(9;11) chromosome translocation in acute myeloid leukemia. 840 20

A new flow cytometric method is described to detect DNA strand breaks associated with apoptosis, by labeling the 3'-OH termini in the breaks with biotinylated dUTP in a reaction employing exogenous terminal deoxynucleotidyl transferase. The method has been applied in studies on leukemic HL-60 and MOLT-4 cell lines to reveal whether it is specific to apoptotic cells, and whether it can be used in the clinic to detect DNA breakage in leukemic cells during chemotherapy. There was labeling of mononuclear cells in peripheral blood of all 11 patients studied during chemotherapy for acute lymphoblastic, acute myelogenous, or chronic myelogenous leukemia (ALL, AML, or CML) in blastic crisis, indicating induced DNA damage; the number of labeled cells increased from 1-8% before treatment up to 80% during the course of treatment. The DNA topoisomerase inhibitors mitoxantrone, VP-16 (etoposide), and m-AMSA (amsacrine) were more effective in inducing DNA breaks than was hydroxyurea or cytosine arabinoside (AraC). Cells with DNA breaks were identified in peripheral blood for up to 5 days following administration of Mitoxantrone and VP-16. In the case of DNA aneuploid leukemias, the DNA breaks were predominant in the aneuploid cell subpopulations, whereas presumably non-neoplastic diploid cells were unlabeled. In one case of ALL there were two distinct subpopulations of aneuploid cells: one responded to the treatment (by DNA breakage) and the other was non-responding. Thus, cells undergoing apoptosis can be detected by this method of labeling DNA strand breaks and the technique is applicable for analysis of response of leukemic cells to chemotherapy. With this method it may be possible to identify tumor cell sensitivity or resistance to particular drugs early in the course of treatment.
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PMID:Induction of DNA strand breaks associated with apoptosis during treatment of leukemias. 848 18

Therapy-related myelodysplastic syndrome (tMDS) and acute nonlymphocytic leukemia (tANLL) are known late complications of cytotoxic drug therapy for hematologic malignancies, solid tumors, and nonmalignant conditions. The alkylating agents are often the causative agents, but a few reports have implicated cisplatin as an etiologic agent. Cisplatin has a significant impact on the treatment of a number of malignant neoplasms, including testicular and ovarian cancer, and is a part of several clinical trials for squamous cell carcinoma of the head and neck region. Given its increasing use, a complication as significant as tMDS is potentially important. In this article, the authors describe the case of a patient who had myelodysplastic syndrome develop after successful treatment for laryngeal cancer with cisplatin. The treatment included cisplatin in combination with 5-fluorouracil, followed by radiation therapy. The authors also present a review of articles in the literature regarding tMDS and tANLL occurrence after treatment with cisplatin-containing regimens. The authors conclude that cisplatin can be a leukemogenic agent. The drug may potentiate the leukemogenic effects of other alkylating agents and drugs that inhibit topoisomerase II action.
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PMID:Myelodysplastic syndrome after cisplatin therapy. 850 9

The National Cancer Institute (NCI) recently alerted clinicians to the possibility that patients, entered on a NCI-sponsored cooperative group trial of doxorubicin and cyclophosphamide adjuvant therapy for breast cancer, may be at high risk of developing secondary acute myeloid leukemia (AML). Secondary AML following standard doses of doxorubicin and cyclophosphamide is uncommon, suggesting that the high risk on this trial may result from its higher-than-standard doses of chemotherapy. However, the cases of secondary AML were characteristic of the type that follows treatment with topoisomerase II-active agents, especially etoposide, and this type of secondary AML is rare after treatment with either cyclophosphamide or doxorubicin at any dose. We raise the possibility that another component of this trial, hematopoietic growth factors to decrease the toxicities related to myelosuppression, may play an important role in the development of secondary AML. Growth factors not only stimulate hematopoietic progenitor proliferation and differentiation, they also regulate hematopoietic cell survival by interfering with apoptosis (programmed cell death). Inhibition of apoptosis by a variety of genetic factors is an important mechanism of oncogenesis, and appears to be the initiating event in some malignancies. Growth factor-mediated suppression of the apoptotic death of hematopoietic progenitors damaged by chemotherapy may contribute to their leukemic transformation.
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PMID:Are growth factors leukemogenic? 855 25

Several recurring chromosomal translocations involve the AML1 gene at 21q22 in myeloid leukemias resulting in fusion mRNAs and chimeric proteins between AML1 and a gene on the partner chromosome. AML1 corresponds to CBFA2, one of the DNA-binding subunits of the enhancer core binding factor CBF. Other CBF DNA-binding subunits are CBFA1 and CBFA3, also known as AML3 and AML2. AML1, AML2 and AML3 are each characterized by a conserved domain at the amino end, the runt domain, that is necessary for DNA-binding and protein dimerization, and by a transactivation domain at the carboxyl end. AML1 was first identified as the gene located at the breakpoint junction of the 8;21 translocation associated with acute myeloid leukemia. The t(8;21)(q22;q22) interrupts AML1 after the runt homology domain, and fuses the 5' part of AML1 to almost all of ETO, the partner gene on chromosome 8. AML1 is an activator of several myeloid promoters; however, the chimeric AML1/ETO is a strong repressor of some AML1-dependent promoters. AML1 is also involved in the t(3;21)(q26;q22), that occurs in myeloid leukemias primarily following treatment with topoisomerase II inhibitors. We have studied five patients with a 3;21 translocation. In all cases, AML1 is interrupted after the runt domain, and is translocated to chromosome band 3q26. As a result of the t(3;21), AML1 is consistently fused to two separate genes located at 3q26. The two genes are EAP, which codes for the abundant ribosomal protein L22, and MDS1, which encodes a small polypeptide of unknown function. In one of our patients, a third gene EVI1 is also involved. EAP is the closest to the breakpoint junction with AML1, and EVI1 is the furthest away. The fusion of EAP to AML1 is not in frame, and leads to a protein that is terminated shortly after the fusion junction by introduction of a stop codon. The fusion of AML1 to MDS1 is in frame, and adds 127 codons to the interrupted AML1. Thus, in the five cases that we studied, the 3;21 translocation results in expression of two coexisting chimeric mRNAs which contain the identical runt domain at the 5' region, but differ in the 3' region. In addition, the chimeric transcript AML1/MDS1/EVI1 has also been detected in cells from one patient with the 3;21 translocation as well as in one of our patients. Several genes necessary for myeloid lineage differentiation contain the target sequence for AML1 in their regulatory regions. One of them is the CSF1R gene. We have compared the normal AML1 to AML1/MDS1, AML1/EAP and AML1/MDS1/EVI1 as transcriptional regulators of the CSF1R promoter. Our results indicate that AML1 can activate the promoter, and that the chimeric proteins compete with the normal AML1 and repress expression from the CSF1R promoter. AML1/MDS1 and AML1/EAP affect cell growth and phenotype when expressed in rat fibroblasts. However, the pattern of tumor growth of cells expressing the different chimeric genes in nude mice is different. We show that when either fusion gene is expressed, the cells lose contact inhibition and form foci over the monolayer. In addition, cells expressing AML1/MDS1 grow larger tumors in nude mice, whereas cells expressing only AML1/EAP do not form tumors, and cells expressing both chimeric genes induce tumors of intermediate size. Thus, although both chimeric genes have similar effects in transactivation assays of the CSF1R promoter, they affect cell growth differently in culture and have opposite effects as tumor promoters in vivo. Because of the results obtained with cells expressing one or both genes, we conclude that MDS1 seems to have tumorigenic properties, but that AML1/EAP seems to repress the oncogenic property of AML1/MDS1.
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PMID:Rearrangement of the AML1/CBFA2 gene in myeloid leukemia with the 3;21 translocation: expression of co-existing multiple chimeric genes with similar functions as transcriptional repressors, but with opposite tumorigenic properties. 858 55

Three patients with secondary acute leukaemia after treatment with topoisomerase II inhibitor agents are described. Two patients had acute myeloid leukaemia (AML). FAB M5a, one had pro-B-acute lymphoblastic leukaemia (ALL). The interval between initiation of chemotherapy and the onset of secondary acute leukaemia was 19-20 months. 11q23 rearrangements were detected in all cases. They were due to translocations t(11;19) (q23;p13.3), t(11;16)(q23;p13) and t(4;11)(q21;q23), respectively. Fluorescence in situ hybridization (FISH) with Yeast Artificial Chromosome (YAC) probe 13HH4 spanning the ALL-1 gene on 11q23 confirmed that in each case the ALL-1 gene had been disrupted by the translocations. The study underlined the relationship between the development of secondary acute leukaemias with 11q23 rearrangement and previous chemotherapy with topisomerase II inhibitor agents. So far, however, only six adult patients with secondary ALL with t(4;11) after treatment with topoisomerase II inhibitor agents have been reported. All with t(4;11) mostly occurs in infants or young children. Our patient received epirubicin continuously for >19 months. This indicates that both myeloid and lymphoid leukaemias with involvement of the ALL-1 gene can be induced by exogenous agents, especially topoisomerase II inhibitors. Thus they may have a common biological background. This hypothesis was substantiated by means of combined immunophenotyping and FISH (FICTION). In the case of AML M5a with t(11;19), the tumour cells with ALL-1 rearrangement expressed CD34. Moreover, the pro-B-ALL with t(4;11) was CD34 positive. These findings suggest that the cell of origin of secondary AML and ALL with 11q23 rearrangement is an immature haemopoietic progenitor cell.
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PMID:Secondary acute leukaemias with 11q23 rearrangement: clinical, cytogenetic, FISH and FICTION studies. 861 34

Only two classes of chemotherapeutic agents have shown activity in acute myeloid leukemia (AML): ara-C and topoisomerase II reactive agents. Frontline combinations of these agents produce complete response (CR) rates of 70% and long-term event free survival rates of 25%. New agents with different mechanisms of action are being explored. Nucleoside analogs such as chlorodeoxyadenosine (2-CdA) or fludarabine have shown single-agent efficacy and may be synergistic with ara-C. Combination therapy with ara-C and nucleoside analogs have shown promising results both as salvage therapy and in newly diagnosed patients. Combinations of topotecan with ara-C, VP16, and anthracyclines are being pursued, as is testing of other Topo-I inhibitors. Hypomethylating agents (5-azacytidine, decitabine) are showing activity in AML, producing CR rates of 5% to 30% as AML salvage therapy as a single agent, and 40%-60% in combinations. Decitabine may be synergistic with topo I inhibitors, biologic agents, and differentiating agents. Homoharringtonine has modest anti-AML activity, with CR rates of 10% to 30% as salvage therapy. Other classes of agents worthy of continuing investigation are platinum analogs and agents with novel mechanisms of action such as tallimustine.
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PMID:New chemotherapeutic agents in acute myeloid leukemia. 861 70

A major unresolved question for 11q23 translocations involving MLL is the chromosomal mechanism(s) leading to these translocations. We have mapped breakpoints within the 8.3-kb BamHI breakpoint cluster region in 31 patients with acute lymphoblastic leukemia and acute myeloid leukemia (AML) de novo and in 8 t-AML patients. In 23 of 31 leukemia de novo patients, MLL breakpoints mapped to the centromeric half (4.57 kb) of the breakpoint cluster region, whereas those in eight de novo patients mapped to the telomeric half (3.87 kb). In contrast, only two t-AML breakpoints mapped in the centromeric half, whereas six mapped in the telomeric half. The difference in distribution of the leukemia de novo breakpoints is statistically significant (P = .02). A similar difference in distribution of breakpoints between de novo patients and t-AML patients has been reported by others. We identified a low- or weak-affinity scaffold attachment region (SAR) mapping just centromeric to the breakpoint cluster region, and a high-affinity SAR mapping within the telomeric half of the breakpoint cluster region. Using high stringency criteria to define in vitro vertebrate topoisomerase II (topo II) consensus sites, one topo II site mapped adjacent to the telomeric SAR, whereas six mapped within the SAR. Therefore, 74% of leukemia de novo and 25% of t-AML breakpoints map to the centromeric half of the breakpoint cluster region map between the two SARs; in contrast, 26% of the leukemia de novo and 75% of the t-AML patient breakpoints map to the telomeric half of the breakpoint cluster region that contains both the telomeric SAR and the topo II sites. Thus, the chromatin structure of the MLL breakpoint cluster region may be important in determining the distribution of the breakpoints. The data suggest that the mechanism(s) leading to translocations may differ in leukemia de novo and in t-AML.
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PMID:Distribution of 11q23 breakpoints within the MLL breakpoint cluster region in de novo acute leukemia and in treatment-related acute myeloid leukemia: correlation with scaffold attachment regions and topoisomerase II consensus binding sites. 863 39

Antimetabolites and topoisomerase (topo) II-reactive drugs are frequently combined in the therapy of acute leukemia. The two types of agents are thought to be synergistic in their actions against malignant blasts but the mechanism for this synergism is incompletely described. This study sought to determine whether the combination of two rather than one anti-metabolite with the topo II-reactive intercalator mitoxantrone would be greater than the effect of the single antimetabolite ara-C on mitoxantrone's cytotoxic actions. We also aimed to determine a mechanism for synergism should it occur. The model system used was K562 human leukemia cells. The second anti-metabolite selected was F-ara-A, the active form of fludarabine. The resultant combination (F-ara-A, ara-C, and a topo II reactive drug) is one currently being tested against acute myelogenous leukemia in clinical trials. F-ara-A itself had little effect on the cytotoxicity or the topo II-mediated DNA cleaving actions of mitoxantrone, while ara-C potentiated these actions as it does those of other topo II-reactive drugs. Surprisingly F-ara-A enhanced the actions of ara-C on mitoxantrone-associated cytotoxicity by at least an order of magnitude. The effect of the addition of F-ara-A to ara-C on mitoxantrone-induced DNA cleavage was considerably smaller, but present. Antimetabolite treatment did not increase the amount of topo II within cells measured directly by immunoblotting or indirectly by quantifying the maximum number of topo II-DNA complexes stabilized by mitoxantrone. Rather, the anti-metabolites altered the distribution of the cells in the cell cycle. Antimetabolite treatment caused a large increase in S-phase cells, a phase in which cells are more sensitive to topo II-reactive drugs than the associated topo II-mediated DNA cleavage would predict. Therefore, it is likely that this shift in the distribution of the cells within the cell cycle accounts for both the enhanced cytotoxicity of mitoxantrone in antimetabolite pretreated cells and the discrepancy between the magnitude of antimetabolite action on topo II-mediated DNA cleavage.
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PMID:The effect of 9-beta-D-arabinofuranosyl-2-fluoroadenine and 1-beta-D-arabinofuranosylcytosine on the cell cycle phase distribution, topoisomerase II level, mitoxantrone cytotoxicity, and DNA strand break production in K562 human leukemia cells. 864 1

Gene expression was analyzed by cDNA-PCR at the mRNA level in bone marrow samples (>80% blasts) from ALL (28 primary, 22 first relapses, 10 recurrent relapses), from AML (14 primary, 23 relapses), In peripheral blood lymphocytes from CLL (five untreated, 10 treated), in one CML in blast crisis in the course of the disease (four samples), and in bone marrow samples from healthy donors (12 specimens). We found low mean MDR1 expression in primary ALL, first relapses of ALL, and primary AML. Significantly higher mean relative MDR1 expression levels were seen in recurrent relapses of ALL, and in the group of relapsed state AML. MDR1 expression measured intermediate in bone marrow samples from healthy donors. The CLL lymphocytes showed generally relatively high MDR1 expression levels. MRP gene expression measured very similar in primary ALL, first relapses of ALL, primary AML, and normal bone marrow. Significantly increased MRP mRNA levels were observed in the groups of recurrent ALL and relapsed state AML. CLL lymphocytes also showed high MRP expression levels. A combined increase of MDRI (about 20-fold) and MRP (about four-fold) was monitored in samples obtained from the CML in blast crisis after chemotherapy. While no significant differences of the mean topoisomerase IIbeta mRNA levels were found throughout, a significantly decreased topoisomerase IIalpha gene expression was measured in first and recurrent relapses of ALL. In CLL lymphocytes either the expression of the topoisomerase IIalpha gene was not detectable by cDNA-PCR, or it measured very low. Topoisomerase IIalpha gene expression was correlated to cyclin A gene expression in the samples of acute leukemias, Indicating the link of topoisomerase IIalpha expression to the proliferative activity of these leukemic blast cells. Our results point to a potentially multifactorial emergence of multidrug resistance in particular states and types of leukemias.
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PMID:MDR1, MRP, topoisomerase IIalpha/beta, and cyclin A gene expression in acute and chronic leukemias. 865 99

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