Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recurring translocation t(11;16)(q23;p13.3) has been documented only in cases of acute leukemia or myelodysplasia secondary to therapy with drugs targeting DNA topoisomerase II. We show that the MLL gene is fused to the gene that codes for CBP (CREB-binding protein), the protein that binds specifically to the DNA-binding protein CREB (cAMP response element-binding protein) in this translocation. MLL is fused in-frame to a different exon of CBP in two patients producing chimeric proteins containing the AT-hooks, methyltransferase homology domain, and transcriptional repression domain of MLL fused to the CREB binding domain or to the bromodomain of CBP. Both fusion products retain the histone acetyltransferase domain of CBP and may lead to leukemia by promoting histone acetylation of genomic regions targeted by the MLL AT-hooks, leading to transcriptional deregulation via aberrant chromatin organization. CBP is the first partner gene of MLL containing well defined structural and functional motifs that provide unique insights into the potential mechanisms by which these translocations contribute to leukemogenesis.
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PMID:MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3). 923 46

Therapy with DNA topoisomerase II inhibitors has been shown to result in an increased risk of acute myeloid leukemia (AML), often presenting balanced translocations to chromosome bands 11q23 and 21q22. Also other balanced aberrations, more rarely observed in therapy-related AML (t-AML), such as t(15;17) and inv(16) have been associated with these drugs. Recently we observed a case of chronic myeloid leukemia (CML) with t(9;22) after therapy of a germ cell tumor with etoposide, cisplatin and bleomycin. Based on this case and a review of chemotherapy-related leukemias with t(9;22) from the literature, we suggest a causal relationship between therapy with DNA topoisomerase II inhibitors and development of various types of leukemia carrying the Philadelphia chromosome.
Leukemia 1997 Sep
PMID:Chemotherapy-related - late occurring - Philadelphia chromosome in AML, ALL and CML. Similar events related to treatment with DNA topoisomerase II inhibitors? 930 14

The administration of sodium butyrate at 0.75 mM induced the functional differentiation of U-937 human promonocytic leukemia cells with negligible cell mortality. However, the drug rapidly caused cell death with characteristics of apoptosis when used at concentrations of 5 mM and above. In addition, butyrate stimulated the expression of the stress-responsive heat-shock protein 70 (HSP70) gene when applied at both differentiation-inducing and apoptosis-inducing concentrations. The induction of HSP70 by butyrate was inhibited by the simultaneous addition of cAMP-increasing agents (dibutyryl cAMP or the combination of forskolin plus theophylline). However, these agents did not prevent differentiation and only partially reduced apoptosis. Moreover, the DNA topoisomerase II inhibitor etoposide, which provoked U-937 cell differentiation and apoptosis with the same or greater efficiency than butyrate, failed to stimulate HSP70 expression. Finally, it was observed that cAMP-increasing agents also abrogated the induction of HSP70 and reduced the apoptosis caused by cadmium chloride, a typical inducer of the stress response. Taken together, these results indicate that HSP70 expression is not required for differentiation of promonocytic cells, as earlier proposed, and that butyrate probably triggers the stress response in these cells.
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PMID:Modulation of heat-shock protein 70 (HSP70) gene expression by sodium butyrate in U-937 promonocytic cells: relationships with differentiation and apoptosis. 934 7

Identifying transcriptional regulators of DNA topoisomerase II alpha (topo II alpha) is essential to decipher the mechanisms underlying leukemia cell resistance to topo II-directed antitumor drugs. We have previously reported that the proto-oncogene transcription factor c-Myb transactivates the topo II alpha promoter in several hematopoietic cell lines. Currently, we investigate whether NF-M, a C/EBP beta family member, cooperates with c-Myb in activating topo II alpha transcription. Although NF-M is the most efficacious trans-activator of topo II alpha that we have examined (approximately 38-fold over basal), NF-M does not appear to be involved in the endogenous transcriptional regulation of topo II alpha. Interestingly, we report that the sodium butyrate-dependent induction of the topo II alpha promoter observed previously appears to be mediated by c-Myb, independent of NF-M.
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PMID:NF-M trans-activates the human DNA topoisomerase II alpha promoter independently of c-Myb in HL-60 cells. 944 36

Previous studies have demonstrated decreased levels of DNA topoisomerase II alpha protein and messenger RNA in the Adriamycin-resistant P388 murine leukemia cell line P388/ADR/7 compared to the sensitive P388/4 cell line. An allelic fusion event involving the topoisomerase II alpha and the retinoic acid receptor a genes has been identified in these cells that probably contributes to the decreased topoisomerase II activity in P388/ADR/7 cells. However, this allelic mutation may be a minor contributor or even incidental to the resistance phenotype, since these cells display other candidate mechanisms of resistance, including increased P-glycoprotein, increased glutathione-S-transferase activity and an increased onset of DNA repair. To establish a role for topoisomerase II alpha in mediating the Adriamycin resistance phenotype, complementation of the mutant allele was attempted by transfecting the murine P388/ADR/7 cells with a human topoisomerase II alpha expression construct under the control of the human metallothionein IIA promoter. The majority of transfected cell lines that were obtained by selection in hygromycin B contained copies of the integrated expression construct that were rearranged. Only two of thirty-two transfected cell lines were found to contain a single, unrearranged copy of the human topoisomerase II alpha cDNA. P388/ADR/7 cell lines carrying an integrated, intact human topoisomerase II alpha expression vector were more sensitive to Adriamycin, daunorubicin, mitoxantrone, and etoposide, but not to actinomycin D and vincristine compared to control cells transfected with vector alone or cell lines with rearranged topoisomerase II alpha expression constructs. These findings suggest that topoisomerase II alpha is a selective and significant contributor to multifactorial resistance.
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PMID:Selective sensitization of adriamycin-resistant P388 murine leukemia cells to antineoplastic agents following transfection with human DNA topoisomerase II alpha. 949 16

Translocations of the MLL gene at chromosome band 11q23 are the most common cytogenetic alterations in de novo leukemia in infants and in leukemia related to chemotherapy with DNA topoisomerase II inhibitors. Experiments on knock-in mice suggest that additional mutational events may by required for full leukemogenesis. Therefore, we used single-strand conformation polymorphism analysis and an allele-specific restriction enzyme assay to investigate the frequency of KRAS and NRAS mutations in 32 pediatric leukemias with translocation of the MLL gene. Of 25 de novo cases, 13 were acute lymphoblastic leukemia (ALL), 10 were acute myeloid leukemia (AML), and 2 were biphenotypic. Three secondary leukemias were AML, 1 was biphenotypic, 1 was ALL, and 2 were diagnosed as myelodysplasia. The frequency of RAS mutations was 2 of 10 in de novo AML. Both mutations occurred in infant monoblastic variants. RAS mutations were otherwise absent in this series. This is the first report of congenital leukemias where translocation of the MLL gene and RAS mutation coexist. The frequency of RAS mutations in de novo AMLs with MLL gene translocations is similar to that in other forms of AML, but RAS mutations play a limited role in lymphoid and treatment-related leukemias with similar translocations.
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PMID:RAS mutations in pediatric leukemias with MLL gene rearrangements. 952 5

Bis(2,6-dioxopiperazines) and other catalytic inhibitors of mammalian DNA topoisomerase II have recently been found in natural and synthetic compounds. These compounds target the enzyme within the cell and inhibit various genetic processes involving the enzyme such as DNA replication and chromosome dynamics and thus proved to be good probes for the functional analyses of the enzyme in a variety of eucaryotes from yeast to mammals. Catalytic inhibitors were shown to be antagonists against topoisomerase II poisons under some conditions, but to be synergistic under others. Bis(2,6-dioxopiperazines) have a potential to overcome cardiac toxicity caused by potent antitumor anthracycline antibiotics such as doxorubicin and daunorubicin. ICRF-187, +enantiomer of racemic ICRF-159, has been used in EU countries as cardioprotector in cancer clinics. Furthermore, bis(2,6-dioxopiperazines) enhance the efficacy of antitumor topoisomerase II poisons, e.g. anthracycline antibiotics such as daunorubicin and doxorubicin, by reducing their side effects and by allowing dose escalation of the antitumor drugs in preclinical and clinical settings. Besides bis(2,6-dioxopiperazines) per se having antitumor activity, and one of their derivatives, MST-16 or sobuzoxane, bis(N1-isobutyloxycarbonyloxymethyl-2,6-dioxopiperazine), has been developed in Japan and used in clinics as anticancer drug for malignant lymphomas and adult T-cell leukemia (ATL). Further developments of bis(2,6-dioxopiperazines) as antimetastatic agents are expected.
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PMID:Bis(2,6-dioxopiperazines), catalytic inhibitors of DNA topoisomerase II, as molecular probes, cardioprotectors and antitumor drugs. 961 63

Segmental jumping translocations are chromosomal abnormalities in treatment-related leukemias characterized by multiple copies of the ABL and/or MLL oncogenes dispersed throughout the genome and extrachromosomally. Because gene amplification potential accompanies loss of wild-type p53, we examined the p53 gene in a case of treatment-related acute myeloid leukemia (t-AML) with MLL segmental jumping translocation. The child was diagnosed with ganglioneuroma and embryonal rhabdomyosarcoma (ERMS) at 2 years of age. Therapy for ERMS included alkylating agents, DNA topoisomerase I and DNA topoisomerase II inhibitors, and local radiation. t-AML was diagnosed at 4 years of age. The complex karyotype of the t-AML showed structural and numerical abnormalities. Fluorescence in situ hybridization analysis showed multiple copies of the MLL gene, consistent with segmental jumping translocation. A genomic region including CD3, MLL, and a segment of band 11q24 was unrearranged and amplified by Southern blot analysis. There was no family history of a cancer predisposing syndrome, but single-strand conformation polymorphism (SSCP) analysis detected identical band shifts in the leukemia, ganglioneuroma, ERMS, and normal tissues, consistent with a germline p53 mutation, and there was loss of heterozygosity in the ERMS and the t-AML. Sequencing showed a CGA-->TGA nonsense mutation at codon 306 in exon 8. The results of this analysis indicate that loss of wild-type p53 may be associated with genomic instability after DNA-damaging chemotherapy and radiation, manifest as a complex karyotype and gene amplification in some cases of t-AML.
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PMID:Association of germline p53 mutation with MLL segmental jumping translocation in treatment-related leukemia. 961 38

Translocations involving a breakpoint cluster region of the MLL gene at chromosome band 11q23 are the most common molecular abnormalities in acute leukemias of infants and acute leukemias related to chemotherapy with DNA topoisomerase II inhibitors. Molecular cloning of MLL genomic breakpoints by PCR has previously been difficult because MLL has many translocation partners and several breakpoints involve unknown partner genes. We review a new approach to MLL genomic breakpoint cloning called panhandle PCR. By adding an oligonucleotide sequence to the unknown 3' partner gene that is complementary to a known 5' MLL sequence, we have been able to generate a genomic template with an intrastrand loop for PCR schematically shaped like a pan with a handle. The intrastrand loop contains the translocation breakpoint and unknown partner DNA, while the handle contains the known 5' sequence from MLL and a complement to that sequence. Primers both derived from MLL are used to amplify the breakpoint by panhandle PCR. Panhandle PCR offers the advantage of having specificity for the strand of interest at both primer annealing sites without requiring specific primers for the many partner genes of MLL. Panhandle PCR is a straightforward method that represents a technical advance in MLL genomic breakpoint cloning.
Leukemia 1998 Jun
PMID:Panhandle PCR: a technical advance to amplify MLL genomic translocation breakpoints. 963 29

Catalytic inhibitors of mammalian DNA topoisomerase II have been found recently in natural and synthetic compounds. These compounds target the enzyme within the cell and inhibit various genetic processes involving the enzyme, such as DNA replication and chromosome dynamics, and thus proved to be good probes for the functional analyses of the enzyme in a variety of eukaryotes from yeast to mammals. Catalytic inhibitors were shown to be antagonists against topoisomerase II poisons. Thus bis(2,6-dioxopiperazines) have a potential to overcome cardiac toxicity caused by potent antitumor anthracycline antibiotics such as doxorubicin and daunorubicin. ICRF-187, a (+)-enantiomer of racemic ICRF-159, has been used in clinics in European countries as cardioprotector. Furthermore, bis(2,6-dioxopiperazines) enhance the efficacy of topoisomerase II poisons by reducing their side effects in preclinical and clinical settings. Bis(2,6-dioxopiperazines) per se among others have antitumor activity, and one of their derivatives, MST-16 or Sobuzoxane, bis(N1-isobutyloxycarbonyloxymethyl-2, 6-dioxopiperazine), has been developed in Japan as an anticancer drug used for malignant lymphomas and adult T-cell leukemia in clinics.
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PMID:Catalytic inhibitors of DNA topoisomerase II. 974 52


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