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)

MGCD0103 is an isotype-selective inhibitor of histone deacetylases (HDACs) targeted to isoforms 1, 2, 3, and 11. In a phase 1 study in patients with leukemia or myelodysplastic syndromes (MDS), MGCD0103 was administered orally 3 times weekly without interruption. Twenty-nine patients with a median age of 62 years (range, 32-84 years) were enrolled at planned dose levels (20, 40, and 80 mg/m(2)). The majority of patients (76%) had acute myelogenous leukemia (AML). In all, 24 (83%) of 29 patients had received 1 or more prior chemotherapies (range, 0-5), and 18 (62%) of 29 patients had abnormal cytogenetics. The maximum tolerated dose was determined to be 60 mg/m(2), with dose-limiting toxicities (DLTs) of fatigue, nausea, vomiting, and diarrhea observed at higher doses. Three patients achieved a complete bone marrow response (blasts <or= 5%). Pharmacokinetic analyses indicated absorption of MGCD0103 within 1 hour and an elimination half-life in plasma of 9 (+/- 2) hours. Exposure to MGCD0103 was proportional to dose up to 60 mg/m(2). Analysis of peripheral white cells demonstrated induction of histone acetylation and dose-dependent inhibition of HDAC enzyme activity. In summary, MGCD0103 was safe and had antileukemia activity that was mechanism based in patients with advanced leukemia.
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PMID:Phase 1 study of the oral isotype specific histone deacetylase inhibitor MGCD0103 in leukemia. 1849 56

N-acetyl-dinaline (CI-994) is an investigational anti-cancer drug which inhibits histone deacetylases. We evaluated the interaction between CI-994 and conventional chemotherapeutics used in acute myeloid leukemia (AML) in a rat model for AML and Brown Norway rat acute myelocytic leukemia (BNML). In vitro, CI-994 in combination with cytarabine (ara-C), daunorubicin and mitoxantrone, resulted in moderate synergism. In vivo, higher dosages of CI-994 induced complete remissions. CI-994/ara-C was very active against BNML. The combinations of CI-994/daunorubicin and CI-994/mitoxantrone were also active against BNML. This study demonstrates favorable in vitro and in vivo interactions between CI-994 and conventional anti-cancer agents used for the treatment of AML.
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PMID:CI-994 (N-acetyl-dinaline) in combination with conventional anti-cancer agents is effective against acute myeloid leukemia in vitro and in vivo. 1849 59

Classical chemotherapy has an active, but limited, role in acute leukemia with relapse common in adult patients. Recent evidence has implicated signal transduction pathways in leukemic progression and also in resistance to cytotoxic therapy. We have used a short-term, in-vitro incubation assay with cytotoxic analysis by MTT, confirmed by histone-associated DNA fragmentation, to evaluate both classical and nonclassical combinations of drugs. Isobologram median effect analysis, confirmed by curve shift analysis, was used to identify synergy and antagonism. Fluvastatin, a prenylation inhibitor, demonstrates global enhancement of the effects of classical agents in both AML-193 and KG-1 cell lines. Similarly, the m-TOR inhibitors, RAD-001 (everolimus) and rapamycin, also cause time-dependent global enhancement of cytotoxic agents. At clinically achievable combinations, RAD-001 perturbs the AKT pathway in vitro. The unique combination of fluvastatin and an m-TOR inhibitor was synergistic in both cell lines. These effects were independent of whether or not human plasma was used in the assay system. These studies suggest several novel combinations of agents that need to be evaluated in the management of leukemia.
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PMID:In-vitro synergism of m-TOR inhibitors, statins, and classical chemotherapy: potential implications in acute leukemia. 1859 12

EVI1 is an oncoprotein inappropriately expressed in acute myeloid leukemia and myelodysplastic syndrome cells. In vitro studies indicate that diverse biological properties can be attributed to this protein. Its role in leukemogenesis is still unclear but it is thought that overall EVI1 can act mostly as a transcription repressor through its interaction with a subset of histone deacetylases. Studies with histone deacetylase inhibitors have however indicated that EVI1-mediated repression can be only partially rescued by deacetylase inhibitor drugs, suggesting that additional chromosomal modifications might occur to induce gene repression by EVI1. To investigate whether histone methylation contributes to the repressive potential of EVI1, we examined a potential association between EVI1, the histone methyltransferase (HMT) SUV39H1, and methyltransferase activity in vitro. We find that EVI1 directly interacts with SUV39H1 and that the proteins form an active complex with methyltransferase activity in vitro. Our data indicate that SUV39H1 enhances the transcription repressive potential of EVI1 in vivo. We suggest that EVI1 affects promoters' activity in two different pathways, by association with histone deacetylases and by recruiting chromatin-modifying enzymes to impose a heterochromatin-like structure establishing a lasting transcription repression.
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PMID:EVI1 recruits the histone methyltransferase SUV39H1 for transcription repression. 1865 52

Histone-modified enzymes are involved in various cell functions, including proliferation, differentiation, cell death and carcinogenesis. The protein MOZ (monocytic leukemia zinc finger protein) is a Myst (MOZ, Ybf2 (Sas3), Sas2, Tip60)-type histone acetyltranseferase (HAT) that generates fusion genes, such as MOZ-TIF2, MOZ-CBP and MOZ-p300, in acute myeloid leukemia (AML) by chromosomal translocation. MOZ associates with AML1 (RUNX1), PU.1, and p53, and cooperatively activates target gene transcription. Gene targeting in mice has revealed that MOZ is essential for the generation and maintenance of hematopoietic stem cells (HSC) and for the appropriate development of myeloid, erythroid and B-lineage cell progenitors. In AML, MOZ fusion genes lead to repressed differentiation, hyper-proliferation, and self-renewal of myeloid progenitors through deregulation of MOZ-regulated target gene expression. It is therefore necessary to analyze the roles of MOZ and MOZ fusion genes in normal and malignant hematopoiesis to elucidate the mechanisms underlying and develop therapies for MOZ-related AML.
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PMID:Roles of the histone acetyltransferase monocytic leukemia zinc finger protein in normal and malignant hematopoiesis. 1875 62

The p300 protein shows a striking homology with cyclic-AMP-response-element-binding-protein binding protein (CBP) and both proteins form a family of DNA-binding transcriptional coactivators/histone acetyltransferases. The authors, herein, report a therapy-related acute myeloid leukemia with MLL-p300 fusion gene. Spectral karyotyping clarified that chromosome 11 is involved in complex t(1;22;11)(q44;q13;q23), and is fused to the chromosome 22, and direct sequencing revealed the fusion of exon 8 of MLL and exon 15 of p300 in this case. This is only the second reported case of leukemia with an MLL-p300 fusion gene, and the other case with MLL-p300 was also a therapy-related leukemia. Considering that the MLL-CBP fusion gene is also found almost exclusively in therapy-related leukemia, the association of MLL-p300 and MLL-CBP with therapy-related leukemia rather than de novo leukemia is thereby suggested.
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PMID:A complex t(1;22;11)(q44;q13;q23) translocation causing MLL-p300 fusion gene in therapy-related acute myeloid leukemia. 1877 67

RUNX1-EVI1 is a chimeric gene generated by t(3;21)(q26;q22) observed in patients with aggressive transformation of myelodysplastic syndrome or chronic myelogenous leukemia. RUNX1-EVI1 has oncogenic potentials through dominant-negative effect over wild-type RUNX1, inhibition of Jun kinase (JNK) pathway, stimulation of cell growth via AP-1, suppression of TGF-beta-mediated growth inhibition and repression of C/EBPalpha. Runx1-EVI1 heterozygous knock-in mice die in uteri due to central nervous system (CNS) hemorrhage and severe defects in definitive hematopoiesis as Runx1-/- mice do, indicating that RUNX1-EVI1 dominantly suppresses functions of wild-type RUNX1 in vivo. Acute myelogenous leukemia is induced in mice transplanted with bone marrow cells expressing RUNX1-EVI1, and a Runx1-EVI1 knock-in chimera mouse developed acute megakaryoblastic leukemia. These results suggest that RUNX1-EVI1 plays indispensable roles in leukemogenesis of t(3;21)-positive leukemia. Major leukemogenic effect of RUNX1-EVI1 is mainly through histone deacetyltransferase recruitment via C-terminal binding protein. Histone deacetyltransferase could be a target in molecular therapy of RUNX1-EVI1-expressing leukemia.
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PMID:Role of the RUNX1-EVI1 fusion gene in leukemogenesis. 1901 45

The farnesyltransferase inhibitor tipifarnib exhibits modest activity against acute myelogenous leukemia. To build on these results, we examined the effect of combining tipifarnib with other agents. Tipifarnib inhibited signaling downstream of the farnesylated small G protein Rheb and synergistically enhanced etoposide-induced antiproliferative effects in lymphohematopoietic cell lines and acute myelogenous leukemia isolates. We subsequently conducted a phase 1 trial of tipifarnib plus etoposide in adults over 70 years of age who were not candidates for conventional therapy. A total of 84 patients (median age, 77 years) received 224 cycles of oral tipifarnib (300-600 mg twice daily for 14 or 21 days) plus oral etoposide (100-200 mg daily on days 1-3 and 8-10). Dose-limiting toxicities occurred with 21-day tipifarnib. Complete remissions were achieved in 16 of 54 (30%) receiving 14-day tipifarnib versus 5 of 30 (17%) receiving 21-day tipifarnib. Complete remissions occurred in 50% of two 14-day tipifarnib cohorts: 3A (tipifarnib 600, etoposide 100) and 8A (tipifarnib 400, etoposide 200). In vivo, tipifarnib plus etoposide decreased ribosomal S6 protein phosphorylation and increased histone H2AX phosphorylation and apoptosis. Tipifarnib plus etoposide is a promising orally bioavailable regimen that warrants further evaluation in elderly adults who are not candidates for conventional induction chemotherapy. These clinical studies are registered at www.clinicaltrials.gov as #NCT00112853.
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PMID:Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide. 1944 68

Transcriptional silencing via promoter methylation of genes important for cell growth and differentiation plays a key role in myeloid leukemogenesis. We find that clinically achievable levels of 5-aza-2'-deoxycytidine (5-AZA-dC), a potent inhibitor of DNA methylation, can modify chromatin and restore the ability of tumor necrosis factor alpha (TNFalpha) to induce monocytic differentiation of the acute myeloid leukemia cells NB4 and U937. Although 5-AZA-dC cannot fully induce differentiation, we show that 5-AZA-dC acts directly on TNFalpha-responsive promoters to facilitate TNFalpha-induced transcriptional pathways leading to differentiation. 5-AZA-dC regulates the expression of Dif-2, a TNFalpha target gene, by deacetylating chromatin domains in a methylation-dependent manner. Chromatin immunoprecipitation analyses of the Dif-2 promoter show histone hyperacetylation and a recruitment of the nuclear factor-kappaB transcription factor in response to 5-AZA-dC. Furthermore, 5-AZA-dC plus TNFalpha enhances the level of phosphorylated RNA Pol II at the Dif-2 promoter via synergistic recruitment of TFIIH. We conclude that nonspecific changes in chromatin can allow a specific transcriptional inducer to overcome blocks in leukemic cell differentiation. Our results support the concept of low doses of 5-AZA-dC acting in combination with other agents to target epigenetic changes that drive malignant growth in leukemic cells. [Cancer Res 2009;69(1):55-64].
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PMID:Inhibition of DNA methyltransferase activates tumor necrosis factor alpha-induced monocytic differentiation in acute myeloid leukemia cells. 1911 87

A number of molecular targets have been identified in leukemia, based on the understanding of signaling pathways controlling cell differentiation, proliferation, apoptosis, and malignant transformation. Growth factors and integrins interact with their receptors and activate signaling cascades with intimate interconnections. The specific niches within the bone marrow microenvironment may provide a sanctuary for subpopulations of leukemic cells to escape chemotherapy-induced death and acquire drug resistance. Investigations into bone marrow stroma-leukemia crosstalk may result in the development of strategies against the acquisition of a chemo-resistant phenotype and enhance the efficacy of therapies in leukemia. In recent studies, we proposed novel therapeutic interventions targeting the microenvironment/leukemia interaction focusing on SDF1/CXCR4, ILK/PI3K/Akt, TGF-beta, and Notch signaling. Gene transcriptional activity is regulated by chromatin modification and DNA methylation. Nuclear receptors such as RAR, RXR, and PPARgamma exert histone acetyl transferase activity (HAT). The transcription of target genes is initiated following the ligation of these receptors, recruitment of co-activators, and replacement of repressors. We demonstrated that histone acetylation by the PPARgamma agonist CDDO, RAR/RXR agonist ATRA, and/or histone deacetylase inhibitors (HDACIs) reversed the silenced RARbeta and MDR1 genes in acute promyelocytic leukemia, and that HDACI induced apoptosis with phagocytosis through the induction of Annexin A1 in AML1/ETO-positive acute myelocytic leukemia (AML) cells. The translation of research findings into effective clinical laboratory tests is an important approach. The flow cytometric technique is a powerful tool in the field of clinical laboratory medicine, with its accurate and rapid analysis. We carried out phospho-specific flow cytometry to investigate protein phosphorylation in AML cells and detect ZAP-70 in chronic lymphocytic leukemia cells, including the evaluation of antibodies, staining epitopes, fixing and permeabilizing methods, and analyzing systems. Finally, we emphasize the potential applications of research findings and methods in the fields of clinical medicine, molecular diagnosis, and targeting therapy.
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PMID:[Molecular diagnosis of and molecular targeting therapy for leukemia]. 1931 19


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