Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vitamin supplements have been proposed for children with Down's syndrome (DS) with claims of improving cognitive abilities, or immune or thyroid function. Several studies have shown decreased levels of zinc in this population. Because children with DS have a 50-fold increased risk of developing acute leukaemia during the first 5 years of life, we explored the relation between child vitamin and herbal supplement use and the risk of leukaemia in a case-control study. During the period 1997-2002, we enrolled 158 children with DS aged 0-18 years that were diagnosed with acute lymphoblastic leukaemia (ALL) (n = 97) or acute myeloid leukaemia (AML) (n = 61) at participating Children's Oncology Group institutions. We enrolled 173 DS children without leukaemia (controls), selected from the cases' primary care clinic and frequency-matched on age. Data were collected via telephone interviews with mothers of the index child regarding use of multivitamins, zinc, vitamin C, iron and herbal supplements, including age at first use, frequency and duration. Among controls, 57% reported regular multivitamin use (>/=3 times/week for >/=3 months) compared with 48% of ALL cases and 61% of AML cases. We found no evidence of an association between children's regular multivitamin use and ALL or AML (adjusted odds ratios [OR] = 0.94 [95% CI 0.52, 1.70] and 1.90 [0.73, 4.91] respectively). There was a suggestion of an increased risk for AML associated with regular multivitamin use during the first year of life or for an extended duration (ORs = 2.38 [0.94, 5.76] and 2.59 [1.02, 6.59] respectively). Despite being the largest study of DS-leukaemia, our sample size was small, resulting in imprecise effect estimates. Future research should include larger sample sizes as well as a full assessment of diet including vitamin supplementation to adequately examine the relation between nutritional status and childhood leukaemia.
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PMID:Vitamin supplement use among children with Down's syndrome and risk of leukaemia: a Children's Oncology Group (COG) study. 1842 24

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and a tendency to transition to acute myeloid leukemia. Due to the increasing number of older patients in Austria and the high frequency of therapy-associated MDS following successful chemo- and/or radiotherapy of a primary tumor, the frequency and relevance of MDS are continuously increasing. While therapeutic options were until recently limited to best supportive care, AML-like induction chemotherapy and hematopoietic stem cell transplantation (HSCT) in younger patients, in recent years new therapeutic options have become available. Supportive care was improved through the introduction of effective iron chelation and the availability of hematopoietic growth factors like erythropoiesis-stimulating factors (ESF) and granulocyte colony-stimulating factors (G-CSF). In addition, immune-modulating drugs (IMiDs) like lenalidomide or epigenetically effective agents like the cytosine analogues or histone deacetylase (HDAC) inhibitors have become available and are highly effective in distinct subgroups of MDS patients. The development of state-of-the art recommendations is one of the major aims of the MDS Platform of the Austrian Society of Hematology and Oncology. This manuscript reviews recent developments in clinical scoring and targeted and individualized MDS therapy and discusses their relevance in and potential applicability to daily practice.
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PMID:[Individualized management and therapy of myelodysplastic syndromes]. 1898 5

Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms defined by morphologic dysplasia, peripheral cytopenia and clonal instability with enhanced risk of transformation into acute myeloid leukemia. The prognosis and clinical picture in MDS vary depending on patient-related factors (age, gender, comorbidity), the disease variant, cell types affected and genes involved in the malignant process. In fact, more and more data suggest that cytogenetic and molecular defects and gene variants are associated with the clinical course and prognosis in MDS. Although certain molecular defects are indicative of distinct cytogenetic abnormalities, others represent point mutations in critical target genes (RUNX1, N-RAS, JAK2, KIT, others) and sometimes are associated with a particular type of MDS, an overlap disease, a co-existing hematopoietic neoplasm or disease progression. Although most are somatic mutations, germ line mutations and gene polymorphisms have also been described in MDS. Some of these mutations may influence the natural course of disease, iron accumulation or disease progression. The present article provides a summary of our current knowledge about molecular and genetic markers in MDS, with special reference to their potential prognostic and therapeutic implications.
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PMID:Update on genetic and molecular markers associated with myelodysplastic syndromes. 1926 96

Acute myeloid leukemia (AML), a class of prevalent hematopoietic malignancies, is caused by the acquisition of gene mutations that confer deregulated proliferation, impaired differentiation and a survival advantage of hematopoietic progenitors. More recently, we reported that cobalt chloride (CoCl(2))/iron chelator desferrioxamine (DFO)-mimicked hypoxia or moderate hypoxia (2% and 3% O(2)) can directly trigger differentiation of many subtypes of AML cells. Also, intermittent hypoxia significantly prolongs the survival of the transplanted leukemic mice with differentiation induction of leukemic cells. Additionally, these hypoxia-simulating agents selectively stimulate differentiation in acute promyelocytic leukemic cells induced by arsenic trioxide, an effective second-line drug for this unique type of leukemia. Based on this interesting evidence in vitro and in vivo, the ongoing investigations showed the role of hypoxia-inducible factor-1alpha (HIF-1alpha) protein through its non-transcriptional activity in myeloid cell differentiation, as evidenced by chemical interference, the conditional HIF-1alpha induction, the specific short hairpin RNAs (shRNAs) against HIF-1alpha and HIF-1beta, an essential partner for transcription activity of HIF-1. Furthermore, HIF-1alpha and two hematopoietic transcription factors CCAAT/enhancer binding protein alpha (C/EBPalpha) and Runx1/AML1 interact directly with each other. Such interactions increase the transcriptional activities of C/EBPalpha and Runx1/AML1, while C/EBPalpha competes with HIF-1beta for direct binding to HIF-1alpha protein, and significantly inhibits the DNA-binding ability of HIF-1. As a protein is rapidly responsive to all-trans retinoic acid (ATRA), a classical clinical differentiation-inducing drug for AML, HIF-1alpha also plays a role in ATRA-induced differentiation of leukemic cells.
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PMID:Hypoxia-HIF-1alpha-C/EBPalpha/Runx1 signaling in leukemic cell differentiation. 1928 40

The epithelial-mesenchymal transition (EMT) plays a critical role in tumor progression. To obtain a broad view of the molecules involved in EMT, we carried out a comparative proteomic analysis of transforming growth factor-beta1 (TGF-beta1)-induced EMT in AML-12 murine hepatocytes. A total of 36 proteins with significant alterations in abundance were identified. Among these proteins, ferritin heavy chain (FHC), a cellular iron storage protein, was characterized as a novel modulator in TGF-beta1-induced EMT. In response to TGF-beta1, there was a dramatic decrease in the FHC levels, which caused iron release from FHC and, therefore, increased the intracellular labile iron pool (LIP). Abolishing the increase in LIP blocked TGF-beta1-induced EMT. In addition, increased LIP levels promoted the production of reactive oxygen species (ROS), which in turn activated p38 mitogen-activated protein kinase. The elimination of ROS inhibited EMT, whereas H2O2 treatment rescued TGF-beta1-induced EMT in cells in which the LIP increase was abrogated. Overexpression of exogenous FHC attenuated the increases in LIP and ROS production, leading to a suppression of EMT. We also showed that TGF-beta1-mediated down-regulation of FHC occurs via 3' untranslated region-dependent repression of the translation of FHC mRNA. Moreover, we found that FHC down-regulation is an event that occurs between the early and highly invasive advanced stages in esophageal adenocarcinoma and that depletion of LIP or ROS suppresses the migration of tumor cells. Our data show that cellular iron homeostasis regulated by FHC plays a critical role in TGF-beta1-induced EMT.
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PMID:Ferritin heavy chain-mediated iron homeostasis and subsequent increased reactive oxygen species production are essential for epithelial-mesenchymal transition. 1953 52

Off-patent drugs with previously unrecognized anticancer activity could be rapidly repurposed for this new indication. To identify such compounds, we conducted 2 independent cell-based chemical screens and identified the antimicrobial ciclopirox olamine (CPX) in both screens. CPX decreased cell growth and viability of malignant leukemia, myeloma, and solid tumor cell lines as well as primary AML patient samples at low-micromolar concentrations that appear pharmacologically achievable. Furthermore, oral CPX decreased tumor weight and volume in 3 mouse models of leukemia by up to 65% compared with control without evidence of weight loss or gross organ toxicity. In addition, oral CPX prevented the engraftment of primary AML cells in nonobese diabetic/severe combined immunodeficiency mouse models, thereby establishing its ability to target leukemia stem cells. Mechanistically, CPX bound intracellular iron, and this intracellular iron chelation was functionally important for its cytotoxicity. By electron paramagnetic resonance, CPX inhibited the iron-dependent enzyme ribonucleotide reductase at concentrations associated with cell death. Thus, in summary, CPX has previously unrecognized anticancer activity at concentrations that are pharmacologically achievable. Therefore, CPX could be rapidly repurposed for the treatment of malignancies, including leukemia and myeloma.
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PMID:Chelation of intracellular iron with the antifungal agent ciclopirox olamine induces cell death in leukemia and myeloma cells. 1979 31

Abstract Estimates of cancer risks posed to space-flight crews by exposure to high atomic number, high-energy (HZE) ions are subject to considerable uncertainty because epidemiological data do not exist for human populations exposed to similar radiation qualities. We assessed the leukemogenic efficacy of one such HZE species, 1 GeV (56)Fe ions, a component of space radiation, in a mouse model for radiation-induced acute myeloid leukemia. CBA/CaJ mice were irradiated with 1 GeV/nucleon (56)Fe ions or (137)Cs gamma rays and followed until they were moribund or to 800 days of age. We found that 1 GeV/nucleon (56)Fe ions do not appear to be substantially more effective than gamma rays for the induction of acute myeloid leukemia (AML). However, (56)Fe-ion-irradiated mice had a much higher incidence of hepatocellular carcinoma (HCC) than gamma-irradiated mice, with an estimated RBE of approximately 50. These data suggest a difference in the effects of HZE iron ions on the induction of leukemia compared to solid tumors, suggesting potentially different mechanisms of tumorigenesis.
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PMID:Incidence of acute myeloid leukemia and hepatocellular carcinoma in mice irradiated with 1 GeV/nucleon (56)Fe ions. 1963 May 25

Myelodysplastic syndromes (MDS) represent a collection of heterogeneous malignant bone marrow stem cell disorders that result in the production of dysplastic and ineffective blood cells. The disease is marked by gradually worsening cytopenias and a variable risk for the eventual transformation to acute myelogenous leukemia (AML). The risk of developing MDS increases with age, and disease onset before 50 years is unusual. Several morphologic subtypes of MDS have been identified. Each of these subtypes has specific prognostic and morphologic and/or cytogenetic features which make it unique. The International Prognostic Scoring System (IPSS) was developed to aid in determining the prognosis of patients with MDS; this system categorizes patients into four risk groups for both overall survival and transformation to AML: low, intermediate-1, intermediate-2, and high. The management of MDS is based on the goal of controlling cytopenia-related symptoms, improving survival, improving quality of life, and decreasing risk of progression to AML. Treatment strategies include supportive care, iron chelation, treatment with hematopoietic growth factors,immunosuppressive therapies including lenalidomide, antithymocyte globulin, chemotherapy (eg, azacitidine, decitabine, low-dose Ara-C, 7+3 chemotherapy), and stem cell transplantation. However, selecting the appropriate therapy for each individual patient is critical to optimize clinical benefit. This monograph discusses treatment selection for the MDS patient,including a discussion of the overall survival and maintenance of MDS patients, how an appropriate therapy should be chosen in the community setting, and how MDS classification and risk stratification impacts treatment decisions.
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PMID:Clinical roundtable monograph. Overall survival and maintenance of MDS patients. 1970 87

Recent studies have suggested that the presence of iron overload prior to stem cell transplantation is associated with decreased survival. Within these studies, the criteria used to define iron overload have varied considerably. Given the lack of consensus regarding the definition of iron overload in the transplant setting, we sought to methodically examine iron status among transplant patients. We studied 78 consecutive patients at risk for transfusion-related iron overload (diagnoses included AML, ALL, MDS, and aplastic anemia) who received either autologous or allogeneic stem cell transplant. Multiple measures of iron status were collected prior to transplantation and examined for their association with survival. Using this data, three potentially prognostic iron measures were identified and incorporated into a rational and unified scoring system. The resulting Transplant Iron Score assigns a point for each of the following variables: (1) greater than 25 red cell units transfused prior to transplantation; (2) serum ferritin > 1000 ng/ml; and (3) a semi-quantitative bone marrow iron stain of 6+. In our cohort, the score (range 0 to 3) was more closely associated with survival than any available single iron parameter. In multivariate analysis, we observed an independent effect of iron overload on transplant survival (p = 0.01) primarily attributable to an increase in early treatment-related deaths (p = 0.02) and lethal infections. In subgroup analysis, the predictive power of the iron score was most pronounced among allogeneic transplant patients, where a high score (> or = 2) was associated with a 50% absolute decrease in survival at one year. In summary, our results lend further credence to the notion that iron overload prior to transplant is detrimental and suggest iron overload may predispose to a higher rate of lethal infections.
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PMID:The transplant iron score as a predictor of stem cell transplant survival. 1985 46

The myelodysplastic syndromes (MDS) are characterized by cytopenias and risk of transformation to acute myeloid leukemia (AML). Although new treatments are available, a mainstay in MDS remains supportive care, which aims to minimize the impact of cytopenias and transfusion of blood products. Red blood cell (RBC) transfusions place patients at risk of iron overload (IOL). In beta-thalassemia major (BTM), IOL from chronic RBC transfusions inevitably leads to organ dysfunction and death. With iron chelation therapy (ICT), survival in BTM improved from the second decade to near normal and correlated with ICT compliance. Effects of ICT in BTM include reversal of cardiac arrhythmias, improvement in left ventricular ejection fraction, arrest of hepatic fibrosis, and reduction of glucose intolerance. It is not clear whether these specific outcomes are applicable to MDS. Although retrospective, recent studies in MDS suggest an adverse effect of transfusion dependence and IOL on survival and AML transformation, and that lowering iron minimizes this impact. These data raise important points that warrant further study. ICT is potentially toxic and cumbersome, is costly, and in MDS patients should be initiated only after weighing potential risks against benefits until further data are available to better justify its use. Since most MDS patients eventually require RBC transfusions, the public health implications both of transfusion dependence and ICT in MDS are considerable. This paper summarizes the impact of cytopenias in MDS and treatment approaches to minimize their impact, with a focus on RBC transfusions and their complications, particularly with respect to iron overload.
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PMID:Supportive care and chelation therapy in MDS: are we saving lives or just lowering iron? 2000 52


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