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)

CD200 was recently described as a new prognosis factor in multiple myeloma and acute myeloid leukemia. CD200 is a membrane glycoprotein that imparts an immunoregulatory signal through CD200R, leading to the suppression of T-cell-mediated immune responses. We investigated the expression of CD200 in cancer using publicly available gene expression data. CD200 gene expression in normal or malignant human tissues or cell lines was obtained from the Oncomine Cancer Microarray database, Amazonia database and the ITTACA database. We found significant overexpression of CD200 in renal carcinoma, head and neck carcinoma, testicular cancer, malignant mesothelioma, colon carcinoma, MGUS/smoldering myeloma, and in chronic lymphocytic leukemia compared to their normal cells or their tissue counterparts. Moreover, we show that CD200 expression is associated with tumor progression in various cancers. Taken together, these data suggest that CD200 is a potential therapeutic target and prognostic factor for a large array of malignancies.
 ...
PMID:CD200: a putative therapeutic target in cancer. 1806 Aug 62

The apoptotic mode of cell death is a major regulatory process in all complex organisms. The low proliferative index and slow accumulation of malignant cells in chronic lymphocytic leukemia (CLL), the most frequent type of leukemia in Europe and North America, suggests that the disease is caused by a defect in apoptosis regulation. Classical apoptosis is executed through the activation of caspases, cysteine proteases which are regulated by a number of pro- and anti-apoptotic proteins. One such checkpoint is the control of caspase activation by a relatively new family of inhibitor of apoptosis proteins (IAPs). They block both the mitochondrial-dependent and -independent apoptotic pathways. The IAP family inhibits apoptosis by binding to specific caspases and possibly by other mechanisms. They also participate in the regulation of cellular and intracellular signal transduction. Six human IAPs have been identified: XIAP, cIAP1, cIAP2, NAIP, livin, and survivin. Because of their important role in regulating apoptosis, IAPs are being investigated as a potential prognostic factor as well as a treatment target in cancer patients. Overexpression of several IAPs has been detected in various hematological malignancies, including acute leukemias, myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), and many types of lymphoid malignancies, such as chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL). Many publications revealed significant correlation between a high level of IAPs, especially of XIAP and survivin, and tumor progression. It seems that overexpression of XIAP in acute myeloid leukemia (AML) and survivin in acute lymphoblastic leukemia (ALL) and DLBCL could become a new unfavorable prognostic factor. Many studies are now concentrating on evaluating the expression and significance of the other proteins of the IAP family. In this paper the current knowledge of the importance of IAPs in hematological malignancies is presented.
 ...
PMID:[The role of the inhibitor of apoptosis protein (IAP) family in hematological malignancies]. 1828 36

The metalloprotease 9 (MMP-9), a known mediator of tumour invasion, is secreted as a 92 kDa pro-form but a non-secreted variant of 85 Kda has been described. The importance of this variant pro-form in tumor progression remains poorly defined. We previously showed that the DNA repair protein Ku interacts at the cell surface of leukaemia cell lines with the 85 Kda pro-form of MMP-9 and these Ku/MMP-9 complexes regulates cell invasion, highlighting their importance in haematological malignancies. We demonstrate here that all samples of acute myeloid leukaemia (AML) blasts purified from bone marrow of 16 affected patients express the 85 Kda form of MMP-9. However, only AML that display monocytic lineage markers (AML4/5) express this form at the cell surface with co-expression of the membrane associated form of Ku. Blocking antibodies directed against Ku or MMP-9 specifically inhibited cell invasion of those expressing Ku/MMP-9 on the cell surface. The membrane form of Ku might represent an important factor in the exposition to the cell surface of this specific MMP-9 pro-form in AML with monocytic features. These results might have important functional significance in the occurrence of extra-medullar infiltrates of leukaemia cells that occurs frequently during the onset of monocyte-related AML sub-types.
 ...
PMID:Cell-surface MMP-9 regulates the invasive capacity of leukemia blast cells with monocytic features. 1841 48

Preferentially expressed antigen of melanoma (PRAME) is expressed in a wide variety of tumors, but in contrast with most other tumor associated antigens, it is also expressed in leukemias. In a previous study, we showed that overexpression of PRAME induced apoptosis, inhibited cell proliferation and reduced tumorigenicity of leukemic cells in vivo. We also demonstrated that PRAME overexpression induced the repression of three genes (Hsp27, S100A4 and p21) associated with an unfavorable prognosis in leukemia. Here, we further investigated the mechanisms of PRAME-induced tumor suppression in vitro and in vivo. We performed a gene profiling study by analysing PRAME shRNA-silenced leukemic cells on high-density micro-arrays (Affymetrix) and found that PRAME altered the expression of two additional genes potentially involved in cancerogenesis and cancer progression: IL-8 and IGFBP-2. In a series of 28 acute myeloid leukemia pediatric patients, we observed that PRAME expression was associated with an increased leukemia-free survival. Importantly, the correlation between PRAME expression in leukemic cell lines and the decreased expression of Hsp27, S100A4, p21, IL-8 and the increased expression of IGFBP-2 was also observed in vivo, in leukemic patients. Our results suggest that the favorable prognosis of PRAME could be mediated, at least in part, by the modified expression of those genes.
 ...
PMID:Tumor associated antigen PRAME is a marker of favorable prognosis in childhood acute myeloid leukemia patients and modifies the expression of S100A4, Hsp 27, p21, IL-8 and IGFBP-2 in vitro and in vivo. 1845 7

The potent bioactive sphingolipid mediator, sphingosine-1-phosphate (S1P), is produced by 2 sphingosine kinase isoenzymes, SphK1 and SphK2. Expression of SphK1 is up-regulated in cancers, including leukemia, and associated with cancer progression. A screen of sphingosine analogs identified (2R,3S,4E)-N-methyl-5-(4'-pentylphenyl)-2-aminopent-4-ene-1,3-diol, designated SK1-I (BML-258), as a potent, water-soluble, isoenzyme-specific inhibitor of SphK1. In contrast to pan-SphK inhibitors, SK1-I did not inhibit SphK2, PKC, or numerous other protein kinases. SK1-I decreased growth and survival of human leukemia U937 and Jurkat cells, and enhanced apoptosis and cleavage of Bcl-2. Lethality of SK1-I was reversed by caspase inhibitors and by expression of Bcl-2. SK1-I not only decreased S1P levels but concomitantly increased levels of its proapoptotic precursor ceramide. Conversely, S1P protected against SK1-I-induced apoptosis. SK1-I also induced multiple perturbations in activation of signaling and survival-related proteins, including diminished phosphorylation of ERK1/2 and Akt. Expression of constitutively active Akt protected against SK1-I-induced apoptosis. Notably, SK1-I potently induced apoptosis in leukemic blasts isolated from patients with acute myelogenous leukemia but was relatively sparing of normal peripheral blood mononuclear leukocytes. Moreover, SK1-I markedly reduced growth of AML xenograft tumors. Our results suggest that specific inhibitors of SphK1 warrant attention as potential additions to the therapeutic armamentarium in leukemia.
 ...
PMID:A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia. 1851 10

To understand the cytogenetic mechanisms responsible for multiple RUNX1 gene copy numbers in hematologic malignancies, we analyzed the chromosomal and molecular cytogenetic findings in bone marrow or peripheral blood samples of individuals who were diagnosed with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or acute lymphoblastic leukemia (ALL). Included in the analysis were 113 consecutive samples received in our laboratory between January 2005 and June 2007. Bone marrow and/or peripheral blood samples were characterized using conventional G-banding techniques and fluorescent in situ hybridization (FISH) techniques with commercially available RUNX1/RUNX1T1 or ETV6/RUNX1 dual-color fusion probes. Eighty-one (72%) of the 113 samples showed an abnormal karyotype and/or abnormal FISH results. Eight of these had, by interphase FISH, RUNX1/RUNX1T1 or RUNX1/ETV6 fusion, and 19 had three or more RUNX1 signals not related to fusion with RUNX1T1 or ETV6 gene. Of the 19 cases with multiple RUNX1 gene signals, 5 had high-level RUNX1 amplification--defined as 5 or more RUNX1 signals in interphase cells--whereas the remaining 14 had 3-4 RUNX1 signals. Four of the five tumors with high-level RUNX1 amplification were myeloid disorders--three cases of AML and one case of MDS. The karyotypes of tumors with high-level amplification of RUNX1 were significantly characterized by the presence of marker chromosomes that harbored extra copies of the RUNX1 gene compared with tumors that had three to four RUNX1 gene signals (P=0.026, Fisher's exact test). Our findings show that high-level RUNX1 amplification, especially in myeloid disorders, often results from marker chromosomes harboring extra copies of the RUNX1 gene . This suggests that amplification of RUNX1 in these tumors may be secondary to a previous rearrangement of 21q22, which later evolved into a complex marker chromosome as part of tumor progression.
 ...
PMID:Marker chromosomes are a significant mechanism of high-level RUNX1 gene amplification in hematologic malignancies. 1916 8

The genetic heterogeneity of cancer influences the trajectory of tumor progression and may underlie clinical variation in therapy response. To model such heterogeneity, we produced genetically and pathologically accurate mouse models of common forms of human acute myeloid leukemia (AML) and developed methods to mimic standard induction chemotherapy and efficiently monitor therapy response. We see that murine AMLs harboring two common human AML genotypes show remarkably diverse responses to conventional therapy that mirror clinical experience. Specifically, murine leukemias expressing the AML1/ETO fusion oncoprotein, associated with a favorable prognosis in patients, show a dramatic response to induction chemotherapy owing to robust activation of the p53 tumor suppressor network. Conversely, murine leukemias expressing MLL fusion proteins, associated with a dismal prognosis in patients, are drug-resistant due to an attenuated p53 response. Our studies highlight the importance of genetic information in guiding the treatment of human AML, functionally establish the p53 network as a central determinant of chemotherapy response in AML, and demonstrate that genetically engineered mouse models of human cancer can accurately predict therapy response in patients.
 ...
PMID:Mouse models of human AML accurately predict chemotherapy response. 1933 91

Altered glycosylation may be a hallmark of malignant transformation and cancer progression. In the work described, a specific mannose-binding lectin, Pinellia pedatisecta agglutinin (PPA), was genetically fused with the extracellular domain of coxsackie-adenovirus receptor (CAR) to generate the soluble CAR (sCAR)-PPA fusion protein. The adenoviral transduction of acute myeloid leukemia (AML) cell lines Kasumi-1 and HL-60 was increased by sCAR-PPA, indicating that a fraction of AML cells exposing mannose residues was detected by PPA. However, sCAR-PPA did not increase the adenoviral infection of KG-1 cells, suggesting the mannose exposure of AML cells may be cell type specific. Furthermore, the infectious efficiency of Ad-EGFP in chronic myeloid leukemia cell line K562 was significantly increased by sCAR-PPA as well. We, herein, report that PPA recognized a fraction of myeloid leukemia cells showing mannose-exposing phenotype. The sCAR-PPA fusion protein combined with the adenoviral vector system may provide a useful tool for investigating myeloid leukemia cells exposing mannose residues and further elucidating the role of these cells in the leukemia development.
 ...
PMID:Mannose-exposing myeloid leukemia cells detected by the sCAR-PPA fusion protein. 1937 43

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.
 ...
PMID:Ferritin heavy chain-mediated iron homeostasis and subsequent increased reactive oxygen species production are essential for epithelial-mesenchymal transition. 1953 52

Tumor microenvironment has a major role in cancer progression and resistance to treatment. The bone marrow (BM) is a dynamic network of growth factors, cytokines and stromal cells, providing a permissive environment for leukemogenesis and progression. Both BM stroma and leukemic blasts promote angiogenesis, which is increased in acute lymphoblastic leukemia and acute myeloid leukemia. Growth factors like vascular endothelial growth factor (VEGF), basic fibroblast growth factor and angiopoietins are the main proangiogenic mediators in acute leukemia. Autocrine proleukemic loops have been described for VEGF and angiopoietin in hematopoietic cells. Interactions of stromal cells and extracellular matrix with leukemic blasts can also generate antiapoptotic signals that contribute to neoplastic progression and persistence of treatment-resistant minimal residual disease. High expression of CXC chemokine ligand 4 (CXCR4) by leukemic blasts and activation of the CXCR4-CXCL12 axis is involved in leukemia progression and disruption of normal hematopoiesis. Leukemia-associated bone microenvironment markers could be used as prognostic or predictive indicators of disease progression and/or treatment outcome. Studies related to bone microenvironment would likely provide a better understanding of the treatment resistance associated with leukemia therapy and design of new treatments.
 ...
PMID:Contribution of bone microenvironment to leukemogenesis and leukemia progression. 1972 27


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>