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)

The inv(11)(p15q22) is a recurrent chromosomal abnormality associated with de novo and therapy-related myeloid malignancies. Here we report the molecular definition of this chromosomal aberration in four patients. Positional cloning showed the consistent rearrangement of the DDX10 gene on chromosome 11q22, which encodes a putative RNA helicase. The translocation targets the NUP98 gene on 11p15, a member of the FG peptide repeat nucleoporin family. In DDX10 and NUP98, the inv(11) breakpoints occurred within two introns of each gene and the two genes merged in-frame to produce the chimeric transcripts characteristic of this translocation. Although two reciprocal chimeric products, NUP98-DDX10 and DDX10-NUP98, were predicted, only NUP98-DDX10 appears to be implicated in tumorigenesis. DDX10 is predicted to be involved in ribosome assembly. NUP98 has been identified as a nuclear pore complex protein and a target of chromosomal translocation in acute myeloid leukemia through the t(7;11)(p15;p15) translocation. The predicted NUP98-DDX10 fusion protein may promote leukemogenesis through aberrant nucleoplasmic transport of mRNA or alterations in ribosome assembly.
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PMID:The inv(11)(p15q22) chromosome translocation of de novo and therapy-related myeloid malignancies results in fusion of the nucleoporin gene, NUP98, with the putative RNA helicase gene, DDX10. 916 30

The ETS family of genes are implicated in cancers such as Ewings sarcoma, acute myeloid leukemia and chronic myelomonocytic leukemia. Further, they have important functions in embryonic development. Hence, identification and characterization of members of this family are important. We identify a novel ETS family member, ELF3, and report its human and murine cDNA sequences. The mouse cDNA has an alternatively spliced transcript with an extra 60 bp inserted. Hence we present the organization of the murine Elf3 gene together with its exon/intron structure. This gene consists of 9 exons and 8 introns spanning 4.8 kb. ELF3 binds and transactivates ETS sequences and interestingly also shows the ability to bind a GGAT-like purine core, a preferential ETS1/ETS2 type binding site. The expression of ELF3, unlike most other ETS family members, is absent in hematopoietic cells and hematopoietic organs in humans and mice. Intriguingly, the gene is specifically expressed in cell lines of epithelial origin and in organs such as lung, stomach, intestine, kidney that have specialized epithelial cells. We localize the human gene to 1q32.2, a region that is amplified in epithelial tumors of the breast, lung and prostate. Finally, we show that ELF3 expression is increased in a lung carcinoma and adenocarcinoma, as compared to normal tissue. ELF3 is also expressed in cell lines derived from lung cancers. These results suggest that this novel ETS gene may be involved in lung tumorigenesis.
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PMID:A novel epithelial-expressed ETS gene, ELF3: human and murine cDNA sequences, murine genomic organization, human mapping to 1q32.2 and expression in tissues and cancer. 939 41

Cyclin A is a cell cycle regulatory protein that functions in mitotic and S phase control in mammalian cells. However, in contrast to other G1 phase regulatory proteins, such as cyclin D, retinoblastoma protein and p16INK4A, cyclin A seems not to be commonly involved in tumorigenesis. Recently, a second human cyclin A--cyclin A1--has been identified. In contrast to cyclin A which is expressed throughout embryonic development and in adult tissue, the expression of cyclin A1 has been reported to be restricted to embryonic and germ line cells. We have confirmed the absence of cyclin A1 mRNA from normal peripheral blood leukocytes of seven healthy donors by single step reverse transcriptase-polymerase chain reaction (RT-PCR). Furthermore, we have examined the expression of cyclin A1 mRNA in 173 peripheral blood samples of 162 patients with various hematological malignancies. Cyclin A1 mRNA was detectable in 11 of 11 patients with acute myeloid leukemia, three of three patients with acute biphenotypic leukemia, eight of eight patients with myelodysplastic syndrome, 59 of 69 patients with chronic myelogenous leukemia (CML) at diagnosis, 13 of 15 patients with CML in blastic transformation, 10 of 18 patients with chronic lymphocytic leukemia, two of nine patients with essential thrombocythemia, and only two of 10 patients with acute lymphoblastic leukemia (ALL) with both cyclin A1 RT-PCR positive ALL leukemias being undifferentiated relapses. In addition, cyclin A1 mRNA was found in one of six leukapheresis products, harvested from individuals without hematological disorders. Taken together, cyclin A1 is expressed in the majority of myeloid and undifferentiated hematological malignancies as well as in normal hematopoietic progenitor cells. We conclude that cyclin A1, a protein potentially involved in G1/S phase progression of immature cells, might be necessary for proliferation of early hematopoietic progenitor cells and their leukemic counterparts being blocked at that stage of differentiation.
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PMID:Cyclin A1 is predominantly expressed in hematological malignancies with myeloid differentiation. 963 17

Genes encoding the Phe-Gly (FG) repeat-containing nucleoporins NUP98 and CAN/NUP214 are at the breakpoints of several chromosomal translocations associated with human acute myeloid leukemia (AML), but their role in oncogenesis is unclear. Here we demonstrate that the NUP98-HOXA9 fusion gene encodes two nuclear oncoproteins with either 19 or 37 NUP98 FG repeats fused to the DNA binding and PBX heterodimerization domains of the transcription factor HOXA9. Both NUP98-HOXA9 chimeras transformed NIH 3T3 fibroblasts, and this transformation required the HOXA9 domains for DNA binding and PBX interaction. Surprisingly, the FG repeats acted as very potent transactivators of gene transcription. This NUP98-derived activity is essential for transformation and can be replaced by the bona fide transactivation domain of VP16. Interestingly, FG repeat-containing segments derived from the nucleoporins NUP153 and CAN/NUP214 functioned similarly to those from NUP98. We further demonstrate that transactivation by FG repeat-rich segments of NUP98 correlates with their ability to interact functionally and physically with the transcriptional coactivators CREB binding protein (CBP) and p300. This finding shows, for the first time, that a translocation-generated fusion protein appears to recruit CBP/p300 as an important step of its oncogenic mechanism. Together, our results suggest that NUP98-HOXA9 chimeras are aberrant transcription factors that deregulate HOX-responsive genes through the transcriptional activation properties of nucleoporin-specific FG repeats that recruit CBP/p300. Indeed, FG repeat-mediated transactivation may be a shared pathogenic function of nucleoporins implicated human AML.
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PMID:CREB binding protein interacts with nucleoporin-specific FG repeats that activate transcription and mediate NUP98-HOXA9 oncogenicity. 985 99

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia characterized by hypergranular leukemic cells, bleeding diathesis and t(15; 17) translocation. The t(15; 17) translocation leads to the production of the PML-RAR alpha fusion protein which plays a vital role in the pathogenesis of APL by arresting normal differentiation of myeloid precursors. However, in the presence of high concentrations of all-trans-retinoic acid (ATRA), the PML-RAR alpha fusion protein serves to stimulate cell differentiation. The diagnosis of APL and the detection of residual disease are based on the t(15; 17) translocation. Treatment with a combination of ATRA and anthracycline-AraC chemotherapy has shown a higher rate of complete remission in APL. We report the case of a 71-year-old male with the rare microgranular variant of APL to illustrate these findings. The patient was treated with a combination of ATRA and Daunorubicin-AraC chemotherapy and achieved complete remission. He developed retinoic acid syndrome as a complication of therapy with ATRA. The methods for diagnosis, the molecular mechanisms in the oncogenesis of APL, rationale of treatment of APL with ATRA, complications of therapy and the new concepts in the treatment of ATRA-resistant APL are discussed.
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PMID:Acute promyelocytic leukemia. New methods in diagnosis and treatment. 1007 58

Activating mutations in c-Kit, the receptor for Stem Cell Factor (SCF), have been identified in dysplasias and leukaemias of the mast cell lineage and have been shown to contribute to transformation in model systems. Early myeloid cells also normally express c-Kit and their survival, proliferation and differentiation is promoted by SCE It might therefore be expected that c-Kit mutations could also be involved in some acute and/or chronic myeloid leukaemias. We have found that mutant c-Kit (and normal c-Kit in the presence of SCF) provides a strong differentiation stimulus in normal and immortalised murine early myeloid cells. Since maturation of haemopoietic cells, with the exception of mast cells, results in down-regulation of c-Kit expression, the transforming effects of mutant receptor may be self-limiting in most lineages. This is consistent with the observation that multipotential progenitor cells from some patients with systemic mastocytosis express mutant c-Kit. However, c-Kit mutations have been observed in a few cases of myelodysplastic syndromes or AML without mast cell features. Oncogenesis involves multiple genetic changes and the phenotype of malignant haemopoietic cells expressing mutant c-Kit may be influenced by co-oncogenic events. For example mutations blocking the differentiative effect of mutant c-Kit might result in AML rather than mastocytosis. Thus the extent to which c-Kit mutations contribute to malignancies of early myeloid phenotype remains unknown, and resolution of this issue is complicated by the heterogeneity of this family of diseases.
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PMID:Effects of mutant c-Kit in early myeloid cells. 1072 93

Resistance to apoptosis may contribute to tumorigenesis and, in part, explains treatment failures in neoplastic diseases. We evaluated in vitro drug-induced apoptosis in leukemic cells using TdT-dependent labeling of DNA breaks with digoxigenine-dUTP and PI DNA staining in multiparameter flowcytometry. In cell lines developing drug resistance, a significant inhibition of proliferation and increased cell clearance via apoptosis was shown. Moreover, in drug resistant sub-lines and in blasts from AML patients, a variable apoptotic response to in vitro exposure to cytostatics was seen. Half of the studied AML cases were completely resistant to Novantrone-induced apoptosis with no correlation between sensitivity to Novantrone and bcl-2 expression. One case showed intraclonal heterogeneity with two coexisting populations: an immature blast population resistant to Novantrone and a differentiating blast population showing apoptotic response. Another case showed complete resistance to various cytostatics, but incubation with anti-CD95 monoclonal antibody resulted in a considerable apoptotic response. This case demonstrates that a lack of apoptotic response to cytostatics does not preclude sensitivity to other apoptotic stimuli. Our results confirm the role apoptosis plays in selection of drug-resistant clones and suggest different signaling pathways for apoptosis operating in various leukemic blasts.
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PMID:Balance between proliferation and apoptosis in leukemic cell lines resistant to cytostatics. 1061 63

The product of the Wilms' tumor gene WT1 is a transcription factor overexpressed not only in leukemic blast cells of almost all patients with acute myeloid leukemia, acute lymphoid leukemia, and chronic myeloid leukemia, but also in various types of solid tumor cells. Thus, it is suggested that the WT1 gene plays an important role in both leukemogenesis and tumorigenesis. Here we tested the potential of WT1 to serve as a target for immunotherapy against leukemia and solid tumors. Four 9-mer WT1 peptides that contain HLA-A2.1-binding anchor motifs were synthesized. Two of them, Db126 and WH187, were determined to bind to HLA-A2.1 molecules in a binding assay using transporter associated with antigen processing-deficient T2 cells. Peripheral blood mononuclear cells from an HLA-A2.1-positive healthy donor were repeatedly sensitized in vitro with T2 cells pulsed with each of these two WT1 peptides, and CD8(+) cytotoxic T lymphocytes (CTLs) that specifically lyse WT1 peptide-pulsed T2 cells in an HLA-A2.1-restricted fashion were induced. The CTLs also exerted specific lysis against WT1-expressing, HLA-A2.1-positive leukemia cells, but not against WT1-expressing, HLA-A2.1-negative leukemia cells, or WT1-nonexpressing, HLA-A2. 1-positive B-lymphoblastoid cells. These data provide the first evidence of human CTL responses specific for the WT1 peptides, and provide a rationale for developing WT1 peptide-based adoptive T-cell therapy and vaccination against leukemia and solid tumors.
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PMID:Human cytotoxic T-lymphocyte responses specific for peptides of the wild-type Wilms' tumor gene (WT1 ) product. 1066 72

We previously defined a common region of 17q25 loss in breast and ovarian tumors, suggesting localization of at least one putative tumor suppressor gene. Genomic clones from the interval were used to isolate candidate transcripts. One novel transcript had strong homology to a septin family of GTPase genes involved in cytokinesis. This gene was recently identified as a myeloid/lymphoid leukemia (MLL) fusion protein partner in acute myeloid leukemia and was named MSF (MLL septin-like fusion). As this gene may play roles in both leukemogenesis and tumorigenesis, it is essential to understand its structure and normal expression. We cloned two human alternative transcripts and identified a third database variant of MSF. RNA expression studies with a probe common to the three novel sequences showed differential expression of 4.0- and 3.0-kb transcripts in all adult and fetal tissues tested. A probe spanning sequence unique to one MSF variant detected specific expression of the 4.0-kb transcript in all tissues. Another probe unique to a different MSF variant detected a 4.0-kb transcript only in skeletal muscle. Proteins of 422 and 586 amino acids were predicted from the novel alternate transcripts and included both a xylose isomerase 1 domain and a GTPase domain. Nine common exons, three alternatively spliced exons, and six polymorphisms were identified.
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PMID:Genomic and expression analyses of alternatively spliced transcripts of the MLL septin-like fusion gene (MSF) that map to a 17q25 region of loss in breast and ovarian tumors. 1067 29

Activating mutations in c-Kit, the receptor for Stem Cell Factor (SCF), have been identified in dysplasias and leukaemias of the mast cell lineage and have been shown to contribute to transformation in model systems. Early myeloid cells also normally express c-Kit and their survival, proliferation and differentiation is promoted by SCF. It might therefore be expected that c-Kit mutations could also be involved in some acute and/or chronic myeloid leukaemias. We have found that mutant c-Kit (and normal c-Kit in the presence of SCF) provides a strong differentiation stimulus in normal and immortalised murine early myeloid cells. Since maturation of haemopoietic cells, with the exception of mast cells, results in down-regulation of c-Kit expression, the transforming effects of mutant receptor may be self-limiting in most lineages. This is consistent with the observation that multipotential progenitor cells from some patients with systemic mastocytosis express mutant c-Kit. However, c-Kit mutations have been observed in a few cases of myelodysplastic syndromes or AML without mast cell features. Oncogenesis involves multiple genetic changes and the phenotype of malignant haemopoietic cells expressing mutant c-Kit may be influenced by co-oncogenic events. For example mutations blocking the differentiative effect of mutant c-Kit might result in AML rather than mastocytosis. Thus the extent to which c-Kit mutations contribute to malignancies of early myeloid phenotype remains unknown, and resolution of this issue is complicated by the heterogeneity of this family of diseases.
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PMID:Effects of mutant c-kit in early myeloid cells. 1049 68


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