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)

Many new insights into the diagnosis, pathogenesis, clinical manifestation, treatment and prognosis of patients with AML reflect the heterogeneity of the disease. The initial descriptions of the various subtypes of AML, established by the FAB classification, were based on morphology and cytochemical stains. Although morphology remains the foundation for the diagnosis, additional diagnostic studies including immunophenotyping, cytogenetic evaluation, and molecular genetic studies have become critical, and in some specific cases, mandatory, complementary tools. Several specific subtypes of AML are now treated with directed or targeted therapy. Acute promyelocytic leukemia is currently the only example of a subtype of AML to which specific therapy targeted to a molecular genetic abnormality is available and this subtype now is highly curable. Future studies will address newly identified prognostic factors and gene mutations such as FLT3, Wilm's tumor (WTI), and CEBPA which will enable the further pathologic classification of patients with AML. Finally, microarray analysis will likely identify genes critically involved in the pathogenesis of specific pathologic subtypes.
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PMID:Relevance of pathologic classifications and diagnosis of acute myeloid leukemia to clinical trials and clinical practice. 1521 6

Prognostic assessment is crucial for the management of AML. Although the use of karyotype analysis for risk-stratification is widely accepted, prognosis of AML remains ambiguous, particularly for patients categorized into the intermediate cytogenetic risk group and additional markers are required for an accurate prediction of outcome. For this study, we used multiplex real-time RT-PCR, which can simultaneously quantify WT1 and 10 distinct fusion gene transcripts, to prospectively evaluate the pre-treatment bone marrow findings of 53 de novo AML patients. Five patients with normal karyotype or insufficient metaphases detected by conventional karyotype analysis proved to have AML1-MTG8, CBFbeta-MYH11 or PML-RARalpha fusion transcripts. WT1 overexpression was observed in 92% of the patients, and the levels were significantly higher in the cytogenetic favorable risk group, especially patients with PML-RARalpha. WT1 levels also correlated with the percentage of blasts in bone marrow, especially in cases of core-binding factor leukemia. There was no association between initial WT1 levels and outcome in terms of event-free survival or overall survival. These results suggest that multiplex real-time RT-PCR is rapid and useful for the precise cytogenetic stratification of AML, and that WT1 levels at presentation correlate with several biologic features of leukemia, but have no prognostic significance.
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PMID:Multiplex real-time RT-PCR for prospective evaluation of WT1 and fusion gene transcripts in newly diagnosed de novo acute myeloid leukemia. 1522 39

Ionizing radiation and a variety of genetic conditions are thought to explain 5-10% of childhood cancers. Infection with Epstein-Barr virus (EBV) in parts of Africa and human immunodeficiency virus (HIV) increase the risk of Burkitt's lymphoma and Kaposi's sarcoma, respectively. Other risk factors have not been conclusively identified. A review of the data on international variation in incidence, recent changes in incidence, and risk factors suggests that many childhood cancers are likely to have nongenetic causes. The pattern of international variation and associations with surrogates of infection suggest an infectious etiology for acute lymphoblastic leukemia, although no agent has been identified. The biologic plausibility is strong that maternal consumption of food containing DNA topoisomerase II inhibitors may increase the risk of acute myeloid leukemia, although the data are limited now. For brain tumors, cured meats, polyomaviruses, and farm exposures may have etiologic roles. Changes in the incidence and characteristics of children with hepatoblastoma as well as risk factor studies suggest a role for an exposure of very low birth weight babies. High birth weight, tea or coffee consumption, and certain paternal occupations have shown some consistency in their association with Wilms' tumor. For most of the other cancers, very few epidemiologic studies have been conducted, so it is not surprising that nongenetic risk factors have not been detected. The most important difference between the cancers for which there are good etiologic clues and those for which there are not may be the number of relevant studies.
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PMID:Nongenetic causes of childhood cancers: evidence from international variation, time trends, and risk factor studies. 1531 82

WT1 is a transcription factor involved in differentiation and proliferation of acute myeloid leukemia (AML) blasts and is expressed in 90% of cases, as determined by nested reverse transcription polymerase chain reaction (RT-PCR). It is proposed to be a key molecule in leukemia promotion. To assess the relevance of WT1 expression, we analyzed blood and bone marrow samples from 58 AML patients (37 at diagnosis, 8 in hematological remission, and 13 at relapse) for the level of WT1 expression, using quantitative real-time RT-PCR. In addition, 21 randomly chosen samples were also analyzed for the quantitative expression of the main WT1 splice variants. As expected, samples from patients at the time of diagnosis or relapse showed significantly higher WT1 expression compared to samples from patients in remission or control samples. No striking difference in expression levels was found between various French-American-British (FAB) subtypes. The level of WT1 expression observed in patients at the time of initial diagnosis was similarly high in patients at relapse. Expression of the four main isoforms (E5+/KTS+, E5-/KTS+, E5+/KTS-, and E5-/KTS-) was found in all samples with significantly higher expression levels of the E5+ variants. Together, these findings support the potential of WT1 as a target for novel treatment approaches in AML.
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PMID:Expression of Wilms' tumor gene 1 at different stages of acute myeloid leukemia and analysis of its major splice variants. 1534 Jul 62

To study the expression and significance of WT1 gene in patients with myelodysplastic syndrome (MDS) and acute leukemia (AL), RT-PCR was applied to monitor WT1 gene expression in 22 patients with MDS and in 69 patients with AL. The results showed that the positive rate of WT1 mRNA in MDS-RA and MDS-RAS was lower than that in MDS-RAEB and MDS-RAEB-t (10% versus 91.7%, P < 0.01). WT1 mRNA could be expressed in all subtype of AL, It was detected in 69% of newly diagnosed and relapsed patients, and in 12.5% patients CR. There was no difference at the relative expression level between newly diagnosed AL patients and relapsed patients, while the relative level of WT1 in MDS-RAEB and MDS-RAEB-t was lower than that in newly diagnosed AL. The CR rate in AML patients with positive expression was lower than that in patients with negative expression (41% versus 78%, P </= 0.05). AML patients with relative level of WT1 mRNA >/= 1 had lower CR rate (18%) than those with relative level < 1 (55%). It is concluded that the expression of WT1 gene in patients with MDS-RAEB and RAEB-t was higher than that in patients with RA and RAS. The detection of WT1 gene may be useful for assessing disease progress of patients with MDS. The expression of WT1 gene and its expression level have associated with the prognosis of newly diagnosed patients with AL, that WT1 gene may be an independent prognostic factor in AML.
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PMID:[Expression of WT1 gene in patients with myelodysplastic syndrome and acute leukemia]. 1536 32

The Wilms' tumor gene WT1 is overexpressed in leukemias and various types of solid tumors, and the WT1 protein was demonstrated to be an attractive target antigen for immunotherapy against these malignancies. Here, we report the outcome of a phase I clinical study of WT1 peptide-based immunotherapy for patients with breast or lung cancer, myelodysplastic syndrome, or acute myeloid leukemia. Patients were intradermally injected with an HLA-A*2402-restricted, natural, or modified 9-mer WT1 peptide emulsified with Montanide ISA51 adjuvant at 0.3, 1.0, or 3.0 mg per body at 2-week intervals, with toxicity and clinical and immunological responses as the principal endpoints. Twenty-six patients received one or more WT1 vaccinations, and 18 of the 26 patients completed WT1 vaccination protocol with three or more injections of WT1 peptides. Toxicity consisted only of local erythema at the WT1 vaccine injection sites in patients with breast or lung cancer or acute myeloid leukemia with adequate normal hematopoiesis, whereas severe leukocytopenia occurred in patients with myelodysplastic syndrome with abnormal hematopoiesis derived from WT1-expressing, transformed hematopoietic stem cells. Twelve of the 20 patients for whom the efficacy of WT1 vaccination could be assessed showed clinical responses such as reduction in leukemic blast cells or tumor sizes and/or tumor markers. A clear correlation was observed between an increase in the frequencies of WT1-specific cytotoxic T lymphocytes after WT1 vaccination and clinical responses. It was therefore demonstrated that WT1 vaccination could induce WT1-specific cytotoxic T lymphocytes and result in cancer regression without damage to normal tissues.
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PMID:Induction of WT1 (Wilms' tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression. 1536 88

A rare case of pulmonary LAM in combination with AML and multilocular cystic nephroma of the kidney in a 18-year-old female is described. Granules of the melanosomic type in AML, HMB-45 antigen and steroid receptors expression in LAM and AML were observed.
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PMID:[Combination of pulmonary lymphangioleiomyomatosis (LAM) with angiomyolipoma (AML) of the kidney and multilocular cystic nephroma]. 1544 88

Recent progress in understanding the pathobiology of the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have led to the development of various immunologically oriented therapies for these diseases. The existence of elevated levels of tumor necrosis factor-alpha (TNF-alpha) in bone marrow during early stages of MDS, and the possibility that TNF- proportional, variant suppresses normal hematopoiesis led to studies of attempts to block the activity of TNF-alpha. An anti-TNF monoclonal antibody and an antibody comprised of the soluble extracellular ligand-binding portion of the TNF receptor have both been evaluated recently in several small pilot studies. The recognition that marrow suppression in MDS may, in part, be a T-cell mediated autoimmune process has stimulated various trials of antithymocyte globulin and other similar agents. Gemtuzumab ozogamicin, an antibody against CD33 conjugated to the cytotoxic agent calicheamicin, is approved for use in AML and is currently being investigated as a potential therapeutic agent in MDS. Clinical trials were conducted as either monotherapy or in combination with cytokines such as IL-11 and chemotherapeutic agents including idarubicin, fludarabine, and/or cytarabine. Other antibodies are being developed as immunoconjugates with radioisotopes as part of conditioning regimens prior to bone marrow transplantation for AML or MDS. These include (131)I-anti-CD45 antibody (BC8), (131)I anti-CD33 antibody (p67), (213)Bi-M195 antibody, and (188)Re-labeled anti-CD66 antibody. The clearest example of successful immunotherapy for MDS (and AML) is the use of the graft-versus-tumor effect associated with allogeneic hematopoietic cell transplantation. Recently, nonmyeloablative transplants have been explored with encouraging results. Vaccines using overexposed self-antigens such as WT1 and PR1 are other attempts to induce a T-cell mediated response against MDS.
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PMID:Immunobiologic therapies for myelodysplastic syndrome. 1549 1

As more and more effective targeted therapeutics have been developed to treat adults with cancer, it is of critical importance to devise appropriate in vitro experimental models to study their use in pediatric patients. Acute lymphoblastic leukemia (ALL) with Bcr-Abl translocation is one of the most difficult to treat and deadly diseases in children. The targeted kinase inhibitor imatinib mesylate has been shown to induce an initial response but resistance often develops. Recently, the geldanamycin family of antibiotics has been found to induce apoptosis in many malignant cells, including adult CML and AML. We describe experiments in which 17-allylamino-17-demethoxygeldanamycin (17-AAG) was evaluated in the context of Bcr-Abl and resistance to imatinib mesylate. Pediatric ALL cell lines with varying Bcr-Abl status and imatinib mesylate sensitivity were generated and their growth inhibition by 17-AAG was studied in vitro. Western blots were used to follow the changes in proteins that correlate with cell survival. Results show that apoptosis was induced in all lines with an increased 50% inhibitory concentration (IC50) for Bcr-Abl positive but imatinib mesylate-resistant cells. Addition of 17-AAG greatly increased imatinib sensitivity in vitro. A decrease in p53, survivin, Her2/neu, and WT1 was seen in cells that expressed these proteins. With some notable exceptions, when combined with 17-AAG, the IC50 of most of the common chemotherapeutic agents decreased. We describe an experimental approach to investigate the complex interaction between Bcr-Abl status, imatinib mesylate sensitivity, and 17-AAG in pediatric ALL. Information from such an approach will provide means to devise combined treatment approaches and to follow their effectiveness in vitro.
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PMID:Effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG) on pediatric acute lymphoblastic leukemia (ALL) with respect to Bcr-Abl status and imatinib mesylate sensitivity. 1565 98

Although improvement in outcomes has occurred in younger adults with acute myeloid leukemia (AML) during the past 4 decades, progress in older adults has been much less conspicuous, if at all. Approximately 50% to 75% of adults with AML achieve complete remission (CR) with cytarabine and an anthracycline such as daunorubicin or idarubicin or the anthracenedione mitoxantrone. However, only approximately 20% to 30% of the patients enjoy long-term disease survival. Various postremission strategies have been explored to eliminate minimal residual disease. The optimal dose, schedule, and number of cycles of postremission chemotherapy for most patients are not known. A variety of prognostic factors can predict outcome and include the karyotype of the leukemic cells and the presence of transmembrane transporter proteins, which extrude certain chemotherapy agents from the cell and confer multidrug resistance and mutations in or over expressions of specific genes such as WT1, CEBPA, BAX and the ratio of BCL2 to BAX, BAALC, EVI1, KIT, and FLT3. Most recently, insights into the molecular pathogenesis of AML have led to the development of more specific targeted agents and have ushered in an exciting new era of antileukemia therapy. Such agents include the immunoconjugate gemtuzumab ozogamicin, multidrug resistance inhibitors, farnesyl transferase inhibitors, histone deacetylase and proteosome inhibitors, antiangiogenesis agents, Fms-like tyrosine kinase 3 (FLT3) inhibitors, and apoptosis inhibitors.
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PMID:Drug therapy for acute myeloid leukemia. 1587 Jan 83


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