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)

Besides its application in biological research, fluorescence in situ hybridization (FISH) is increasingly used for the cytogenetic analysis of human malignancies. Compared to conventional cytogenetic analysis, FISH allows delineation of specific numerical and structural chromosome aberrations in interphase cells (interphase cytogenetics). We have developed sets of genomic DNA probes for the identification of chromosome aberrations associated with chronic lymphocytic leukemia (CLL), chronic myeloid leukemias (CML), and acute myeloid leukemia (AML). In CLL, interphase cytogenetics will greatly contribute to the evaluation of the true incidence of specific chromosome aberrations and will provide the basis for more accurate correlations with the clinical outcome. The Philadelphia chromosome can be detected by FISH with high specificity and sensitivity in both CML and acute lymphoblastic leukemia. In CML, it can be used to better assess the cytogenetic remission status following therapy with interferon-alpha. Finally, in AML interphase cytogenetics provides a rapid and reliable technique for the identification of chromosome aberrations which are one of the most important prognostic factors in this disease. With the design of complex DNA probe sets and the development of digital microscopy and automated image analysis, it will be possible to use such disease-specific probe sets for monitoring residual disease following chemotherapy.
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PMID:Diagnosis and monitoring of chromosome aberrations in hematological malignancies by fluorescence in situ hybridization. 874 92

To study acute myelogenous leukemia 1 (AML1) transcription factor, ETO protein, and t(8;21) AML chimeric AML1/ ETO protein in normal hematopoiesis and in leukemia, we raised rabbit antisera to a bacterially expressed polypeptide containing amino acid residues 1 to 220 of ETO and to synthetic peptides extending from residues 528 to 548 of ETO and 32 to 50 of AML1. The latter was selected to have little chance of cross-reactivity with other members of the PEBP2 alpha family. With affinity-purified reagents, we observed immunofluorescent staining for both AML1 and ETO in the nucleus of HEL, K562, and Kasumi-1 leukemic cell lines, the last from a t(8;21) AML. Biochemical analysis confirmed specificity of the antibodies and the nuclear localization of the antigens, the latter being exclusive for AML1 and primary for ETO. Immunoprecipitations of metabolically labeled 32P-proteins from Kasumi-1 cells show that AML1 and ETO are phosphorylated on serine and threonine. Investigations with normal bone marrow reveal AML1 and ETO are coexpressed in megakaryocytes and that each is expressed in a portion of the approximately 10-microns-diameter cells residing there. Using a CD34+ enriched population mobilized to peripheral blood, we found AML1 and, unexpectedly, ETO present in these cells. Because of this, we conclude that the expression of ETO in hematopoietic cells is not by itself leukemogenic. Also, because ETO would not be exclusively expressed as part of chimeric AML1/ETO in leukemic patients, its presence cannot be used to monitor t(8;21) AML residual disease.
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PMID:ETO and AML1 phosphoproteins are expressed in CD34+ hematopoietic progenitors: implications for t(8;21) leukemogenesis and monitoring residual disease. 878 39

Serial peripheral blood specimen from eight adult patients after sex-mismatched bone marrow transplantation (BMT) for Chronic Myeloid Leukemia (CML) (N = 3). Ewing sarcoma (N = 1), Acute Myeloid Leukemia (AML) in second remission (N = 1), Acute Lymphoid Leukemia (ALL) (N = 1), of multiple myeloma (N = 2) were analyzed by the simultaneous immunophenotypic (moAbs/ APAAP-staining) and genotypic analysis (for X and Y chromosomes) of interphase cells to characterize mixed chimerism, residual host cells, and leukemic relapse. Although a stable donor chimerism for T cells, myelomonocytic cells, and granulocytes was developed in seven of the eight patients at Days +21 to +28 post BMT, 0.5 to 1% host cells of different lineages remained continuously in five of the eight patients post BMT (> day 100). In two patients, one with common ALL and the other with multiple myeloma and long-term stable mixed chimerism, a tumor cell relapse was detected first in a sample at Day +176 and confirmed at Day +294. These malignant cells were genotypically of host origin and presented phenotypes identical to those at diagnosis. In the three patients with CML, residual host cells were identified as CD13 (Patient 3) of CD13/CD34 (Patient 4) positive and in one case as CD4/CD8 positive (Patient 7). Since no exclusive antigenic marker is available for this discrimination in these CML patients, normal host hematopoiesis can interfere with the identification of residual disease. Therefore, the identification of the bcr-abl transcripts by a two-step reverse transcriptase-polymerase chain reaction (RT-PCR) was included in this analysis. Patient 3 was bcr-abl positive at [Days +21, +28, +35, and +311, but negative at Days +121 and +400; Patient 4 was bcr-abl positive at only Day +166 post BMT. These results are interpreted as signaling a continuing risk of relapse. In Patient 7, the bcr-abl RT-PCR was negative at Days +142, +166, and +237. Thus, the combination of the simultaneous immunophenotypic and genotypic analysis and the bcr-abl detection by RT-PCR clearly improves the discrimination between malignant cells and normal residual host cells.
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PMID:Qualitative assessment of mixed chimerism after allogeneic bone marrow transplantation with regard to leukemic relapse. 893 46

Cytogenetic analysis performed at diagnosis is widely recognised to provide one of the most valuable prognostic indicators in AML. Yet any role for this technique in residual disease assessment, particularly in the context of subsequent transplantation procedures has been incompletely explored. The present study considers the outcome of 190 patients drawn from the UK MRC AML 10 trial in whom cytogenetics were assessed whilst in morphological CR at the time of bone marrow harvest. Cytogenetics at this stage were abnormal in 19 patients (10%). In 11/19 patients, the abnormalities detected reflected the acquisition of new clonal (3/11) or nonclonal changes (8/11) that were not identified at diagnosis; comparison of this group to patients with normal cytogenetics at harvest provided no evidence that such acquired changes are of prognostic significance. In 8/19 patients, abnormalities detected were indicative of persistence of the disease-related clone in harvested marrow. Two of these patients died of sepsis during consolidation therapy. Two received ABMT in first morphological CR: one patient with AML associated with a favourable karyotype (+8,inv(16)) remains in CR, 5.5 years post-transplant, whereas the other with cytogenetic abnormalities considered to confer a poor prognosis (inv(3q),-7), relapsed within 5 months of ABMT. All four of the remaining patients with cytogenetic evidence of persistent disease who were not transplanted in first CR, relapsed within 6.5 months of harvest. Therefore, among 101 of 190 patients with AML characterised by abnormal karyotype at diagnosis, persistence of the disease-related clone in eight patients (8%), revealed by conventional cytogenetic assessment at bone marrow harvest whilst in morphological remission, was found to predict a poor prognosis. Nevertheless, transplantation procedures using marrow which is obviously contaminated with the original leukaemic clone may occasionally still be associated with long-term survival.
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PMID:What happens subsequently in AML when cytogenetic abnormalities persist at bone marrow harvest? Results of the 10th UK MRC AML trial. Medical Research Council Leukaemia Working Parties. 919 55

Samples of peripheral blood were taken from 11 patients (blood group A, B and O), suffering from acute myeloblastic leukemia (AML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS), before and after chemotherapy, compared to normal control samples. The RBC's typing was done by standard agglutination technique (with conventional human and murine anti-sera) and flow cytometry. While using different reagent dilutions, a lower expression of the A or B antigen was noticed in all patients, even if direct typing of the RBC's revealed an apparently normal pattern. The most important depletion of antigenic expression was found to correspond to the highest concentration of myeloblasts in the bone marrow, with hypoplastic erythrocytic series. The modified H reactivity, detected at admission, was still present after complete remission, as an expression of the residual disease. Studies of the H expression could eventually become a parameter of evaluating the moment of relapse of the myeloproliferative disease.
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PMID:[Temporary changes and permanent changes in the erythrocyte blood-group antigens in malignant hemopathies]. 922 Oct 50

The study of minimal residual disease (MRD) is an attempt to detect and define the significance of leukemia invisible to normal morphologic examination. In many circumstances the clinical significance of MRD detection is unclear, because the technical ability to detect and quantify it has outpaced studies demonstrating its clinical significance. The detection of minimal residual disease most consistently has been associated with relapse in acute lymphoblastic leukemia, t(15;17) acute myeloid leukemia, and chronic myeloid leukemia post-transplant, especially after T-cell depletion. But, in many types of leukemia, including acute myeloid leukemia and acute lymphoblastic leukemia, MRD can be detected in long-term remission patients without subsequent relapse. The study of MRD is evolving from detecting residual disease and predicting relapse to the study of the mechanisms that explain how minimum residual disease can coexist in a "cured" patient.
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PMID:Advances in the detection of minimal residual disease. 926 51

A high complete remission rate is currently achieved in patients with acute myeloid leukemia (AML). However, many patients eventually relapse due to the persistence of low numbers of residual leukemic cells that are undetectable by conventional cytomorphologic criteria (minimal residual disease [MRD]). Using immunophenotypic multiparametric flow cytometry, we have investigated in sequential studies (diagnosis and follow-up) the impact of MRD detection on the outcome of 53 AML patients that had achieved morphologic remission with standard AML protocols and displayed at diagnosis an aberrant phenotype. Patients were studied at diagnosis with a panel of 35 monoclonal antibodies in triple staining combinations for detection of aberrant or uncommon phenotypic features. According to these features, a patient's probe was custom-built at diagnosis for the identification of possible residual leukemic cells during follow-up. The level of MRD at the end of induction and intensification therapy correlated with the number of relapses and relapse-free survival (RFS). Thus, patients with more than 5 x 10(-3) residual cells (5 residual cells among 1,000 normal bone marrow [BM] cells) identified as leukemic by immunophenotyping in the first remission BM showed a significant higher rate of relapse (67% v 20% for patients with less than 5 x 10(-3) residual cells; P = .002) and a lower median RFS (17 months v not reached; P = .01). At the end of intensification, with a cut-off value of 2 x 10(-3) leukemic cells, AML patients also separated into two distinct groups with relapse rates of 69% versus 32% (P = .02), respectively, and median RFS of 16 months versus not reached (P = .04). In addition, overall survival was also significantly related to the level of residual cells in the marrow obtained at the end of induction and particularly after intensification therapy (P = .008). Furthermore, we have explored whether residual disease was related with the functional expression of multidrug resistance (MDR-1) at diagnosis as assessed by the rhodamine123 assay. Patients with > or =5 x 10(-3) residual leukemic cells at the end of induction therapy had a significantly higher rhodamine-123 efflux (mean, 56% +/- 24%) than those with less than 5 x 10(-3) residual cells (mean, 32% +/- 31%; P = .04). Finally, multivariate analysis showed that the number of residual cells at the end of induction or intensification therapy was the most important prognostic factor for prediction of RFS. Overall, our results show that immunophenotypical investigation of MRD strongly predicts outcome in patients with AML and that the number of residual leukemic cells correlates with multidrug resistance.
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PMID:Immunophenotyping investigation of minimal residual disease is a useful approach for predicting relapse in acute myeloid leukemia patients. 931 Apr 99

Eleven patients, 13 to 76 (mean, 40) years of age, had granulocytic sarcoma of the female genital tract (FGT) (ovary, seven cases; vagina, three cases; cervix, one case). In nine cases, the FGT involvement was the initial clinical presentation of the disease, and in the other two cases, the FGT involvement was discovered during a relapse of acute myeloid leukemia. The tumors ranged from 0.5 to 14 (mean, 7.5) cm in greatest dimension. Two ovarian tumors were bilateral, and three were green. Microscopic examination revealed a predominantly diffuse pattern of growth, but cords and pseudoacinar spaces were also present focally in several cases. Sclerosis was seen in five tumors and was prominent in one. Prominent myeloid differentiation was readily recognizable on routinely stained sections in three cases, whereas the neoplastic cells in the other cases were primitive with only rare eosinophilic myelocytes. All 11 tumors were positive for chloroacetate esterase, nine of nine were strongly and diffusely positive for lysozyme, eight of eight for myeloperoxidase, seven of seven for CD68, and six of six for CD43. Examination of bone marrow or peripheral blood performed after the diagnosis of FGT involvement revealed acute myeloid leukemia in three of five cases. Two of these patients died of disease, 1 and 16 months after the initial diagnosis, and the third, who received chemotherapy, is alive and free of disease 8 months after the initial diagnosis. One of the two patients with negative bone marrow had recurrent granulocytic sarcoma 30 months after diagnosis and died of sepsis 1 month later; no residual disease was noted at autopsy. The other patient is alive and free of disease 18 months after the diagnosis. One of the four remaining patients with primary FGT involvement who did not have a bone marrow biopsy died of leukemia 24 months later; no follow-up information is available for the other three patients. One of the two patients with a prior diagnosis of acute myeloid leukemia was alive with disease 26 months later; follow-up is not available for the second patient. The diagnosis was often difficult in these cases, the most common problem being distinction from malignant lymphoma, but carcinoma, granulosa cell tumor, and, rarely, other tumors were considered. Immunohistochemical and enzyme histochemical staining were useful in establishing the diagnosis, although suspicion of the diagnosis on examination of routinely stained sections was of paramount importance.
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PMID:Granulocytic sarcoma of the female genital tract: a clinicopathologic study of 11 cases. 933 Dec 87

Advances in the molecular characterization of leukemic cells have greatly improved the precision of diagnosis and treatment assignment as well as the monitoring of residual disease in both acute lymphoblastic leukemia and acute myeloid leukemia. Currently, specific genetic rearrangements can be identified in as many as 50% of children with either acute lymphoblastic leukemia or acute myeloid leukemia. The genes p16 (or MTS1) and TEL/AML1 are now respectively recognized as the most common tumor suppressor and fusion genes in childhood acute lymphoblastic leukemia. Increasingly, contemporary protocols for the acute leukemias are relying on genetic information to guide treatment decisions. Examples include the use of allogeneic hematopoietic stem cell transplantation for acute lymphoblastic leukemia with the BCR-ABL fusion gene or MLL rearrangement, and for acute myeloid leukemia with monosomy 7; antimetabolite-based therapy for acute lymphoblastic leukemia cases with hyperdiploidy of more than 50 chromosomes (DNA index > or = 1.16); and retinoic acid and anthracycline-containing regimens for the acute promyelocytic acute myeloid leukemia subtype with PML-RARA fusion. Other efforts are being made to reduce the long-term sequelae of treatment. Indeed, extended intrathecal therapy and intensive systemic chemotherapy will, in all likelihood, replace cranial irradiation as subclinical central nervous system therapy for patients with intermediate-risk acute lymphoblastic leukemia, and perhaps even for those with high-risk acute lymphoblastic leukemia. The challenge now is to identify specific treatments for other genetically defined subtypes of leukemia. This goal will be realized only through protocol-based studies employing uniform criteria for defining risk status.
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PMID:Acute leukemia in children. 937 85

Cytogenetic and molecular analyses are essential for the classification of childhood hematologic malignancies. Nearly all children with leukemia should have an adequate cytogenetic analysis which in 80-90% is expected to show clonal chromosomal abnormalities. Moreover, with the availability of appropriate gene probes and sophisticated molecular techniques, genetic rearrangements become detectable in the majority of leukemia patients. Genetic abnormalities often associate with particular clinical-biological characteristics of the disease. In ALL, for example, genetic alterations together with distinct immunologic and clinical features, define various subgroups. In AML, unique cytogenetic rearrangements have been identified and associated with distinct morphological subgroups. Apart from the diagnostic assessment, cytogenetic studies provide valuable prognostic information which may influence treatment choices. Molecular analysis has also become of important value in the management of children with leukemias, as it serves, for example, to identify genetic abnormalities not detected by chromosomal analysis and to monitor residual disease during treatment and follow-up. Thus, genetic analyses of leukemic cells provide information of clinical relevance as well as contributing to our understanding of leukemogenesis. Alternative classifications of acute leukemias which take into account genetic information are being proposed. The available cytogenetic and molecular data have then to be included in clinical protocols, either by selecting individualized therapies in certain leukemia subtypes or by modifying treatment according to quantification of residual disease. We are closer to our main goal which is not only to classify 100% of childhood leukemias accurately, but to cure all of them.
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PMID:Molecular cytogenetics of childhood hematological malignancies. 944 14


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