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)

Interphase fluorescence in situ hybridization (iFISH) is increasingly used for the identification of BCR/ABL gene rearrangements in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). In the present study, we have explored the incidence of both typical and atypical iFISH patterns of BCR/ABL gene rearrangements in a series of 168 consecutive BCR/ABL+ patients--135 CML, 31 precursor B-ALL and two acute myeloblastic leukemia (AML) cases--and established their underlying genetic alterations through further molecular and chromosome analyses. Two different FISH probes (Vysis Inc., Downers Grove, IL, USA) were used: the LSI BCR/ABL dual color extra signal (ES) and the dual color dual fusion BCR/ABL probe (D-FISH). Our results show that most BCR/ABL+ patients (83%, including 88% of all CML, 61% of ALL and one of two AML) displayed typical iFISH patterns of either Major (M) BCR/ABL (87% of CML, 13% of ALL and one of the two AML) or minor (m) BCR/ABL gene rearrangements (1% of all CML and 48% of ALL cases) with the two probes. Further molecular and cytogenetic studies confirmed the presence of such typical rearrangements in all except one of these ALL cases who had coexistence of an MBCR/ABL and an mBCR/ABL gene rearrangement together with monosomy 9. In the remaining 29 cases (17%), up to five different atypical iFISH patterns were detected with the ES probe. Atypical iFISH patterns were most frequently due to additional numerical changes--most often supernumerary Philadelphia (Ph) chromosome (7%) but also gain or loss of chromosome 9 (1%) or 22 (1%). Deletion of 9q sequences proximal to the breakpoint were also frequently observed with the ES probe (8%). Application of the D-FISH probe showed that in most of these latter cases (5%) deletion of 22q sequences distal to the breakpoint also occurred. The remaining cases with atypical iFISH had cryptic insertion of BCR in 9q34 (1%). Exact interpretation of each iFISH pattern was supported by FISH on metaphases and molecular determination of the BCR breakpoint. In summary, our results indicate that despite the high incidence of typical iFISH patterns of BCR/ABL gene rearrangements, atypical patterns are also found in BCR/ABL+ acute leukemias; the precise definition of the alteration present in individual cases is dependent on metaphase studies and molecular definition of the breakpoint.
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PMID:Patterns of BCR/ABL gene rearrangements by interphase fluorescence in situ hybridization (FISH) in BCR/ABL+ leukemias: incidence and underlying genetic abnormalities. 1460 34

Accurate subclassification of leukemia and the identification of prognostic determinants are essential to guide therapy and to improve patients' outcome. According to present standards, pre-therapeutic assessment depends on a combination of different methods. We aimed to expand the molecular characterization of different acute leukemia subtypes to identify new genome-wide diagnostic markers. Total RNA from 90 adult patients suffering from acute lymphoblastic leukemia (ALL, n = 25) and acute myeloid leukemia (AML, n = 65) was extracted at diagnosis and high density oligonucleotide microarrays were used to analyze the expression profiles of 12,000/22,000 genes in all specimens (Affymetrix U95Av2/U133A). All cases were thoroughly characterized by individual combinations of cytomorphology, cytogenetics, multiparameter immunophenotyping, and molecular genetics. The expression signature of a small set of differentially expressed genes was sufficient to accurately discriminate eight clinically relevant acute leukemia subgroups. Underlying chromosomal aberrations or immunophenotypical characteristics were strictly correlated with a distinct gene expression pattern for AML with t(8;21), t(15;17), t(11q23)/MLL, or inv(16) as well as for precursor B-ALL with t(9;22), t(8;14), or t(11q23)/MLL and precursor T-ALL. These data support a possible future application of microarray technology for classification of the acute leukemias.
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PMID:Molecular characterization of acute leukemias by use of microarray technology. 1280 Jan 51

We report the results of a phase 2 nonrandomized single-arm trial of a combination therapy for relapsed or refractory leukemia. From January 1999 to June 2002, 28 patients with multiple relapsed or refractory acute leukemia received a combination of topotecan, vinorelbine, thiotepa, dexamethasone, and, for patients with an M3 marrow on day 7, gemcitabine. A total of 14 patients had pre-B-ALL (acute lymphoblastic leukemia), three had T-cell leukemia, nine acute myeloblastic leukemia (AML), and two biphenotypic leukemia. In all, 13 patients achieved a significant response (10 complete responses and three partial responses). Among the responders, five had pre-B-ALL, two had T-cell leukemias, five had AML, and one had biphenotypic leukemia. In total, 10 of these patients subsequently underwent hematopoietic stem cell transplantation, and four are alive without disease. One patient died, while in remission, of complications resulting from an episode of sepsis and pneumonia that occurred during topotecan, vinorelbine, thiotepa, dexamethasone, and gemcitabine (TVTG) reinduction. Other toxicities included grade 4 neutropenia in all patients and transient grade 2 hepatotoxicity in 10 patients (36%). In summary, we report that 47% of heavily pretreated pediatric patients with multiply relapsed or refractory leukemia achieved a significant response after therapy on the TVTG protocol. Further studies are warranted to evaluate the role of the TVTG combination in the treatment of leukemia.
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PMID:A new multidrug reinduction protocol with topotecan, vinorelbine, thiotepa, dexamethasone, and gemcitabine for relapsed or refractory acute leukemia. 1451 46

Thrombospondin-1 (TSP-1) is a naturally occurring anti-angiogenic compound that induces apoptosis of endothelial and cancer cells via its receptor CD36. The objectives of our study were to investigate the in vitro effects of TSP-1 on the apoptosis of primary human leukemia cells as well as leukemia cell lines and the possible mechanism involving CD36. Our results demonstrated that TSP-1 induced apoptosis in CD36 positive cell lines CHRF-288-11, Meg-01 and HL-60, but not CD36 negative K562, at a dose-dependent manner as demonstrated by DNA ladder formation, Annexin V and propidium iodide (PI) stainings. The addition of anti-CD36 antibody FA6-152 or thrombopoietin (TPO) significantly nullified the effects of TSP-1. TSP-1-mediated apoptosis was consistently associated with the up-regulation of active Caspase-3. Responses of 2 CD36 positive primary AML samples to TSP-1 and FA6-152 were similar with those of leukemia cell lines. TSP-1 significantly induced apoptosis in B-ALL but the counter-effects of FA6-152 were less apparent. CD36 negative AML cells appeared less susceptible to TSP-1 and FA6-152. Our data provided strong evidence that TSP-1 exerted direct apoptotic effects on leukemia cells and could be developed as an adjunct to conventional therapy, particularly for leukemia cells that express CD36 or other TSP-1 receptors.
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PMID:Thrombospondin-1 induces apoptosis in primary leukemia and cell lines mediated by CD36 and Caspase-3. 1461 80

The aim of this study was to assess the possible relationship between the silver stained nucleolar organizer regions (AgNOR) and immunocytochemically detected p53 and bcl-2 proteins in ALL, AML, B-CLL and CML patients (adults and children) at the initial presentation. AgNORs are loops of DNA, correlated with proliferative potential of cells. Alteration in p53 and bcl-2 proteins expression may characterize the malignant potential of leukemic cells. The patients were subdivided according to the p53 positivity and negativity. The frequency of p53-positive patients was relatively low in T-ALL (29%) and B-CLL (16%). B-ALL, AML and CML patients revealed higher frequency of p53 protein (46%, 47% and 88%, respectively). The overall frequency of positive cytoplasmic staining for bcl-2 protein was demonstrated in the majority of patients. No significant differences in the percentage of p53-positive cells among leukemia subtypes were seen. The proportion of bcl-2 protein positive cells did not differ significantly among various leukemia subtypes, except for significant differences between p53-positive and p53-negative peripheral blood (p=0.0073) and bone marrow (p=0.0175) cells of B-CLL patients. The samples from healthy subjects used as controls exhibited relatively low numbers of AgNOR dots in both, peripheral blood and bone marrow cells. Highly significant differences in AgNOR quantities between healthy donors and p53 protein positive peripheral blood as well as bone marrow cells of distinct leukemia subtypes (except for bone marrow cells in B-CLL patients, p=0.1727) were observed. Significant differences in AgNOR count between p53 protein positive and p53 protein negative samples of peripheral blood cells of B-ALL (p=0.0099) as well as B-CLL (p=0.0117) cases were found. No significant differences (except for B-CLL, p=0.0558) were encountered in bone marrow cells. P53 protein positivity or negativity did not influence the amount of AgNOR proteins in cells of our T-ALL and AML cases. Mutual comparing the number of AgNOR dots among different leukemias showed that for both peripheral blood and bone marrow cells the differences between ALL and AML (p=0.0383 and p=0.0033, respectively) as well as for peripheral blood of AML and CML (p=0.0302) were statistically significant. The bcl-2 protein positivity did not affect significantly the AgNOR distribution either in p53 protein positive or p53-negative cases of our leukemia patients. However, an association between the lowest AgNOR quantity and highest bcl-2 protein expression in p53-negative B-CLL patients was seen for both peripheral blood and bone marrow cells. The correlation between relatively high AgNOR numbers and relatively increased percentage of bcl-2 protein in the p53-positive cases of CML patients was found in some cases. Regarding the age and sex, the AgNOR distribution in p53-positive and p53-negative leukemia cases in children and adults showed neither relationship nor dependence. The WBC count differed evidently among distinct leukemia subtypes, with enormous heterogeneity in range as well. Larger studies are needed in order to consolidate these preliminary results and characterize the possible prognostic value of AgNOR in association with p53 and bcl-2 proteins expression.
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PMID:Argyrophilic nucleolar organizer regions (AgNORs) in relation to p53 and bcl-2 protein expression in leukemia patients. 1468 61

The aim of this study was to evaluate the heterogeneity of immunophenotype features in acute leukemia patients and to detect the presence of leukemia-associated immunophenotypes. We prospectively investigated the phenotype of blast cells from 44 adult acute leukemia patients using a large panel of monoclonal antibodies by multiparametric flow cytometry. Thirty-three patients were classified as AML according to the FAB classification. Eleven patients were diagnosed as ALL (10 cases B-ALL, 1 case T-ALL) according to both FAB and immunnophenotyping. We found leukemia-associated phenotypes in 28 of 33 AML patients (84.8%) and in 8 of 11 ALL patients (72.7%). In 61.1% of patients more than one aberrant phenotype was observed. Linear infidelity was the most frequent aberrancy in both AML (64.3%) and ALL (37.5%) subgroups. The present study shows that MFC is a helpful method for sufficient identification of leukemic cells and for determination of blast cells immunophenotype heterogeneity. The double stain flow cytometry in our study revealed aberrant phenotypes in up to 81.8% patients.
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PMID:Leukemic cells and aberrant phenotypes in acute leukemia patients: a flow cytometry analysis. 1468 63

We describe a case of a 38-year old male with inv(16)(p13q22) positive acute myeloid leukaemia (AML) with eosinophilia, relapsing after a molecular remission of almost three years. Remarkably, the leukaemia at relapse was identified as a precursor-B-cell acute lymphoblastic leukaemia (B-ALL) by cytology and immunophenotyping, but was inv(16)(p13q22) positive as revealed by interphase FISH, FICTION analysis, and real-time quantitative PCR. Analysis of immunoglobulin and T-cell receptor genes showed a bi-allelic DH2-JH rearrangement at relapse, but not at diagnosis. These findings indicate a myeloid to lymphoid lineage switch from an inv(16)(p13q22) positive leukaemia and show that IGH gene rearrangements can occur in the presence of CBFB-MYH11 fusion transcripts.
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PMID:An inv(16)(p13q22) positive acute myeloid leukaemia relapsing as acute precursor B-cell lymphoblastic leukaemia. 1533 97

To explore differentially expressed genes in leukemia gene expression profile and identify main related genes in acute leukemia, gene expression profiles were analyzed in bone marrow/leucopheresis peripheral blood stem cells samples from 9 acute leukemia patients and their sibling donors with the use of oligonucleotide microarrays. 163 reported leukemia-related genes were involved in the study. The oligonucleotide primers were designed, synthesized and spotted on the chemical-material-coated-glass plates in array. The total RNAs were isolated from nine patients' bone marrow or leucopheresis peripheral blood cells and from nine their sibling donors peripheral blood stem cells treated by G-CSF, then collected by CS-3000 cell selection machine, and were reversely transcribed to cDNAs with the incorporations of fluorescent dUTP. The mixed probes were then hybridized to the oligonucleotide microarray. The results showed that in four patient/donor pairs with B-ALL, 5 up-regulated (RIZ, STK-1, T-cell leukemia/lymphoma 1A, Cbp/p300, Op18) and 1 down-regulated genes (hematopoietic proteoglycan core protein) were identified; In five patient/donor pairs with AML-M(4) and AML-M(5), 6 up-regulated (STAT5B, ligand p62 for the Lck SH2, CST3, LTC4S, myeloid leukemia factor 2 and epb72) and 1 down-regulated genes (CCR5) were identified. In conclusion, on the basis of distinguishing study of specific genetic related recipient/sibling donor pairs, screening leukemia-related genes with oligonucleotide microarrays, a set of 13 up-regulated or down-regulated genes among 163 leukemia-related genes has been identified. The result has further confirmed that above genes play critical role in the molecular mechanism of acute leukemia.
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PMID:[Identification of acute leukemia-specific genes from leukemia recipient/sibling donor pairs by distinguishing study with oligonucleotide microarrays]. 1536 29

Patterns of DNA methylation are substantially altered in malignancies compared to normal tissue, with both genome-wide hypomethylation and regional increase of cytosine methylation at dinucleotides of cytosine and guanine, i.e., CpG dinucleotides. While genome-wide hypomethylation renders chromosomes instable, hypermethylation of CpGs in promoter regions is generally associated with transcriptional silencing, e.g., of tumor suppressor genes. To investigate whether disease-specific methylation profiles exist for different entities of acute leukemia, a microarray-based DNA methylation analysis simultaneously assessing 249 CpG dinucleotides originating from 57 genes was employed. Hereby, samples from precursor B-cell acute lymphoblastic leukemia (ALL) could be distinguished from cases of acute myeloid leukemia by virtue of N33, EGR4, CDC2, CCND2, or MOS hypermethylation in ALL.
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PMID:Distinction of acute lymphoblastic leukemia from acute myeloid leukemia through microarray-based DNA methylation analysis. 1553 67

The SH2 domain-containing protein-tyrosine phosphatase PTPN11 (Shp2) is required for normal development and is an essential component of signaling pathways initiated by growth factors, cytokines, and extracellular matrix. In many of these pathways, Shp2 acts upstream of Ras. About 50% of patients with Noonan syndrome have germ-line PTPN11 gain of function mutations. Associations between Noonan syndrome and an increased risk of some malignancies, notably leukemia and neuroblastoma, have been reported, and recent data indicate that somatic PTPN11 mutations occur in children with sporadic juvenile myelomonocytic leukemia, myelodysplasic syndrome, B-cell acute lymphoblastic leukemia, and acute myelogenous leukemia (AML). Juvenile myelomonocytic leukemia patients without PTPN11 mutations have either homozygotic NF-1 deletion or activating RAS mutations. Given the role of Shp2 in Ras activation and the frequent mutation of RAS in human tumors, these data raise the possibility that PTPN11 mutations play a broader role in cancer. We asked whether PTPN11 mutations occur in other malignancies in which activating RAS mutations occur at low but significant frequency. Sequencing of PTPN11 from 13 different human neoplasms including breast, lung, gastric, and neuroblastoma tumors and adult AML and acute lymphoblastic leukemia revealed 11 missense mutations. Five are known mutations predicted to result in an activated form of Shp2, whereas six are new mutations. Biochemical analysis confirmed that several of the new mutations result in increased Shp2 activity. Our data demonstrate that mutations in PTPN11 occur at low frequency in several human cancers, especially neuroblastoma and AML, and suggest that Shp2 may be a novel target for antineoplastic therapy.
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PMID:Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. 1560 38


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