Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:Q8NB91 (FAB)
3,573 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The frequency of leukemia and myelodysplasia following treatment with cytotoxic agents is increasing. Theses treatment-related leukemias raise both theoretical and practical concerns. On a theoretical basis, cytogenetic and molecular abnormalities described constitute useful models to study leukemogenesis. On a practical basis, prognosis of treatment related-leukemia is somehow unfavorable and implies to take in account this risk in the development of combination therapy for solid tumors or hematological malignancies. There are two distinctive types of treatment-induced leukemia: those secondary after alkylating agents and those secondary after topoisomerase-II- inhibitors. These two types of leukemia after regarding their clinical and their hematological characteristics, but also regarding their prognosis and their associated molecular abnormalities. Leukemias induced by alkylating agents occur generally 5 or 6 years after the beginning of the chemotherapy and are preceded by a more or less long phase of pancytopenia or myelodysplasia and according to their cytologic aspects are difficult to be classified within FAB classification. Their prognosis is pejorative. The most commonly found cytogenetic abnormalities associated with these types of induced leukemia are losses or deletions of chromosomes 5 and 7. Leukemias induced by topoisomerase-II-inhibitors occur shortly after the treatment (12 to 30 months), they begin generally suddenly without preleukemia prodom and their more frequent cytological aspects are M4 and M5 type. The prognosis is less severe than alkylating agent related forms with higher response rates and is dependant of discovered cytogenetic abnormalities. The more frequent molecular abnormalities are not chromosome deletions but balanced translocations. They affect particularly the MLL gene located at band 11q23. Other translocations have been described in this type of leukemia and are comparable to the one found in the de novo leukemia (t8;21, t15;17) for example. The evaluation of the risk of treatment-related leukemia for a given chemotherapeutic agent is difficult as for as current treatment use the combination of several agents potentially leukemogenic (chemotherapy and radiotherapy, combination chemotherapy). It is necessary to set up an up-dated data register in order to centralize all therapy-related myelodysplasia and leukemia within the treatment of a given type of cancer.
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PMID:[Leukemias induced by anticancer chemotherapies]. 1058 9

Jumping translocation (JT) is a very rare cytogenetic event, occurring especially in cancer. We describe a case of secondary acute monocytic leukemia (AML5b) with a JT involving the 3q13-3qter segment and leading to a partial trisomy 3. Each clone with JT was associated with trisomy 8 or tetrasomy 8. The literature of JT in AML cases is reviewed: only 13 cases of AML associated with JT have been previously described, seven of which are AML4/5 FAB subtype. Jumping translocation involvement in leukemogenesis is discussed. Leukemia (2000) 14, 119-122.
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PMID:Jumping translocation in acute leukemia of myelomonocytic lineage: a case report and review of the literature. 1063 86

We describe a boy with Fanconi anemia (FA) who developed acute lymphoblastic leukemia (ALL) (FAB-LI) followed by acute myeloid leukemia (AML) (FAB-M5) at relapse. The patient was diagnosed with early pre-B-cell ALL without preceding aplastic anemia and was treated with ALL-oriented chemotherapy which included doxorubicin (a total dose of 140 mg/m(2) administered), which is a topoisomerase II inhibitor. Complete remission was obtained, but after 38 weeks AML developed. The karyotype of ALL cells at diagnosis showed 46,XY, and that of AML cells at relapse was 46,XY, t(11;16)(q23;p13). An MLL gene rearrangement and MLL-CBP chimeric mRNA were found in AML, but not in ALL. A diagnosis of FA was confirmed by an increased number of chromosomal breaks and rearrangements in peripheral blood lymphocytes cultured with mitogen in the presence of mitomycin C. We conclude that this FA patient developed ALL followed by a therapy-related t(11;16)-AML resulting in an MLL-CBP fusion. Further examination of such patients would shed light on leukemogenesis in FA patients. Genes Chromosomes Cancer 27:264-269, 2000.
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PMID:MLL-CBP fusion transcript in a therapy-related acute myeloid leukemia with the t(11;16)(q23;p13) which developed in an acute lymphoblastic leukemia patient with Fanconi anemia. 1067 15

MLF1 is a novel protein identified as the NPM-MLF1 chimeric protein produced by a t(3;5)(q25.1;q34) chromosomal translocation, which is associated with myelodysplastic syndrome (MDS), often prior to acute myeloid leukemia (AML), except for M3. The clinical features of t(3;5)-positive myeloid disorders suggest that this chimeric protein is involved in dysregulation of progenitor cells with the capability to differentiate into multiple lineages. So far, involvement of wild-type MLF1 in hematopoiesis or in leukemogenesis has not been fully investigated. In the present study, 65 patients with AML and 44 patients with MDS were tested for the expression of MLF1 using the quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method. A significantly higher level of MLF1 expression (ratio of MLF1/beta-actin mRNA >0.4) was readily detected in seven of 65 patients with de novo AML, three of 12 with post-MDS AML and seven of 44 with MDS, but not in any patients with ALL (n = 18). According to the FAB classification, high levels of MLF1 were found in patients with relatively immature subtypes of AML (M1, M2, M6 and M7) and high risk MDS (RAEB and RAEB-T). These findings indicate that the pattern of MLF1 expression is identical to the clinical morphology appearing in the t(3;5)-positive myeloid disorders and is correlated to the MDS-associated AML and transformation phase of MDS in t(3;5)-negative myeloid disorders. A CD34+ population of normal bone marrow cells preferentially expressed MLF1 with obviously decreasing levels of expression during maturation. Therefore, MLF1 normally functions in multi-potent progenitor cells and its dysregulation may take part in leukemogenesis from MDS.
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PMID:Elevated MLF1 expression correlates with malignant progression from myelodysplastic syndrome. 1102 51

The human AML1 gene (also named CBFA2 or RUNX1), located in the 21q22 chromosomal band, encodes for one of the two subunits forming a heterodimeric transcription factor, the human core binding factor (CBF). AML1 protein contains a highly evolutionary conserved domain of 128 amino acids called runt domain, responsible for both heterodimerization with the beta subunit of CBF and for DNA binding. AML1 is normally expressed in all hematopoietic lineages and acts to regulate the expression of various genes specific to hematopoiesis playing a pivotal role in myeloid differentiation. AML1 is one of the genes most frequently deregulated in leukemia through different mechanisms including translocation, mutation and amplification. Translocations lead to the formation of fusion genes encoding for chimerical proteins such as AML1-ETO which induces leukemogenesis. Recently, new mechanisms of AML1 deregulation by point mutations or amplification have been reported. To our knowledge, 51 patients (among 805 studied) with AML1 point mutations have been described. Forty of them have acute myeloid leukemia (AML) most often M0 AML. In this subtype of AML, the frequency of AML1 mutation is significantly higher; 21.5% of patients mutated (34/158). Mutations have also been found with lower frequency in other FAB subtype AML (6 cases), in myeloproliferative disorders (6 cases), in myelodysplastic syndrome (3 cases) and rarely in acute lymphoblastic leukemia (1 case). AML1 gene amplification has been found essentially in childhood ALL (12 cases) and more rarely in myeloid malignancies (4 cases). Here, we reviewed all these cases of AML1 point mutations and amplification and focused on the mechanisms of AML1 deregulation induced by these alterations.
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PMID:New mechanisms of AML1 gene alteration in hematological malignancies. 1252 54

In this study, we examined a pediatric case of therapy-related myelodysplastic syndrome (tMDS). The symptoms developed 17 months after treatment for acute myeloblastic leukemia (AML, M2 subtype according to the French-American-British [FAB] classification) involving a chromosome abnormality at t(8;21)(q22;q22). Upon diagnosis of tMDS, spectral karyotyping analysis detected a new chromosomal translocation at t(2;8)(p23;p11.2). In addition, fluorescence in situ hybridization analysis suggested a rearrangement in the monocytic leukemia zinc finger (MOZ) gene, located in the 8p11 region of chromosome 8. However, no partner gene on 2p23 could be identified. To our knowledge, this is the first report of tMDS associated with a rearrangement of the MOZ gene. MOZ-linked fusion proteins such as MOZ-CBP (CREB binding protein), MOZ-TIF2 (transcriptional intermediary factor 2), and MOZ-p300 (adenoviral E1A-associated protein) are associated with AML chromosomal abnormalities at t(8;16)(p11;p13), inv(8)(p11q13), and t(8;22)(p11;q13), respectively, and are thought to account for leukemogenesis occurring through the aberrant regulation of histone acetylation. Through a similar mechanism, we believe that MOZ, fused to an unidentified partner gene at 2p23, may have caused an alteration in histone acetylation, resulting in the development of tMDS in this patient.
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PMID:Rearrangement of the MOZ gene in pediatric therapy-related myelodysplastic syndrome with a novel chromosomal translocation t(2;8)(p23;p11). 1261 66

The t(8;21)(q22;q22) translocation, occurring in 40% of patients with acute myeloid leukemia (AML) of the FAB-M2 subtype (AML with maturation), results in expression of the RUNX1-CBF2T1 [AML1-ETO (AE)] fusion oncogene. AML/ETO may contribute to leukemogenesis by interacting with nuclear corepressor complexes that include histone deacetylases, which mediate the repression of target genes. However, expression of AE is not sufficient to transform primary hematopoietic cells or cause disease in animals, suggesting that additional mutations are required. Activating mutations in receptor tyrosine kinases (RTK) are present in at least 30% of patients with AML. To test the hypothesis that activating RTK mutations cooperate with AE to cause leukemia, we transplanted retrovirally transduced murine bone marrow coexpressing TEL-PDGFRB and AE into lethally irradiated syngeneic mice. These mice (19/19, 100%) developed AML resembling M2-AML that was transplantable in secondary recipients. In contrast, control mice coexpressing with TEL-PDGFRB and a DNA-binding-mutant of AE developed a nontransplantable myeloproliferative disease identical to that induced by TEL-PDGFRB alone. We used this unique model of AML to test the efficacy of pharmacological inhibition of histone deacetylase activity by using trichostatin A and suberoylanilide hydroxamic acid alone or in combination with the tyrosine kinase inhibitor, imatinib mesylate. We found that although imatinib prolonged the survival of treated mice, histone deacetylase inhibitors provided no additional survival benefit. These data demonstrate that an activated RTK can cooperate with AE to cause AML in mice, and that this system can be used to evaluate novel therapeutic strategies.
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PMID:An activated receptor tyrosine kinase, TEL/PDGFbetaR, cooperates with AML1/ETO to induce acute myeloid leukemia in mice. 1288 86

Acute myeloid leukemia (AML) has distinct subgroups characterized by different maturation and specific chromosomal translocation. In order to gain insight into the gene expression activities in AML, we carried out a gene expression profiling study with 21 AML samples using cDNA microarrays, focusing on acute promyelocytic leukemia with specific translocation t(15;17)(q22;q12) [French-American-British or FAB-M3 with t(15;17)] and AML without maturation (FAB-M1) characterized by morphologically and phenotypically immature AML blasts and no recurrent chromosomal abnormalities. Using a multivariate sigma-classifier algorithm, we identified 33 strong feature genes that distinguish FAB-M3 with t(15;17) from other AML samples, and 24 strong feature genes that classify FAB-M1. A direct comparison between FAB-M3 with t(15;17) and FAB-M1 led to selection of 13 strong feature genes. Those genes include some known to be related to leukemogenesis and cell differentiation. RIN1, a gene in the ras pathway, was up-regulated in FAB-M3 with t(15;17). Growth factor-binding protein 2 gene was down-regulated in FAB-M1. Huntingtin gene was up-regulated in FAB-M1. Others include syndecan 4, interleukin-2 receptor beta, folate receptor beta, low affinity immunoglobulin gamma, Fc receptor IIC precursor, insulin-like growth factor binding protein 2, and myeloperoxidase, which are involved in cell differentiation. Overexpression of myeloperoxidase in FAB-M3 cells with t(15;17) compared to FAB-M1 cells is consistent with the conventional cytochemical staining pattern. Thus, the study revealed that a morphologically-defined FAB-M1 subtype has a distinct gene expression signature that contributes to its cell differentiation and proliferation as well as FAB-M3 with a recurrent cytogenetic abnormality t(15;17)(q22;q12).
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PMID:Identification of signature genes by microarray for acute myeloid leukemia without maturation and acute promyelocytic leukemia with t(15;17)(q22;q12)(PML/RARalpha). 1288 96

The p14(ARF), p15(INK4B), and p16(INK4A) genes are important negative cell-cycle regulators often inactivated by deletions, mutations, or hypermethylation in malignancy. Hypermethylation of the three genes was studied in 81 patients with therapy-related myelodysplasia (t-MDS) or acute myeloid leukemia (t-AML) by methylation-specific PCR, and p15 methylation additionally by bisulfite genomic sequencing. In all, 55 patients disclosed p15 methylation, five patients showed p16 methylation, whereas p14 methylation was not observed. Methylation of p15 was closely associated with deletion or loss of chromosome arm 7q (P=0.0006). In t-MDS, the p15 methylation frequency and the p15 methylation density both increased significantly by stage (P=0.004 and 0.0002), and p15 methylation frequency increased with an increasing percentage of myeloblasts in the bone marrow (P=0.006). In a two-variable Cox model including the percentage of myeloblasts, p15 methylation was an independent prognostic factor (P=0.005). Methylation of p15 was less common in t-AML of subtype M5 than in other FAB subtypes (P=0.03). Methylation of p15 was unrelated to type of previous therapy, to latent period from start of therapy, to platelet count, and to p53 mutations. Inactivation of p15 and deletion of genes on chromosome arm 7q possibly cooperate in leukemogenesis.
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PMID:Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia. 1297 Jul 81

SHP-2 is a protein tyrosine phosphatase functioning as signal transducer downstream to growth factor and cytokine receptors. SHP-2 is required during development, and germline mutations in PTPN11, the gene encoding SHP-2, cause Noonan syndrome. SHP-2 plays a crucial role in hematopoietic cell development. We recently demonstrated that somatic PTPN11 mutations are the most frequent lesion in juvenile myelomonocytic leukemia and are observed in a smaller percentage of children with other myeloid malignancies. Here, we report that PTPN11 lesions occur in childhood acute lymphoblastic leukemia (ALL). Mutations were observed in 23 of 317 B-cell precursor ALL cases, but not among 44 children with T-lineage ALL. In the former, lesions prevalently occurred in TEL-AML1(-) cases with CD19(+)/CD10(+)/cyIgM(-) immunophenotype. PTPN11, NRAS, and KRAS2 mutations were largely mutually exclusive and accounted for one third of common ALL cases. We also show that, among 69 children with acute myeloid leukemia, PTPN11 mutations occurred in 4 of 12 cases with acute monocytic leukemia (FAB-M5). Leukemia-associated PTPN11 mutations were missense and were predicted to result in SHP-2 gain-of-function. Our findings provide evidence for a wider role of PTPN11 lesions in leukemogenesis, but also suggest a lineage-related and differentiation stage-related contribution of these lesions to clonal expansion.
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PMID:Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. 1498 69


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