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: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T-cell acute lymphoblastic leukemia (T-ALL) may affect children in very early age. However, the critical events leading to this brief latency is still unclear. We used standard methods to explore NOTCH1 mutations and other specific molecular markers in 15 early childhood T-ALL cases. Most of them consisted of immature differentiation subtype. Despite being found in a lower frequency than that described for overall pediatric T-ALL, NOTCH1 alterations were the most frequent ones. Other alterations included MLL(+) (n=4), SIL-TAL1(+) (n=3), FLT3 mutation (n=1) and HOX11L2(+) (n=1). Our results suggest that NOTCH1 and MLL abnormalities are primary leukemogenic hits in early T-ALL.
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PMID:T-cell lymphoblastic leukemia in early childhood presents NOTCH1 mutations and MLL rearrangements. 1963 84

Numerous genetic abnormalities which can not be identified by cytogenetic detection (e.g., gene mutations, gene expression abnormalities) have been gradually found, which means that the further molecular classification of AML (acute myeloid leukemia) with distinctive prognosis have arrived. For example, mutations of the transcription factor (CCAAT enhancer binding factor alpha, C/EBPalpha) or nucleophosmin-1 (NPM1) may predict better prognosis, whereas partial tandem duplications of the MLL gene (MLL-PTD), internal tandem duplications of FLT3 (FLT3-ITD) or mutations of WT1 gene confer worse prognosis. This review focuses on the features and relationship of these genetic abnormalities, as well as their influence on the prognosis of AML.
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PMID:[Molecular markers related to prognosis of acute myeloid leukemia-review]. 1969 66

Several mouse models studying the MLL fusion-induced leukemic transformation showed that a myeloproliferation stage precedes leukemia or occurred as the only phenotype of hematological disorder in mice. We established 6 MLL/AF10(OM-LZ)-immortalized cell lines by retrovirally transducing the fusion gene into bone marrow cells from B6 or congenic GFP-B6 mice. Immunophenotypic and cytological analyses revealed that the immortalized cell lines could be divided into 2 types. Type I had a high percentage of cells expressing monocytic lineage marker CD115 in the medium containing IL3 and could terminally differentiate into granulocytes and monocytes in response to granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF) treatments, respectively. On the other hand, type II had a low percentage of cells expressing CD115. The type II cell lines could not differentiate into granulocytes by G-CSF treatment and died rapidly in response to M-CSF treatment. Transplantation of both types I and II cells induced lethal myeloproliferative disease (MPD)-like myeloid leukemia in most of the sublethally irradiated B6 mice. Flow cytometric analysis of GFP and lineage markers of the peripheral blood cells from MPD mice revealed that the monocytes and granulocytes were generated not only from the donor cells but also from the host cells. RT-PCR analysis revealed that the MLL/AF10(OM-LZ)-immortalized cells expressed mRNAs encoding colony-stimulating factors (CSFs) of M-CSF and GM-CSF and inflammatory cytokines of IL-1alpha, IL-1beta and TNF-alpha. Our results showed that the MLL/AF10(OM-LZ)-immortalized cells could induce host cell proliferation in the transplanted mice, probably through stimulation by CSFs or cytokines produced by the donor cells.
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PMID:MLL/AF10(OM-LZ)-immortalized cells expressed cytokines and induced host cell proliferation in a mouse bone marrow transplantation model. 1971 40

Myeloid leukemia in this series corresponds to the myeloid neoplasms of the 4th WHO classification of pathology and genetics of tumor of haematopoietic and lymphoid tissue. The myeloid neoplasms are composed of six categories, which are 1) myeloproliferative neoplasms (MPN), a new category of 2) myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1, 3) myelodysplastic syndrome (MDS)/MPN, 4) MDS, 5) acute myeloid leukemia (AML) and related precursor neoplasms, and 6) acute leukemias of ambiguous lineage. In MPNs without chronic myelogenous leukemia, the genetic marker of JAK2 V617F is added to the diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis. MDS has the new subtype of refractory cytopenia with unilineage dysplasia composed of refractory anemia, refractory neutropenia and refractory thrombocytopenia. AML with t(9; 11) (p22;q23); MLLT3-MLL, AML with t(6;9) (p23; q34); DEK-NUP214, AML with inv(3) (q21q26.2) or t(3; 3) (q21 ; q26.2); RPN1-EVI1 and AML (megakaryoblastic) with t(1; 22) (p13; q13); RBM15-MKL1 are added to the subtype of AML with recurrent genetic abnormalities, and AML with gene mutations of NPM1 and CEBPA are also added as provisional entities of it. The myeloid neoplasms of the 4th WHO classification are comprehensive and seem to be dynamic by incorporating the results of leukemia researches.
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PMID:[Classification of myeloid leukemias]. 1986 Jan 79

Acute myeloid leukemia (AML) is a malignant hematopoietic neoplasm characterized by clonal proliferation of tumor cells that arise from the hematopoietic stem/progenitor population within the bone marrow. Cytogenetic abnormalities or point mutations of the hematopoiesis-specific genes are frequently found in patients with AML, and these genetic aberrations are closely associated with the pathophysiology of the disease. Molecular pathogenesis of AML has been disclosed through analyses of such gene aberrations, including AML1 and MLL abnormalities, PML-RARA chimeric gene, activating mutations of FLT3, and EVI-1 abnormalities. Through prediction of prognosis and targeted therapy, this knowledge on pathogenesis of AML has been applied to the clinical practice, and further investigation should improve the outcome of therapy for AML in the future.
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PMID:[Molecular mechanisms in the development of acute myeloid leukemia]. 1986 Jan 85

Management of patients with acute myeloid leukemia relies on genetic tests that inform diagnosis and prognosis, predict response to therapy, and measure minimal residual disease. The value of genetics is reinforced in the revised 2008 World Health Organization acute myeloid leukemia classification scheme. The various analytic procedures-karyotype, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, DNA sequencing, and microarray technology-each have advantages in certain clinical settings, and understanding their relative merits assists in specimen allocation and in effective utilization of health care resources. Karyotype and array technology represent genome-wide screens, whereas the other methods target specific prognostic features such as t(15;17) PML-RARA, t(8;21) RUNX1-RUNX1T1, inv(16) CBFB-MYH11, 11q23 MLL rearrangement, FLT3 internal tandem duplication, or NPM1 mutation. New biomarkers and pharmacogenetic tests are emerging. The pathologist's expertise is critical in 1) consulting with clinicians about test selection as well as specimen collection and handling; 2) allocating tissue for immediate testing and preserving the remaining specimen for any downstream testing that is indicated once morphology and other pertinent test results are known; 3) performing tests that maximize outcome based on the strengths and limitations of each assay in each available specimen type; and 4) interpreting and conveying results to the rest of the health care team in a format that facilitates clinical management. Acute myeloid leukemia leads the way for modern molecular medicine.
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PMID:Genetic tests to evaluate prognosis and predict therapeutic response in acute myeloid leukemia. 1995 1

The pretreatment karyotype of leukemic blasts is currently the key determinant in therapy decision making in acute myeloid leukemia (AML). The World Health Organization (WHO) has recognized this important information by including, besides clinical, cytological, cytochemical, and immunophenotypical features, recurrent cytogenetic abnormalities in its classification (Table 1). However, although the WHO defines important biologically and clinically relevant entities, the prognostic value of some of the well-defined cytogenetic subgroups is partially masked in the WHO classification. Moreover, in the recent past a number of novel molecular aberrations with marked prognostic value, which are not yet incorporated in the WHO classifications have been identified. These molecular abnormalities include mutations (e.g., in FLT3, c-KIT, and NPM1), partial duplications (e.g., of MLL and FLT3), and abnormal expression of pathogenetic genes (e.g., EVI1, WT1, BCL2, MDR1, BAALC, and ERG). In addition, novel molecular approaches in genomics, like monitoring the expression levels of thousands of genes in parallel using DNA microarray technology, open possibilities for further refinement of prognostication of AML. Gene expression profiling in AML is already well established and has proven to be valuable to recognize various cytogenetic subtypes, discover novel AML subclasses, and predict clinical outcome. The current advances made in molecular understanding of AML will ultimately lead to a further refinement of prognostics of AML.
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PMID:Genes predictive of outcome and novel molecular classification schemes in adult acute myeloid leukemia. 2030 46

PURPOSE To analyze the frequency and associations with prognostic markers and outcome of mutations in IDH genes encoding isocitrate dehydrogenases in adult de novo cytogenetically normal acute myeloid leukemia (CN-AML). PATIENTS AND METHODS Diagnostic bone marrow or blood samples from 358 patients were analyzed for IDH1 and IDH2 mutations by DNA polymerase chain reaction amplification/sequencing. FLT3, NPM1, CEBPA, WT1, and MLL mutational analyses and gene- and microRNA-expression profiling were performed centrally. Results IDH mutations were found in 33% of the patients. IDH1 mutations were detected in 49 patients (14%; 47 with R132). IDH2 mutations, previously unreported in AML, were detected in 69 patients (19%; 13 with R172 and 56 with R140). R172 IDH2 mutations were mutually exclusive with all other prognostic mutations analyzed. Younger age (< 60 years), molecular low-risk (NPM1-mutated/FLT3-internal tandem duplication-negative) IDH1-mutated patients had shorter disease-free survival than molecular low-risk IDH1/IDH2-wild-type (wt) patients (P = .046). R172 IDH2-mutated patients had lower complete remission rates than IDH1/IDH2wt patients (P = .007). Distinctive microarray gene- and microRNA-expression profiles accurately predicted R172 IDH2 mutations. The highest expressed gene and microRNAs in R172 IDH2-mutated patients compared with the IDH1/IDH2wt patients were APP (previously associated with complex karyotype AML) and miR-1 and miR-133 (involved in embryonal stem-cell differentiation), respectively. CONCLUSION IDH1 and IDH2 mutations are recurrent in CN-AML and have an unfavorable impact on outcome. The R172 IDH2 mutations, previously unreported in AML, characterize a novel subset of CN-AML patients lacking other prognostic mutations and associate with unique gene- and microRNA-expression profiles that may lead to the discovery of novel, therapeutically targetable leukemogenic mechanisms.
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PMID:IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. 2036 43

The prognosis for patients with acute myelogenous leukemia (AML) is dependent on age, karyotype, and the genetics of the neoplastic cell. The molecular markers with prognostic impact include mutations in FLT3, NPM1, MLL, WT1, c-KIT, and expression levels of BAALC, NM1, ERG, and CXCR4. Gene expression profiles and microRNA expression patterns in AML may prove highly useful in defining the prognosis of AML. Cytogenetic and, increasingly, molecular findings are used in determining the best therapy for AML patients, especially the choice of whether to perform allogeneic stem cell transplantation.
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PMID:The role of molecular tests in acute myelogenous leukemia treatment decisions. 2042 4

Acute myelogenous leukemia (AML) results from a differentiation block of hematopoietic progenitor cells along with uncontrolled proliferation. The cytogenetic abnormality at initial diagnosis is the single most important prognostic factor classifying AML patients into three prognostic categories: favorable, intermediate, and poor risk. Currently, favorable-risk AML patients are usually treated with contemporary chemotherapy, and poor-risk AML patients receive allogeneic stem cell transplantation if suitable stem cell donors exist. The approximately 40% of AML patients without identifiable cytogenetic abnormalities (NC AML) are classified as intermediate risk. The optimal therapeutic strategies for these patients are largely unclear. Emerging data recently suggested that molecular study of the mutations of NPM1, FLT3, MLL, and CEBPalpha and alterations in expression levels of BAALC, MN1, and ERG may identify poor-risk patients with NC AML. Further prospective studies are needed to confirm whether NC AML patients with poor risk have improved clinical outcomes after more aggressive therapy.
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PMID:Genetic abnormalities in acute myelogenous leukemia with normal cytogenetics. 2042 51


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