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)

Estrogen receptors are historically perceived as nuclear ligand activated transcription factors. An estrogen receptor has now been found localized to the plasma membrane of human myeloblastic leukemia cells (HL-60). Its expression occurs throughout the cell cycle, progressively increasing as cells mature from G(1) to S to G(2)/M. To ascertain that the receptor functioned, the effect of ligands, including a non-internalizable estradiol-BSA conjugate and tamoxifen, an antagonist of nuclear estrogen receptor function, were tested. The ligands caused activation of the ERK MAPK pathway. They also modulated the effect of retinoic acid, an inducer of MAPK dependent terminal differentiation along the myeloid lineage in these cells. In particular the ligands inhibited retinoic acid-induced inducible oxidative metabolism, a functional marker of terminal myeloid cell differentiation. To a lesser degree they also diminished retinoic acid-induced earlier markers of cell differentiation, namely CD38 and CD11b. However, they did not regulate retinoic acid-induced G(0) cell cycle arrest. There is thus a membrane localized estrogen receptor in HL-60 myeloblastic leukemia cells that can cause ERK activation and modulates the response of these cells to retinoic acid, indicating crosstalk between the membrane estrogen and retinoic acid evoked pathways relevant to propulsion of cell differentiation.
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PMID:Human myeloblastic leukemia cells (HL-60) express a membrane receptor for estrogen that signals and modulates retinoic acid-induced cell differentiation. 1869 45

Acute myelogenous leukemia (AML) with chromosomal translocation (6;9)(p23;q34) is a rare disease with poor prognosis and distinct clinical and morphologic features. t(6;9) results in a chimeric fusion gene between DEK (6p23) and CAN/NUP214 (9q34). FLT3-ITD mutation is one of the most frequent mutations in AML and correlates with poor clinical outcome. Prevalence of FLT3-ITD is as high as 70% among patients with t(6;9) AML, and patients with t(6;9) AML and FLT3-ITD mutations usually have higher white blood cell counts, higher bone marrow blasts, and significantly lower rates of complete remission. t(6;9) is most commonly associated with AML-FAB-M2 and is considered by some researchers to be a separate disease entity because of its distinct clinical and morphologic features and poor prognostic implication. Distinct morphologic features of this entity include marrow basophilia and myelodysplasia, and immunophenotypically, the blast cells are positive for CD9, CD13, CD33, and HLA-DR; are usually positive for CD45 and CD38; and may be positive for CD15, CD34, and terminal deoxynucleotidyl transferase.
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PMID:Acute myelogenous leukemia with t(6;9)(p23;q34) and marrow basophilia: an overview. 1897 25

Nicotinamide, the amide derivative of vitamin B(3), cooperates with retinoic acid (RA), a form of vitamin A, and 1,25-dihydroxyvitamin D(3) (D3), to regulate cell differentiation and proliferation of human myeloblastic leukemia cells. In human myeloblastic leukemia cells, RA or D3 are known to cause MAPK signaling leading to myeloid or monocytic differentiation and G0 cell cycle arrest. In this process, RA or D3 induces the early expression of CD38, a receptor that causes ERK signaling and propels further differentiation. Our study demonstrates that nicotinamide in combination with RA or D3 affected induced expression levels of CD38, CD11b and CD14, suggesting a cooperative function of nicotinamide and RA or D3. Nicotinamide transiently retarded the initial RA- or D3-induced expression of CD38, which subsequently reached the same nearly 100% expression. Nicotinamide induced ERK activation and further enhanced the RA-induced ERK activation, but the D3-induced ERK activation was diminished by nicotinamide, although levels still exceeded those induced by RA, suggesting lineage-specific nicotinamide responses. Nicotinamide enhanced both RA- and D3-induced CD11b expression, inducible oxidative metabolism, and G0 cell cycle arrest, accelerating their induced occurrence in all instances. Consistent with this, the RA- or D3-induced downregulation of PARP was enhanced by nicotinamide. Nicotinamide thus regulated RA- or D3-induced differentiation and G0 arrest, causing a transient delay in certain early aspects of the progression to terminal differentiation but ultimately accelerating the occurrence of terminally, functionally differentiated G0 cells.
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PMID:Nicotinamide cooperates with retinoic acid and 1,25-dihydroxyvitamin D(3) to regulate cell differentiation and cell cycle arrest of human myeloblastic leukemia cells. 1912 80

A new myeloid leukemia cell line (CG-SH) with normal cytogenetics was established from a patient with acute myelogenous leukemia (AML) following myelodysplastic syndrome (MDS). The cells of CG-SH are immature blasts and have an immature myeloid phenotype (positive for myeloperoxidase, CD7, CD34, CD38, CD117, HLA-DR, negative for CD10, CD19, CD20, CD41, CD42). A partial expression of CD13, CD15, CD65 and a weak expression of CD33 and CD133 was noted. The cells are negative for EBER. By molecular analysis, a mutation of NRAS and heterozygous mutations of RUNX1 were detected. No mutations were detected in FLT3-ITD, MLL-PTD or NPM1. By real-time PCR, a series of 19 microRNAs was identified which are strongly expressed in CG-SH. In conclusion, a new cell line was established which will be useful for the study of AML with normal cytogenetics and mutations in NRAS and/or RUNX1.
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PMID:Characterization of a new myeloid leukemia cell line with normal cytogenetics (CG-SH). 1941 91

Chronic basophilic leukemia is a rare and poorly characterized entity. Only a limited number of cases have been described. Herein, we report a patient who presented with fatigue, weight loss, leukocytosis, persistent prominent basophilia, and mild eosinophilia. The bone marrow showed features characteristic of a myeloproliferative neoplasm with a marked increase in maturing basophils. The basophils exhibited nuclear hypersegmentation, abnormal granulation, and abnormally low CD38 expression. Conventional karyotyping revealed a t(5;12)(q31;p13). ETV6 but not PDGFRB rearrangement was detected by fluorescence in situ hybridization.
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PMID:Chronic basophilic leukemia: a rare form of chronic myeloproliferative neoplasm. 1942 22

It was hypothesized that contact between chronic lymphocytic leukaemia (CLL) B-cells and marrow stromal cells impact both cell types. To test this hypothesis, we utilized a long-term primary culture system from bone biopsies that reliably generates a mesenchymal stem cell (MSC). Co-culture of MSC with CLL B-cells protected the latter from both spontaneous apoptosis and drug-induced apoptosis. The CD38 expression in previously CD38 positive CLL B-cells was up-regulated with MSC co-culture. Upregulation of CD71, CD25, CD69 and CD70 in CLL B-cells was found in the co-culture. CD71 upregulation was more significantly associated with high-risk CLL, implicating CD71 regulation in the microenvironment predicting disease progression. In MSC, rapid ERK and AKT phosphorylation (within 30 min) were detected when CLL B-cells and MSC were separated by transwell; indicating that activation of MSC was mediated by soluble factors. These findings support a bi-directional activation between bone marrow stromal cells and CLL B-cells.
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PMID:Bi-directional activation between mesenchymal stem cells and CLL B-cells: implication for CLL disease progression. 1975 Dec 40

Relapse in acute myeloid leukaemia (AML) is considered to result from the persistence of drug-resistant leukaemic stem and progenitor cells (LSPC) within a bone marrow 'niche' microenvironment. Identifying novel agents that have the potential to target these LSPC in their niche microenvironment will aid in the characterization of candidate agents for post-remission chemotherapy. Using an in vitro model, we found that 48-h culture with gemtuzumab ozogamicin (Mylotarg) resulted in a 34% reduction in CD34(+)CD38(-)CD123(+) LSPC number, whereas normal CD34(+)CD38(-) haemapoietic stem cells were insensitive to this agent. As there was considerable heterogeneity in LSPC response to Mylotarg treatment, various factors potentially underpinning the differential response were assessed. LSPC that overexpressed CD33 (P=0.01), which were P-glycoprotein-negative (P=0.008) and with internal tandem duplication (ITD) of the FLT3 gene (FLT3/ITD) status (P=0.006) responded better to Mylotarg treatment. LSPC from patient samples that have these combined characteristics as well as low LSPC burden showed significantly more chemosensitivity to Mylotarg compared with all other cases (P=0.002). In multivariate analysis, LSPC burden and FLT3 status were found to be predictors of LSPC chemosensitivity to Mylotarg treatment (P<0.0001). In conclusion, we have shown heterogeneity in the LSPC compartment of AML patients underpinning differential in vitro sensitivity to Mylotarg.
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PMID:Analysis of factors that affect in vitro chemosensitivity of leukaemic stem and progenitor cells to gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukaemia. 1977 61

Myeloid cell leukemia-1 (MCL-1) is an essential survival factor for hematopoiesis. In humans, hematopoietic stem cells (HSCs) express MCL-1 at the highest level in response to FMS-like tyrosine kinase-3 (FLT3) signaling. We here show that this FLT3-dependent stem cell maintenance system also plays a critical role in survival of leukemic stem cells (LSCs) in acute myeloid leukemia (AML). The CD34(+)CD38(-) LSC fraction expresses high levels of FLT3 as well as MCL-1, even compared with normal HSCs. Treatment with FLT3 ligand induced further MCL-1 up-regulation in LSCs in all AML cases tested. Interestingly, the group of samples expressing the highest levels of MCL-1 constituted AML with FLT3-internal tandem duplications (ITD). In FLT3-ITD AML cell lines, cells expressed a high level of MCL-1, and an inhibition of MCL-1 induced their apoptotic cell death. A tyrosine kinase inhibitor suppressed MCL-1 expression, and induced apoptosis that was reversed by the enforced MCL-1 expression. Finally, transduction of FLT3-ITD into HSCs strongly activated MCL-1 expression through its signal transducer and activator of transcription 5 (STAT5)-docking domains. This effect was completely abrogated when STAT5 activation was blocked. Thus, the acquisition of FLT3-ITD ensures LSC survival by up-regulating MCL-1 via constitutive STAT5 activation that is independent of wild-type FLT3 signaling.
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PMID:FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation. 1980 98

Alkylphospholipids and alkylphosphocholines (APCs) are promising antitumor agents, which target the plasma membrane and affect multiple signal transduction networks. We investigated the therapeutic potential of erucylphosphohomocholine (ErPC3), the first intravenously applicable APC, in human acute myelogenous leukemia (AML) cells. ErPC3 was tested on AML cell lines, as well as AML primary cells. At short (6-12 h) incubation times, the drug blocked cells in G2/M phase of the cell cycle, whereas, at longer incubation times, it decreased survival and induced cell death by apoptosis. ErPC3 caused JNK 1/2 activation as well as ERK 1/2 dephosphorylation. Pharmacological inhibition of caspase-3 or a JNK 1/2 inhibitor peptide markedly reduced ErPC3 cytotoxicity. Protein phosphatase 2A downregulation by siRNA opposed ERK 1/2 dephosphorylation and blunted the cytotoxic effect of ErPC3. ErPC3 was cytotoxic to AML primary cells and reduced the clonogenic activity of CD34(+) leukemic cells. ErPC3 induced a significant apoptosis in the compartment (CD34(+) CD38(Low/Neg) CD123(+)) enriched in putative leukemia-initiating cells. This conclusion was supported by ErPC3 cytotoxicity on AML blasts showing high aldehyde dehydrogenase activity and on the side population of AML cell lines and blasts. These findings indicate that ErPC3 might be a promising therapeutic agent for the treatment of AML patients.
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PMID:Erucylphosphohomocholine, the first intravenously applicable alkylphosphocholine, is cytotoxic to acute myelogenous leukemia cells through JNK- and PP2A-dependent mechanisms. 2020 May 57

The t(8;21) Acute Myeloid Leukaemia (AML) Kasumi-1 cell line with N822K KIT mutation, is a model system for leukemogenesis. As AML initiating cells reside in the CD34(+)CD38(-) fraction, we addressed the refined cytogenomic characterization and miRNA expression of Kasumi-1 cell line and its FACS-sorted subpopulations focussing on this compartment. By conventional cytogenetics, Spectral-Karyotyping and array-CGH the cytogenomic profile of Kasumi-1 cells evidenced only subtle regions differentially represented in CD34(+)CD38(-) cells. Expression profiling by a miRNA platform showed a set of miRNA differentially expressed in paired subpopulations and the signature of miR-584 and miR-182 upregulation in the CD34(+)CD38(-) fraction.
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PMID:Differential cytogenomics and miRNA signature of the Acute Myeloid Leukaemia Kasumi-1 cell line CD34+38- compartment. 2022 11


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