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)

Hypereosinophilic syndrome (HES) includes heterogeneous hematological disorders that are characterized by distinctive blood and tissue eosinophilia. In addition to classical HES criteria, the World Health Organization proposed a set of criteria that distinguish chronic eosinophilic leukemia (CEL) from HES. As such, the fusion gene FIP1L1/PDGFRA was found as a cause of CEL in a significant proportion of patients initially diagnosed as having HES. Several investigations have tried to dissect the mechanism of leukemogenesis; eosinophilia and signaling induced by FIP1L1/PDGFRalpha in cell lines, bone marrow mast cells, primary human eosinophils and in murine myeloproliferative disorder models. In this review, we introduce the current knowledge on the relationship between FIP1L1/PDGFRalpha and cell signaling, eosinophil proliferation, survival and activation and mastocytosis specially focusing on the evidence learned from murine models.
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PMID:Murine model of hypereosinophilic syndromes/chronic eosinophilic leukemia. 1949 14

The mitogen-activated protein kinase/ERK kinase (MEK)/ERK pathway was shown to be constitutively activated in a large number of acute myelogenous leukemia (AML) cells, suggesting the important roles of this pro-survival signaling in leukemogenesis and proliferation of AML cells. This study explored the impact of the MEK inhibitor AZD6244 on the effect of cytarabien (AraC), one of the most commonly used anti-leukemia agents, to induce growth arrest and apoptosis of AML cells. AZD6244 effectively blocked AraC-induced MEK/ERK activation and enhanced its ability to induce growth arrest and apoptosis of NB4 and HL60 cells in parallel with induction of DNA damage as measured by detection of gamma-H2AX by Western Blot analysis, resulting in enhanced expression of p21( waf1 ) and downregulation of c-Myc and Bcl-xl in these cells. Enhanced induction of apoptosis mediated by combination of AZD6244 and AraC was also shown in freshly isolated AML cells (n = 3). Taken together, concomitant administration of AraC and the inhibitor of MEK/ERK signaling may be useful for treatment of individuals with AML.
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PMID:Inhibition of MEK signaling enhances the ability of cytarabine to induce growth arrest and apoptosis of acute myelogenous leukemia cells. 1954 87

The NUP98 gene at chromosome band 11p15 is known to be fused to a number of different partners in various hematological malignancies. The most frequently observed fusion partners of NUP98 are the homeobox family of transcriptional factors (HOX genes). We report a case of de novo AML M4 subtype, with a t(11;12)(p15;q13) translocation, generating a NUP98-HOXC13 chimeric transcript. Molecular analysis showed that the exon 16 of NUP98 was fused in frame with exon 2 of HOXC13. The patient was also positive for FLT3 internal tandem duplication (ITD), another molecular marker for the disease. Comparative study of data on the fusion of HOXC cluster and NUP98 gene revealed that it is a rare event, found exclusively in AML patients. To our knowledge, this is the first case of t(11;12)(p15;q13) in de novo AML-M4 in association with FLT3 ITD mutation. Coexistence of NUP98-HOXC13 fusion and FLT3 ITD mutation is likely relevant in the process of leukemogenesis.
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PMID:Acute myeloid leukemia with NUP98-HOXC13 fusion and FLT3 internal tandem duplication mutation: case report and literature review. 1966 70

In this study, we tested if FLT3/internal tandem duplication (ITD) in acute myeloid leukemia (AML) might occur at different hierarchical stages during leukemogenesis. In 56 AML cases, 10 showed FLT3/ITD (single ITD=5; multiple ITD=5). Myeloblasts from seven cases (CD34-selected=4; unselected=3) were transplanted into NOD/SCID mice. Five cases engrafted successfully into 14 mice. Two patients carried single FLT3/ITD subclones, which were maintained during primary and secondary transplantations. In three patients with multiple FLT3/ITD subclones, some subclones persisted or expanded while others diminished upon transplantation. Their different engraftment capabilities in NOD/SCID mice supported the proposition that FLT3/ITD might occur at different stages during leukemogenesis.
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PMID:FLT3/internal tandem duplication subclones in acute myeloid leukemia differ in their engraftment potential in NOD/SCID mice. 1968 12

FLT3-ITD-mediated leukemogenesis is associated with increased expression of oncogenic PIM serine/threonine kinases. To dissect their role in FLT3-ITD-mediated transformation, we performed bone marrow reconstitution assays. Unexpectedly, FLT3-ITD cells deficient for PIM1 failed to reconstitute lethally irradiated recipients, whereas lack of PIM2 induction did not interfere with FLT3-ITD-induced disease. PIM1-deficient bone marrow showed defects in homing and migration and displayed decreased surface CXCR4 expression and impaired CXCL12-CXCR4 signaling. Through small interfering RNA-mediated knockdown, chemical inhibition, expression of a dominant-negative mutant, and/or reexpression in knockout cells, we found PIM1 activity to be essential for proper CXCR4 surface expression and migration of cells toward a CXCL12 gradient. Purified PIM1 led to the phosphorylation of serine 339 in the CXCR4 intracellular domain in vitro, a site known to be essential for normal receptor recycling. In primary leukemic blasts, high levels of surface CXCR4 were associated with increased PIM1 expression, and this could be significantly reduced by a small molecule PIM inhibitor in some patients. Our data suggest that PIM1 activity is important for homing and migration of hematopoietic cells through modification of CXCR4. Because CXCR4 also regulates homing and maintenance of cancer stem cells, PIM1 inhibitors may exert their antitumor effects in part by interfering with interactions with the microenvironment.
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PMID:Dissection of PIM serine/threonine kinases in FLT3-ITD-induced leukemogenesis reveals PIM1 as regulator of CXCL12-CXCR4-mediated homing and migration. 1968 26

Mixed-lineage-leukemia (MLL) fusion oncogenes are closely involved in infant acute leukemia, which is frequently accompanied by mutations or overexpression of FMS-like receptor tyrosine kinase 3 (FLT3). Earlier studies have shown that MLL fusion proteins induced acute leukemia together with another mutation, such as an FLT3 mutant, in mouse models. However, little has hitherto been elucidated regarding the molecular mechanism of the cooperativity in leukemogenesis. Using murine model systems of the MLL-fusion-mediated leukemogenesis leading to oncogenic transformation in vitro and acute leukemia in vivo, this study characterized the molecular network in the cooperative leukemogenesis. This research revealed that MLL fusion proteins cooperated with activation of Ras in vivo, which was substitutable for Raf in vitro, synergistically, but not with activation of signal transducer and activator of transcription 5 (STAT5), to induce acute leukemia in vivo as well as oncogenic transformation in vitro. Furthermore, Hoxa9, one of the MLL-targeted critical molecules, and activation of Ras in vivo, which was replaceable with Raf in vitro, were identified as fundamental components sufficient for mimicking MLL-fusion-mediated leukemogenesis. These findings suggest that the molecular crosstalk between aberrant expression of Hox molecule(s) and activated Raf may have a key role in the MLL-fusion-mediated-leukemogenesis, and may thus help develop the novel molecularly targeted therapy against MLL-related leukemia.
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PMID:Mixed-lineage-leukemia (MLL) fusion protein collaborates with Ras to induce acute leukemia through aberrant Hox expression and Raf activation. 1971 Jun 96

RUNX1 (previously AML1) is involved in multiple recurrent chromosomal rearrangements in hematological malignances. Recently, we identified a novel fusion between RUNX1 and LPXN from an acute myeloid leukemia (AML) patient with t(11;21)(q12;q22). This translocation generated four RUNX1/LPXN and one LPXN/RUNX1 chimeric transcripts. Two representative RUNX1/LPXN fusion proteins, RL and RLs, were both found to localize in the nucleus and could bring the CBFB protein into the nucleus like the wild-type RUNX1. Both fusion proteins inhibit the ability of RUNX1 to transactivate the CSF1R promoter, probably through competition for its target sequences. Unlike RL and RLs, the LPXN/RUNX1 fusion protein LR was found to localize in the cytoplasm. Thus, we believe it has little impact on the transcriptional activity of RUNX1. We also found that fusion proteins RL, RLs, LR, and wild-type LPXN could confer NIH3T3 cells with malignant transformation characteristics such as more rapid growth, the ability to form colonies in soft agar, and the ability to form solid tumors in the subcutaneous tissue of the BALB/c nude mice. Taken together, our data indicated that the RUNX1/LPXN and LPXN/RUNX1 fusion proteins may play important roles in leukemogenesis and that deregulation of cell adhesion pathways may be pathogenetically important in AML. Our study also suggests that LPXN may play an important role in carcinogenesis.
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PMID:LPXN, a member of the paxillin superfamily, is fused to RUNX1 in an acute myeloid leukemia patient with a t(11;21)(q12;q22) translocation. 1976 Jun 7

The FLT3 receptor tyrosine kinase plays an important role in normal hematopoietic development and leukemogenesis. Point mutations within the activation loop and in-frame tandem duplications of the juxtamembrane domain represent the most frequent molecular abnormalities observed in acute myeloid leukemia. Interestingly these gain-of-function mutations correlate with different clinical outcomes, suggesting that signals from constitutive FLT3 mutants activate different downstream targets. In principle, mass spectrometry offers a powerful means to quantify protein phosphorylation and identify signaling events associated with constitutively active kinases or other oncogenic events. However, regulation of individual phosphorylation sites presents a challenging case for proteomics studies whereby quantification is based on individual peptides rather than an average across different peptides derived from the same protein. Here we describe a robust experimental framework and associated error model for iTRAQ-based quantification on an Orbitrap mass spectrometer that relates variance of peptide ratios to mass spectral peak height and provides for assignment of p value, q value, and confidence interval to every peptide identification, all based on routine measurements, obviating the need for detailed characterization of individual ion peaks. Moreover, we demonstrate that our model is stable over time and can be applied in a manner directly analogous to ubiquitously used external mass calibration routines. Application of our error model to quantitative proteomics data for FLT3 signaling provides evidence that phosphorylation of tyrosine phosphatase SHP1 abrogates the transformative potential, but not overall kinase activity, of FLT3-D835Y in acute myeloid leukemia.
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PMID:A robust error model for iTRAQ quantification reveals divergent signaling between oncogenic FLT3 mutants in acute myeloid leukemia. 2001 52

The standard approaches to the treatment of acute myeloid leukemia (AML) have been predominantly based on cytarabine and anthracyclines. Yet, the outcomes associated with AML continue to be poor, especially for those patients who are older or carry higher-risk disease. In recent years, extensive research has led to the development and study of novel agents which target AML by diverse and varied mechanisms. Among these are targeted therapeutics such as kinase inhibitors and oligonucleotide constructs. These aim to suppress the production or activity of proteins, such as FLT3 and BCL2, among others, and thus disrupt related signaling cascades essential for leukemogenesis and proliferation. In addition, other agents like flavopiridol appear to target the myeloid blast by various mechanisms including suppression of cyclin-dependent kinases and interference with nucleotide synthesis. Another class of novel therapies includes inhibitors of histone deacetylase, which cause growth arrest and apoptosis through histone acetylation and resultant conformational changes. Clinical trials are now studying these and other agents alone and in combination with traditional cytotoxic therapies, with some encouraging results. In this review, we aim to provide a summary of the preclinical and clinical investigations of selected promising agents currently under study.
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PMID:Exploiting cellular pathways to develop new treatment strategies for AML. 2005 34

Mice that accurately model the genetic diversity found in human cancer are valuable tools for interrogating disease mechanisms and investigating novel therapeutic strategies. We performed insertional mutagenesis with the MOL4070LTR retrovirus in Mx1-Cre, Kras(G12D) mice and generated a large cohort of T lineage acute lymphoblastic leukemias (T-ALLs). Molecular analysis infers that retroviral integration within Ikzf1 is an early event in leukemogenesis that precedes Kras(G12D) expression and later acquisition of somatic Notch1 mutations. Importantly, biochemical analysis uncovered unexpected heterogeneity, which suggests that Ras signaling networks are remodeled during multistep tumorigenesis. We tested tumor-derived cell lines to identify biomarkers of therapeutic response to targeted inhibitors. Whereas all T-ALLs tested were sensitive to a dual-specificity phosphoinosityl 3-kinase/mammalian target of rapamycin inhibitor, biochemical evidence of Notch1 activation correlated with sensitivity to gamma-secretase inhibition. In addition, Kras(G12D) T-ALLs were more responsive to a MAP/ERK kinase inhibitor in vitro and in vivo. Together, these studies identify a genetic pathway involving Ikzf1, Kras(G12D), and Notch1 in T lineage leukemogenesis, reveal unexpected diversity in Ras-regulated signaling networks, and define biomarkers of drug responses that may inform treatment strategies.
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PMID:Mutant Ikzf1, KrasG12D, and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents. 2019 33


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