Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ets family (ETS) transcription factors, characterized by an evolutionally conserved Ets domain, play important roles in cell development, cell differentiation, cell proliferation, apoptosis and tissue remodeling. Most of them are downstream nuclear targets of Ras-MAP kinase signaling, and the deregulation of ETS genes results in the malignant transformation of cells. Several ETS genes are rearranged in human leukemia and Ewing tumors to produce chimeric oncoproteins. Furthermore, the aberrant expression of several ETS genes is often observed in various types of human malignant tumors. Considering that some ETS transcription factors are involved in malignant transformation and tumor progression, including invasion, metastasis and neo-angiogenesis through the activation of cancer-related genes, they could be potential molecular targets for selective cancer therapy.
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PMID:ETS transcription factors: possible targets for cancer therapy. 1529 23

Use of all-trans-retinoic acid (ATRA) in combinatorial differentiation therapy of acute promyelocytic leukemia (APL) results in exceptional cure rates. However, potent cell differentiation effects of ATRA are so far largely restricted to this disease and long-term survival rates in non-APL acute myelogeneous leukemia (AML) remain unacceptably poor, requiring development of novel therapeutic strategies. We demonstrate here that myelomonocytic growth factors (granulocyte colony-stimulating factor [G-CSF] and/or granulocyte macrophage colony-stimulating factor [GM-CSF]) potentiate differentiation effects of ATRA in different AML cell lines and primary cells from patients with myeloid leukemia. The ligand-dependent activities of endogenous and transiently expressed retinoic acid receptor alpha (RARalpha) isoforms can be potentiated by G/GM-CSF in U-937 cells and correlate with increased expression of ATRA-inducible RARalpha2 isoform. Specific inhibitors of mitogen mitogen-activated protein kinase (MAPK) (MEK)-1/-2 or p38 extracellular signal-related kinase (ERK) kinase diminish the ATRA as well as ATRA and G/GM-CSF-induced activation of the RARalpha proteins and decreased the differentiation-induced decline in cell numbers. Our data demonstrate that acting, at least in part, via the MAP kinase pathways, myelomonocytic growth factors enhance ATRA-dependent activation of the RARalpha isoforms and maturation of myeloid leukemia cells. These results suggest that combinatorial use of these agents may be effective in differentiation therapy of AML.
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PMID:Retinoids and myelomonocytic growth factors cooperatively activate RARA and induce human myeloid leukemia cell differentiation via MAP kinase pathways. 1533 53

Lesion of the sciatic nerve caused a rapid activation of p38MAP kinase in the injured nerve adjacent to the site of transection. This activation was detectable 3 min after lesioning, increased during the next 15 min and remained high for several hours. Erk1/2 activation was also observed as early as 15 min after lesioning. Activation of these MAP kinases was seen in both the external sheaths and the endoneurium. The separation of the external sheaths from the endoneurium accelerated the p38MAP kinase activation. To evaluate whether the injury-activated MAP kinase cascades are implicated in the rapid gene induction observed after nerve lesion, experiments were performed with an ex vivo model. Segments of sciatic nerves were incubated in oxygenated Krebs-Ringer buffer. MAP kinases were activated at 15 min and remained active after 6 h. Induction of mRNA was also observed for nerve growth factor (NGF), interleukin 6 (IL-6), leukaemia inhibitory factor (LIF) and deiodinases of type 2 (D2) and type 3 (D3). Thus, the ex vivo model mimics events occurring in the animal after nerve section. Finally, nerve segments were incubated in the presence of specific inhibitors of Erk1/2 activation (U0126) and of p38MAP kinase activity (SB203580). U0126 inhibited D3, LIF and to a lesser extent NGF mRNA induction, but did not affect significantly the induction of D2 and IL-6 mRNAs. SB203580 inhibited the expression of the genes for D3 and LIF. We conclude that MAP kinase cascades, activated by nerve transection, are involved in the rapid gene induction in the nerve.
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PMID:The role of MAP kinases in rapid gene induction after lesioning of the rat sciatic nerve. 1538 2

Bone marrow stromal cells are essential for the differentiation, survival and proliferation of normal and leukemic human B-lineage cells. Leukemic cells require stromal cell support for optimal proliferation and apoptotic resistance. Stromal cell contact can promote resistance to chemotherapeutic agents. In this study, we have made use of small molecular weight inhibitors and an established stromal cell-dependent pre-B-ALL cell line, BLIN-2, to investigate the role of the MAP kinase, PI3K/Akt, JAK/STAT and mTOR pathways in the promotion of leukemic cell growth in the presence of stromal cell support. Treatment with PI3K+JAK, PI3K+MEK, or MEK+JAK inhibitor combinations resulted in an inhibition of proliferation as measured by DNA synthesis. However, only inhibition of both PI3K and MEK or both mTOR and MEK resulted in a dramatic increase in the number of annexinV(+)/PI(+) apoptotic events within a 24 h period. Our data suggest that stromal cell-mediated apoptotic protection in B-lineage ALL is mediated by PI3K/mTOR and MEK via a synergistic mechanism(s).
Leukemia 2005 Jan
PMID:Inhibition of PI3K, mTOR and MEK signaling pathways promotes rapid apoptosis in B-lineage ALL in the presence of stromal cell support. 1549 72

Chronic myelogenous leukemia (CML) is characterized by the presence of the chimeric p210bcr/abl oncoprotein that shows elevated and constitutive protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. Although several p210bcr/abl substrates have been identified, their relevance in the pathogenesis of the disease is unclear. We have identified a family of proteins, Dok (downstream of tyrosine kinase), coexpressed in hematopoietic progenitor cells. Members of this family such as p62dok (Dok-1) and p56dok-2 (Dok-2) associate with the p120 rasGTPase-activating protein (rasGAP) upon phosphorylation by p210bcr/abl as well as receptor and nonreceptor tyrosine kinases. Here, we report the generation and characterization of single and double Dok-1 or Dok-2 knockout (KO) mutants. Single KO mice displayed normal steady-state hematopoiesis. By contrast, concomitant Dok-1 and Dok-2 inactivation resulted in aberrant hemopoiesis and Ras/MAP kinase activation. Strikingly, all Dok-1/Dok-2 double KO mutants spontaneously developed transplantable CML-like myeloproliferative disease due to increased cellular proliferation and reduced apoptosis. Furthermore, Dok-1 or Dok-2 inactivation markedly accelerated leukemia and blastic crisis onset in Tec-p210bcr/abl transgenic mice known to develop, after long latency, a myeloproliferative disorder resembling human CML. These findings unravel the critical and unexpected role of Dok-1 and Dok-2 in tumor suppression and control of the hematopoietic compartment homeostasis.
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PMID:Role of Dok-1 and Dok-2 in leukemia suppression. 1561 Dec 95

Pramanicin is a novel anti-fungal drug with a wide range of potential application against human diseases. It has been previously shown that pramanicin induces cell death and increases calcium levels in vascular endothelial cells. In the present study, we showed that pramanicin induced apoptosis in Jurkat T leukemia cells in a dose- and time-dependent manner. Our data reveal that pramanicin induced the release of cytochrome c and caspase-9 and caspase-3 activation, as evidenced by detection of active caspase fragments and fluorometric caspase assays. Pramanicin also activated c-jun N-terminal kinase (JNK), p38 and extracellular signal-regulated kinases (ERK 1/2) with different time and dose kinetics. Treatment of cells with specific MAP kinase and caspase inhibitors further confirmed the mechanistic involvement of these signalling cascades in pramanicin-induced apoptosis. JNK and p38 pathways acted as pro-apoptotic signalling pathways in pramanicin-induced apoptosis, in which they regulated release of cytochrome c and caspase activation. In contrast the ERK 1/2 pathway exerted a protective effect through inhibition of cytochrome c leakage from mitochondria and caspase activation, which were only observed when lower concentrations of pramanicin were used as apoptosis-inducing agent and which were masked by the intense apoptosis induction by higher concentrations of pramanicin. These results suggest pramanicin as a potential apoptosis-inducing small molecule, which acts through a well-defined JNK- and p38-dependent apoptosis signalling pathway in Jurkat T leukemia cells.
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PMID:Pramanicin induces apoptosis in Jurkat leukemia cells: a role for JNK, p38 and caspase activation. 1590 21

We analyzed the structure of the granulocyte colony-stimulating factor (G-CSF) receptor gene in a 6-year-old female patient with severe congenital neutropenia (SCN) who experienced severe recurrent infections since 1 month of age. There is no family history of any similar disease. When the patient was 4 months old, she began receiving treatment with recombinant human G-CSF that resulted in a small increase in the neutrophil count sufficient for the prevention and treatment of bacterial infection. An analysis of complementary DNA for the patient's G-CSF receptor revealed a 3-base pair deletion in the juxtamembrane intracellular sequence. This deletion at the beginning of exon 16 was thought to be caused by alternative splicing; analysis of the DNA revealed a G-to-A point mutation of the final nucleotide of intron 15. To evaluate the functional activity of the G-CSF receptor with this 3-base pair deletion of the juxtamembrane region, we transfected this G-CSF receptor mutant into an interleukin 3-dependent cell line, BAF/3. BAF/3 cells expressing the mutant G-CSF receptor showed augmented proliferation activity in response to G-CSF compared with cells having the wild-type G-CSF receptor. Although the proliferation signal of G-CSF in normal hematopoiesis is transduced through the activation of MAP kinases, this G-CSF receptor mutant showed decreased activation of ERKI/2 in response to G-CSF compared with the wild type, but the transduced sig-nal for Stat3 activation by G-CSF was of the same magnitude as that of the wild-type G-CSF receptor. This result means that the augmented proliferation activity in response to G-CSF that we observed in cells having the G-CSF receptor gene with the 3-base pair deletion is transduced through an intracellular signaling pathway other than MAP kinase. Because SCN patients with a mutation in the G-CSF receptor frequently develop leukemia, this 3-base pair deletion in the juxtamembrane sequence of the G-CSF receptor gene in this patient may be one step in the course of leukemic transformation.
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PMID:A novel mutation in the juxtamembrane intracellular sequence of the granulocyte colony-stimulating factor (G-CSF) receptor gene in a patient with severe congenital neutropenia augments GCSF proliferation activity but not through the MAP kinase cascade. 1622 88

Glioblastoma multiforme is an aggressive form of brain cancer that responds poorly to chemotherapy and is generally incurable. The basis for the poor response of this cancer to chemotherapy is not well understood. The atypical protein kinases C (PKCiota and PKCzeta) have previously been implicated in leukaemia cell chemoresistance. To assess the role of atypical PKC in glioblastoma cell chemoresistance, RNA interference was used to deplete human glioblastoma cells of PKCiota. Transfection of cells with either of two different RNA duplexes specific for PKCiota caused a partial sensitisation to cell death induced by the chemotherapy agent cisplatin. To screen for possible mechanisms for PKCiota-mediated chemoresistance, microarray analysis of gene expression was performed on RNA from glioblastoma cells that were either untreated or depleted of PKCiota. This identified sets of genes that were regulated either positively or negatively by PKCiota. Within the set of genes that were negatively regulated by PKCiota, the function of the gene coding for GMFbeta, an enhancer of p38 mitogen-activated protein kinase (MAP kinase) signaling, was investigated further, as the p38 MAP kinase pathway has been previously identified as a key mediator of cisplatin cytotoxicity. The expression of both GMFbeta mRNA and protein increased upon PKCiota depletion, and this was accompanied by an increase in cisplatin-activated p38 MAP kinase signaling. Transient overexpression of GMFbeta increased cisplatin-activated p38 MAP kinase signaling and also sensitised cells to cisplatin cytotoxicity. The increase in cisplatin cytotoxicity seen with PKCiota depletion was blocked by the p38 MAP kinase inhibitor SKF86002. These data show that PKCiota can confer partial resistance to cisplatin in glioblastoma cells by suppressing GMFbeta-mediated enhancement of p38 MAP kinase signaling.
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PMID:Protection of glioblastoma cells from cisplatin cytotoxicity via protein kinase Ciota-mediated attenuation of p38 MAP kinase signaling. 1633 Dec 46

Mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase SHP-2, causes Noonan syndrome (NS), an autosomal dominant disorder with pleomorphic developmental abnormalities. Certain germline and somatic PTPN11 mutations cause leukemias. Mutations have gain-of-function (GOF) effects with the commonest NS allele, N308D, being weaker than the leukemia-causing mutations. To study the effects of disease-associated PTPN11 alleles, we generated transgenic fruitflies with GAL4-inducible expression of wild-type or mutant csw, the Drosophila orthologue of PTPN11. All three transgenic mutant CSWs rescued a hypomorphic csw allele's eye phenotype, documenting activity. Ubiquitous expression of two strong csw mutant alleles were lethal, but did not perturb development from some CSW-dependent receptor tyrosine kinase pathways. Ubiquitous expression of the weaker N308D allele caused ectopic wing veins, identical to the EGFR GOF phenotype. Epistatic analyses established that csw(N308D)'s ectopic wing vein phenotype required intact EGF ligand and receptor, and that this transgene interacted genetically with Notch, DPP and JAK/STAT signaling. Expression of the mutant csw transgenes increased RAS-MAP kinase activation, which was necessary but not sufficient for transducing their phenotypes. The findings from these fly models provided hypotheses testable in mammalian models, in which these signaling cassettes are largely conserved. In addition, these fly models can be used for sensitized screens to identify novel interacting genes as well as for high-throughput screening of therapeutic compounds for NS and PTPN11-related cancers.
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PMID:Transgenic Drosophila models of Noonan syndrome causing PTPN11 gain-of-function mutations. 1639 95

Noonan syndrome, the most common single-gene cause of congenital heart disease, is characterized by short stature, characteristic facies, learning problems and leukemia predisposition. Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases. SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice. KRAS mutations account for <5% of cases of Noonan syndrome, but the gene(s) responsible for the remainder are unknown. We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation. The prevalence of specific cardiac defects differs in SOS1 mutation-associated Noonan syndrome. Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation. Our results identify SOS1 mutants as a major cause of Noonan syndrome, representing the first example of activating GEF mutations associated with human disease and providing new insights into RAS-GEF regulation.
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PMID:Germline gain-of-function mutations in SOS1 cause Noonan syndrome. 1719 80


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