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)

The t(4;14)(p16.3;q32), associated with 10-20% of cases of multiple myeloma (MM), deregulates the expression of MMSET and FGFR3. To assess the potential of FGFR3 as a drug target, we evaluated the effects of selective inhibitors on MM and control cell lines. SU5402 and PD173074 specifically inhibited the growth of the two t(4;14)-positive MM lines, KMS-11 and OPM-2. Importantly, inhibition was still observed in the presence of IL-6, a growth factor known to play an important role in MM. Both compounds induced a dose-dependent reduction in cell viability and an increase in apoptosis, accompanied by a decrease in extracellular signal-related kinase phosphorylation. In contrast, no inhibition was seen with either compound against t(4;14)-negative cell lines or NCI-H929, a t(4;14)-positive, FGFR3-negative MM cell line. FGFR3 is thus a plausible candidate for targeted therapy in a subset of MM patients.
Leukemia 2004 May
PMID:Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074. 1502 11

We previously reported that favorable and poor prognostic chromosomal rearrangements in acute myeloid leukemia (AML) were associated with distinct levels of HOX expression. We have now analyzed HOX expression in 50 independent adult AML patients (median age=62 years), together with FLT3 and FLT3-ligand mRNA levels, and FLT3 mutation determination. By cluster analysis, we could divide AMLs into cases with low, intermediate and high HOX expression. Cases with high expression were uniquely restricted to a subset of AMLs with intermediate cytogenetics (P=0.0174). This subset has significantly higher levels of FLT3 expression and appears to have an increase of FLT3 mutations (44%), while CEBPalpha mutations were infrequent (6%). FLT3 mRNA levels were correlated with the expression of multiple HOX genes, whereas FLT3 mutations were correlated with HOXB3. In some cases, FLT3 was expressed at levels equivalent to GAPDH in the absence of genomic amplification. We propose that high HOX expression may be characteristically associated with a distinct biologic subset of AML. The apparent global upregulation of HOX expression could be due to growth-factor signaling or, alternatively, these patterns may reflect a particular stage of differentiation of the leukemic cells.
Leukemia 2004 Jun
PMID:Hox expression in AML identifies a distinct subset of patients with intermediate cytogenetics. 1508 54

Using a cDNA microarray, we found that suppressor of cytokine signaling 3 (SOCS3) is highly expressed in anaplastic lymphoma kinase (ALK)+ anaplastic large cell lymphoma (ALCL) cell lines. As SOCS3 is induced by activated signal transducer and activator of transcription 3 (STAT3), and ALK activates STAT3, we hypothesized that SOCS3 may play a role in ALK+ ALCL pathogenesis via the Janus kinase 3 (JAK3)-STAT3 pathway. Using ALCL cell lines, we show by coimmunoprecipitation experiments that SOCS3 physically binds with JAK3 in vitro, and that JAK3 inhibition by WHI-P154 downregulates SOCS3 expression. Western blot analysis confirmed expression of SOCS3 and also showed coexpression of phosphorylated (activated) STAT3 (pSTAT3). Direct sequencing of the SOCS3 gene showed no mutations or alternative splicing. In ALCL tumors that were assessed by immunohistochemistry, nine of 12 (75%) ALK+ tumors were SOCS3 positive and eight (67%) coexpressed pSTAT3. In comparison, 18 of 25 (72%) ALK-- tumors were SOCS3 positive and seven (28%) coexpressed pSTAT3. These results show that SOCS3 is overexpressed in ALCL, attributable to JAK3-STAT3 activation and likely related to ALK in ALK+ tumors. However, SOCS3 is also expressed in tumors that lack STAT3 and ALK suggesting alternative mechanisms of upregulation.
Leukemia 2004 Nov
PMID:Suppressor of cytokine signaling 3 expression in anaplastic large cell lymphoma. 1538 32

The PTPN11 gene encodes SHP-2, a nonreceptor protein tyrosine phosphatase that relays signals from activated growth factor receptors to p21(ras) (Ras) and other signaling molecules. Somatic PTPN11 mutations are common in patients with juvenile myelomonocytic leukemia (JMML) and have been reported in some other hematologic malignancies. We analyzed specimens from 278 pediatric patients with acute myelogenous leukemia (AML) who were enrolled on Children's Cancer Group trials 2941 and 2961 for PTPN11 mutations. Missense mutations of PTPN11 were detected in 11 (4%) of these samples. None of these patients had mutations in NRAS; however, one patient had evidence of a FLT3 alteration. Four of the patients with PTPN11 mutations (36%) were boys with French-American-British (FAB) morphology M5 AML (P=0.012). Patients with mutations also presented with elevated white blood cell counts. There was no difference in clinical outcome for patients with and without PTPN11 mutations. These characteristics identify a subset of pediatric AML with PTPN11 mutations that share clinical and biologic features with JMML.
Leukemia 2004 Nov
PMID:PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children's Cancer Group. 1538 33

We report the cloning of a novel PDGFRB fusion gene partner in a patient with a chronic myeloproliferative disorder characterized by t(5;14)(q33;q32), who responded to treatment with imatinib mesylate. Fluorescence in situ hybridization demonstrated that PDGFRB was involved in the translocation. Long distance inversion PCR identified KIAA1509 as the PDGFRB fusion partner. KIAA1509 is an uncharacterized gene with a predicted coiled-coil oligomerization domain with homology to the HOOK family of proteins. The predicted KIAA1509-PDGFRbeta fusion protein contains the KIAA1509 coiled-coil domain fused to the cytoplasmic domain of PDGFRbeta that includes the tyrosine kinase domain. Imatinib therapy resulted in rapid normalization of the patient's blood counts, and subsequent bone marrow biopsies and karyotypic analysis were consistent with sustained complete remission.
Leukemia 2005 Jan
PMID:KIAA1509 is a novel PDGFRB fusion partner in imatinib-responsive myeloproliferative disease associated with a t(5;14)(q33;q32). 1549 75

Molecular cloning of immunoglobulin heavy chain (IGH) translocation breakpoints identifies genes of biological importance in the development of normal and malignant B cells. Long-distance inverse PCR (LDI-PCR) was first applied to amplification of IGH gene translocations targeted to the joining (IGHJ) regions. We report here successful amplification of the breakpoint of IGH translocations targeted to switch (IGHS) regions by LDI-PCR. To detect IGHS translocations, Southern blot assays using 5' and 3' switch probes were performed. Illegitimate Smu rearrangements were amplified from the 5' end (5'Smu LDI-PCR) from the alternative derivative chromosome, and those of Sgamma or Salpha were amplified from the 3' end (3'Sgamma or 3'alpha LDI-PCR) from the derivative chromosome 14. Using a combination of these methods, we have succeeded in amplifying IGHS translocation breakpoints involving FGFR3/MMSET on 4p16, BCL6 on 3q27, MYC on 8q24, IRTA1 on 1q21 and PAX5 on 9p13 as well as BCL11A on 2p13 and CCND3 on 6p21. The combination of LDI-PCR for IGHJ and IGHS allows rapid molecular cloning of almost all IGH gene translocation breakpoints.
Leukemia 2004 Dec
PMID:Rapid amplification of immunoglobulin heavy chain switch (IGHS) translocation breakpoints using long-distance inverse PCR. 1549 80

CEBPalpha: mutations have been described in adult acute myeloid leukemia (AML) and conferred a favorable prognosis. However, CEBPalpha mutation has not been reported in children. We investigated 117 children with de novo AML using DNA PCR assay followed by sequencing for each PCR product. CEBPalpha mutations were detected in seven patients, four had FAB M2, two M1 and one M4. CEBPalpha mutations only occurred in patients with intermediate cytogenetics and not in 56 children with AML1-ETO, CBFbeta-MYH11, PML-RARalpha or MLL rearrangements. Five patients had mutations occurred in both N-terminal part and basic-leucine zipper (bZIP) domain, one had an N-terminal frameshift mutation and the remaining one had an inframe insertion in the bZIP domain. Cloning analysis on five samples carrying more than one mutations demonstrated one homozygous combined mutations and four heterozygous biallelic mutations. Four of seven CEBPalpha mutation(+) patients had cooperating mutations with FLT3-ITD or N-ras mutations compared to 27 in 109 CEBPalpha mutation(-) patients. Our results showed that CEBPalpha mutations occurred in 6% of childhood AML and most exhibited combined mutations in both N-terminal part and bZIP domain.
Leukemia 2005 Mar
PMID:CEBPalpha mutations in childhood acute myeloid leukemia. 1561 61

The Kasumi-1 cell line is an intensively investigated model system of Acute Myeloid Leukemia with t(8;21) translocation, that represents 1 of the 2 main subtypes of Core Binding Factor Leukemia (CBFL). Since establishment in 1991 the Kasumi-1 cell line has provided the tool to study the peculiar molecular, morphologic, immunophenotypic findings of AML with t(8;21) and the functional consequences of the AML1-ETO fusion oncogene on myeloid differentiation. Leukemogenesis involves multiple genetic changes and, as suggested by murine experiments and other findings in humans, AML1-ETO expression may not be sufficient for full blown leukemia. In agreement with the "two hits" model of leukemogenesis, based on the cooperation between 1 class of mutations that impair hematopoietic differentiation and a second class of mutations that confer a proliferative and/or survival advantage to hematopoietic progenitors an activating mutation in the tyrosine kinase domain of the c-kit gene was identified in the AML1/ETO expressing Kasumi-1 cell line. The dosage of the Asn822Lys mutated allele was shown to be about 5-fold compared to the normal allele and c-kit amplification was found to map to minute 4cen-q11 marker chromosomes, likely derived from the extra chromosome 4 recorded in the newly established cell line. The combination of t(8;21) and trisomy 4 leading to enhanced dosage of a mutated kit allele is a feature of a few CBFL patients reproduced by the Kasumi-1 cell model. The Kasumi-1 cell line, paralleling the commitment stage of CBF leukemia also provides a valuable resource to investigate the effect of tyrosine kinase kit mutant on the main KIT-regulated signal transduction pathways, i.e. MAPK, PI3K/AKT and STAT3 and the diverse inhibitory effect exerted by STI 571 on these KIT mutant activated pathways. PI3K-dependent activation of AKT and STAT activation was observed in Kasumi-1 cells. Contrary to the expectations for an amplified tyrosine kinase kit mutant, we found that STI 571 inhibited KIT Asn822Lys tyrosine phosphorylation and downstream JNK and STAT3 effectors in Kasumi-1 cells, but had no effect on constitutive activation of AKT, suggesting that signaling by tyrosine kinases other than KIT may be responsible for its activation in Kasumi-1 cells. Independent findings on the same model system provide complementary insights into designing strategies for treatment of CBF leukemia associated with mutations in the KIT catalytic domain.
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PMID:The Kasumi-1 cell line: a t(8;21)-kit mutant model for acute myeloid leukemia. 1562 9

Bone marrow samples from 43 adult patients with de novo diagnosed acute myeloid leukemia (AML)--10 acute promyelocytic leukemias (APL) with t(15;17), four AML with inv(16), seven monocytic leukemias and 22 nonmonocytic leukemias--were analyzed using high-density oligonucleotide microarrays. Hierarchical clustering analysis segregated APL, AML with inv(16), monocytic leukemias and the remaining AML into separate groups. A set of only 21 genes was able to assign AML to one of these three classes: APL, inv(16) and other AML subtype without a specific translocation. Quantitative RT-PCR performed for 18 out of these predictor genes confirmed microarray results. APL expressed high levels of FGF13 and FGFR1 as well as two potent angiogenic factors, HGF and VEGF. AML with inv(16) showed an upregulation of MYH11 and a downregulation of a gene encoding a core-binding factor protein, RUNX3. Genes involved in cell adhesion represented the most altered functional category in monocytic leukemias. Two major groups emerged from the remaining 22 AML: cluster A with 10 samples and cluster B with 12. All the eight leukemias that were either refractory to treatment or that relapsed afterwards were assigned to cluster B. In the latter cluster, CD34 upregulation and serine proteases downregulation is consistent with a maturation arrest and lack of granulocytic differentiation.
Leukemia 2005 Mar
PMID:Gene expression profile reveals deregulation of genes with relevant functions in the different subclasses of acute myeloid leukemia. 1567 61

The phosphoinositide 3-kinase (PI3-kinase) signalling pathway plays a key role in the regulation of cell survival and proliferation. We show that the PI3-kinase/Akt pathway is constitutively active in primary acute myeloid leukaemia (AML) cells and that blockade by the selective inhibitor LY294002 reduces survival of the total blast population (mean 52%). The ERK/MAPK module is also constitutively active and treatment with the MAPKK inhibitor U0126 reduces cell survival by 22%. In 10 of 18 samples, PI3-kinase contributes to MAPK activation as incubation with LY294002 leads to a marked reduction in its phosphorylation. PI3-kinase inhibition reduces survival of the CD34+38- AML progenitor subset by 44%, whereas MAPKK inhibition has little effect. Reporter assays in primary AML cells show that blocking PI3-kinase leads to a marked reduction of constitutive NF-kappaB activity and promotes p53-mediated transcription. This is associated with a synergistic interaction between LY294002 and Ara-C. An inducible activated form of Akt protects normal myeloid cells from Ara-C and etoposide-mediated apoptosis. These results show that blocking PI3-kinase has direct antileukaemic effects and potentiates the response to conventional cytotoxics via a number of targets including NF-kappaB, p53 and MAPK. Inhibitors of PI3-kinase and Akt may be useful in the treatment of AML.
Leukemia 2005 Apr
PMID:PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kappaB, Mapkinase and p53 pathways. 1570 83


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