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)

Translocations involving chromosome band 11q23 are associated with acute lymphocytic and myelomonocytic leukemias with poor clinical prognosis. Pulsed-field gel electrophoresis (PFGE) was used to characterize the breakpoint region that has been mapped within a 300-kb fragment between the genes CD3G and PBGD. Using CD3G as a marker on SfuI-restricted DNA separated by PFGE, we detected a rearrangement involving 11q23 in the cell line B1 with a t(4;11) and in the leukemic cells of two patients, one with a t(2;11) and one with a t(11;19). In comparison, lymphoblastoid cell lines established from normal peripheral blood lymphocytes of these two patients had a normal karyotype and showed germline configuration, thus excluding RFL polymorphisms. Digestion of DNA with BssHII or SalI showed heterogeneity of 11q23 involving breakpoints. A rearrangement in the t(4;11) containing lymphoma cell line Karpas422 was seen only with the chromosome 4 probe KIT on SalI-digested DNA. PFGE is a reliable method for the mapping and detection of complex breakpoint regions. The breakpoints on 11q23 involve different introns of the highly spliced HRX/ALL-1/MLL gene.
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PMID:Detection of chromosome 11q23 involving translocations by pulsed field gel electrophoresis. 816 79

A large number of continuous human leukemia cell lines have been established over the last three decades. Clearly, leukemia cell lines have become important research tools. Here, we have summarized the immunological, molecular and standard cytogenetic features of a panel of well characterized B cell precursor (BCP)-leukemia cell lines which were derived from patients with acute lymphoblastic/undifferentiated leukemia (ALL/AUL) or chronic myeloid leukemia (CML) in blast crisis. Following the recently proposed immunological EGIL classification, we assigned our panel of 27 BCP-cell lines to one of the following categories: B-I pro-B cell line; B-II common-B cell line; and B-III pre-B cell line. All cell lines express general B-lineage associated surface markers (HLA-DR, CD22, CD79a) being negative for surface immunoglobulin (Ig); the differences between the subgroups reside in expression of CD10 and cytoplasmic Ig. Several BCP-cell lines show the myelomonocytic cell-associated markers CD13 and/or CD33. These immunologically 'biphenotypic' BCP-cell lines are generally TdT+ CD10+ CD13+ CD19+ CD22+ CD34+ and carry the Philadelphia (Ph) translocation. The BCP-cell lines display surface receptors for interferon-gamma (CD119), interleukin-7 (CD127) and FLT-3 ligand (CD135). All BCP-cell lines examined have complex numerical and structural chromosomal alterations including translocations commonly seen in BCP-ALL such as t(4;11), t(9;22), t(11;19), t(12;21), and t(17;19) involving the fusion genes MLL-AF4, BCR-ABL, ENL-MLL, TEL/ETV6-AML1 and E2A-HLF, respectively. Besides the expected rearrangement of the Ig heavy chain receptor gene, several cell lines also have rearrangements of the T cell receptor genes beta, gamma or delta. While some BCP-cell lines express (aberrantly) myeloperoxidase at the mRNA level, most lines are negative in the immunological or cytochemical staining. Several large series documented the difficulty in establishing such BCP cell lines with success rates in the range of 10-20% (on average 15%). Still, since the establishment of the first bonafide BCP-cell line in 1974 (cell line REH), some 150 cell lines have been established of which, however, only a small percentage have been sufficiently well characterized and described. A higher success rate for immortalizing any given leukemia cell might depend on a closer emulation of the physiological in vivo microenvironment. The possibility to grow in vitro leukemia cells at will would represent ideal experimental systems permitting basic research and patient-specific investigations. In summary, the use of well-characterized BCP-cell lines provide unprecedented opportunities for studying a multitude of biological aspects related to normal and neoplastic B-lymphocytes.
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PMID:Establishment and characterization of human B cell precursor-leukemia cell lines. 968 Jan 6

Tandem duplication (TD) of the MLL or FLT3 gene in acute myeloid leukemia (AML) has been reported. We examined whether TD of these two genes occurs simultaneously. We analyzed 13 AML and 2 myelodysplastic syndrome patients, including 6 adult patients with trisomy 11 and 9 pediatric patients with TD of the FLT3 gene, using RT-PCR followed by sequencing. Among these, TD of the MLL and FLT3 genes was found in 5 and 10 patients, respectively. Notably, TD of both the MLL and FLT3 genes (coduplication) was detected in two AML patients, who died 6 and 14 months after diagnosis. TD of these two genes in AML is rare; thus, coduplication of these genes in the same patient is predicted to be very rare. Although the mechanisms of TD of both genes are different, development of TD of both genes may be related to an unknown similar etiology in leukemia because the frequency of coduplication of these genes in a single patient is considered to be very low. Further studies of the coduplication of these genes in AML patients may lead to the clarification of its mechanism and clinical implications.
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PMID:Coduplication of the MLL and FLT3 genes in patients with acute myeloid leukemia. 1131 6

A 45-year-old male with AIDS presented with a cecal diffuse large B-cell lymphoma. Cytogenetic and flourescence in situ hybridization (FISH) studies revealed a complex karyotype with multiple aberrations that included a translocation, t(8;14) involving MYC on chromosome 14. This is specific to B-cell lymphomas. There were also frequently observed secondary changes such as chromosome 1 rearrangement leading to trisomy of 1q and loss of tp53 from the deleted chromosome 17. A unique secondary abnormality was an hsr on chromosome 7, which by FISH and SKY investigations was shown to originate from chromosome 11 involving 4 copies of the MLL gene region.
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PMID:An hsr on chromosome 7 was shown to be an insertion of four copies of the 11q23 MLL gene region in an HIV-related lymphoma. 1156 39

Eighty-two unselected cases of therapy-related myelodysplasia (t-MDS) or acute myeloid leukemia (t-AML) were investigated for internal tandem duplications of the FLT3 gene (FLT3/ITD), for internal tandem duplications of the MLL gene (MLL/ITD) and for mutations of the WT1 gene. FLT3/ITD were observed in three patients, another two patients presented MLL/ITD whereas mutations of the WT1 gene were not observed. All FLT3/ITD included the tyrosine-rich stretch between codons 589 and 599, and both MLL/ITD presented break points within Alu-repeats, as previously observed in de novo AML. The ITD were not related to any specific type of previous therapy, but three out of the five cases were observed among only six patients with overt t-AML and a normal karyotype (P = 0.0043). Interestingly, one of the patients with FLT3/ITD presented overt t-AML of subtype M1 with a normal karyotype after treatment with an alkylating agent. Complete remission was observed following treatment with daunorubicin and cytosine arabinoside, but after 37 months the patient relapsed with t-AML of subtype M3 with a t(15;17) and the same FLT3/ITD was still present. Thus FLT3/ITD may in this case represent a primary event in leukemogenesis, whereas the t(15;17) may represent a secondary event most likely induced by subsequent therapy. In conclusion, FLT3/ITD and MLL/ITD are mainly observed in uncharacteristic cases of t-AML with a normal karyotype and unrelated to previous therapy for which reason they could represent sporadic cases of de novoAML.
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PMID:Internal tandem duplications of the FLT3 and MLL genes are mainly observed in atypical cases of therapy-related acute myeloid leukemia with a normal karyotype and are unrelated to type of previous therapy. 1175 4

In peripheral blood of at least 50% of healthy individuals, the translocations t(9;22) BCR/ABL, t(14;18) IgH/BCL-2, t(2;5) NPM-ALK and MLL duplications, which characterize chronic myelogenous leukemia and acute lymphoblastic leukemia, follicular lymphoma, anaplastic large cell lymphoma, and acute myelogenous leukemia, respectively, are detectable by sensitive polymerase chain reaction (PCR). No structural differences between these aberrations in normal or disturbed hematopoiesis are apparent. While the total count of t(9;22)- and t(14;18)-positive cells does not exceed 10(4), those with MLL duplications are more frequent and account for approximately 10(7) cells in the total blood pool. t(14;18)-positive cells seem to be immortalized, but the biological consequences of the other aberrations in positive healthy persons have not been studied in detail. Due to the high frequency of positive individuals, most of them will not suffer from the correspondent leukemia or lymphoma, and criteria for subgroups that may be at a higher risk remain to be determined. Most likely, the number of genetic aberrations in healthy individuals, which so far are only associated with hematopoietic disorders, will increase in the near future.
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PMID:Leukemia- and lymphoma-associated genetic aberrations in healthy individuals. 1190 85

The t(4;14)(p16.3;q32) translocation that occurs uniquely in a subset of multiple myeloma tumors results in ectopic expression of wild-type FGFR3 and enhanced expression of MMSET, a gene that is homologous to the MLL gene that is involved in acute myeloid leukemias. Wild-type FGFR3 appears to be weakly transforming in a hematopoietic murine model, whereas FGFR3 that contains kinase-activating mutations is strongly transforming in NIH3T3 cells and the hematopoietic model. The subsequent acquisition of FGFR3 kinase-activating mutations in some tumors with t(4;14) translocations confirms a role for FGFR3 in tumor progression. However, it remains to be proven if and how dysregulation of FGFR3 or MMSET mediates an early oncogenic process in multiple myeloma.
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PMID:The enigma of ectopic expression of FGFR3 in multiple myeloma: a critical initiating event or just a target for mutational activation during tumor progression. 1204 2

The French-American-British (FAB) classification and the new World Health Organization (WHO) classification distinguish acute monoblastic leukaemia (AML M5a) from acute monocytic leukaemia (AML M5b). Not much is known about the underlying genetic differences leading to these clearly different phenotypes. We analysed 58 patients with de novo AML M5a and 66 patients with de novo AML M5b in comparison with a whole group of 1603 de novo AML. An aberrant karyotype was found in 75.9% of AML M5a but in only 28.8% of M5b (P < 0.0001) and in 54.7% of all other AML subtypes (P = 0.0015). 11q23/MLL aberrations were detected in 31% of M5a, 12.1% of M5b (P = 0.01) but only 1.3% of all other AML subtypes (P < 0.0001). Trisomy 8 as the sole cytogenetic aberration was found in 22.4% of M5a, but in only 3% of M5b and in 2.5% of all other AML subcategories (P < 0.0001). Although the frequency of the MLL-partial tandem duplication (MLL-PTD) did not differ between the three cohorts (1.7%, 4.5% and 6.1% respectively, NS), the detection of FLT3 length mutations (FLT3-LM) differed significantly. AML M5a showed a low frequency of only 6.9%, but 28.8% of M5b (P = 0.0014) and 23.5% of all other AML revealed a FLT3-LM. In conclusion, we demonstrated genetic, i.e. biological, differences between AML M5a and AML M5b and all other AML. Therefore, AML M5 should further be categorized as two different groups, as proposed by the WHO classification.
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PMID:Distinct genetic patterns can be identified in acute monoblastic and acute monocytic leukaemia (FAB AML M5a and M5b): a study of 124 patients. 1213 26

In the present fluorescence in situ hybridization (FISH) study of six congenital mesoblastic nephromas (CMNs) using ETV6 and NTRK3 probes as well as a chromosome 15 painting probe, we identified a cryptic reciprocal translocation, t(12;15)(p13;q26), in one tumor, and an insertion, ins(12;15)(p13;q22q26), in another that were not previously identified by cytogenetic analysis. An interphase FISH study with the same probes detected the ETV6-NTRK3 fusion signal in all three cellular or mixed type tumors, but not in all three classical type tumors. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis detected the ETV6-NTRK3 fusion transcript in the three cellular or mixed type tumors, but not in the three classical type tumors. FISH analysis using a chromosome 11-centromere probe detected trisomy or tetrasomy 11 in all three tumors with the ETV6-NTRK3 fusion signal. To clarify whether IGF2, a paternally expressed gene on chromosome 11, has a certain role in the tumorigenic process of CMN through a loss of imprinting (LOI), we studied IGF2 allelic expression. We found no LOI in two cellular or mixed type tumors or in two classical type tumors, and concluded that the role of the LOI of IGF2 is not essential for the development and progression of CMN with or without trisomy 11. Furthermore, we showed no rearrangements of the MLL gene, which is frequently rearranged in acute leukemia with +11 in the three CMN tumors with +11.
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PMID:Cryptic t(12;15)(p13;q26) producing the ETV6-NTRK3 fusion gene and no loss of IGF2 imprinting in congenital mesoblastic nephroma with trisomy 11: fluorescence in situ hybridization and IGF2 allelic expression analysis. 1216 45

Childhood acute myeloid leukemia is a heterogeneous group of disorders that remains challenging to treat. There are multiple common genetic alterations in childhood acute myeloid leukemia. These include chromosomal translocations affecting RUNX1-CBFbeta, RARalpha, and MLL. There are known activating mutations in the genes for the receptor tyrosine kinases FLT3, KIT, and FMS. As these abnormalities are better understood, they are providing important insights into the pathogenesis of disease as well as information about prognosis. Although intensive chemotherapy remains the mainstay of acute myeloid leukemia therapy, long-term cure rates with chemotherapy alone remain approximately 50%, creating an urgent need for better therapies. Multiple avenues are being explored in the design of new treatments for pediatric acute myeloid leukemia. Targeted therapies include targeted antibody therapy; inhibitors of FLT3, KIT, and farnesyltransferase; diphtheria toxin conjugated to the granulocyte-macrophage colony-stimulating factor; and antisense oligonucleotides. Another area of interest is chromatin remodeling and differentiation therapy, including agents such as all- retinoic acid, arsenic trioxide, and inhibitors of DNA methylation and histone deacetylation. There are also ongoing trials of antiangiogenesis agents. Another avenue for novel therapies is immunotherapy with agents such as interleukin-2 and tumor vaccines. This article reviews recent advances in understanding of the molecular basis for childhood acute myeloid leukemia and the design of novel therapies for the treatment of childhood acute myeloid leukemia.
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PMID:Update in childhood acute myeloid leukemia: recent developments in the molecular basis of disease and novel therapies. 1248 9


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