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)

Chromosomal rearrangements involving band 12p13 are found in a wide variety of human leukemias but are particularly common in childhood acute lymphoblastic leukemia. The genes involved in these rearrangements, however, have not been identified. We now report the cloning of a t(12;21) translocation breakpoint involving 12p13 and 21q22 in two cases of childhood pre-B acute lymphoblastic leukemia, in which t(12;21) rearrangements were not initially apparent. The consequence of the translocation is fusion of the helix-loop-helix domain of TEL, an ETS-like putative transcription factor, to the DNA-binding and transactivation domains of the transcription factor AML1. These data show that TEL, previously shown to be fused to the platelet-derived growth factor receptor beta in chronic myelomonocytic leukemia, can be implicated in the pathogenesis of leukemia through its fusion to either a receptor tyrosine kinase or a transcription factor. The TEL-AML1 fusion also indicates that translocations affecting the AML1 gene can be associated with lymphoid, as well as myeloid, malignancy.
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PMID:Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. 776 24

p12I is a small hydrophobic protein encoded by the human T-cell leukemia/lymphotropic virus type 1 (HTLV-1) that interacts with the 16-kDa component of the H+ vacuolar ATPase and cooperates with bovine papillomavirus 1 E5 oncoprotein in cell transformation. Just as an important step in E5 action appears to be its binding to the platelet-derived growth factor receptor, it was found that p12I binds specifically to both the beta and gamma(c) chains of the interleukin-2 receptor (IL-2R). The IL-2R beta and gamma(c) chains associated with p12I are endoglycosidase-H sensitive, suggesting that their interaction occurs in a pre-Golgi compartment. p12I stabilizes the immature forms of the IL-2R beta and gamma(c) chains and decreases their cell surface expression. The interactions of p12I with IL-2R beta and gamma(c) may have important implications in the immunosuppressive effect of HTLV-1 in vivo as well as in the ligand-independent HTLV-1-mediated T-cell proliferation.
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PMID:The human T-cell leukemia/lymphotropic virus type 1 p12I proteins bind the interleukin-2 receptor beta and gammac chains and affects their expression on the cell surface. 864 94

Chromosomal translocations involving band 5q31-35 occur in several hematologic disorders. A clone with a t(5; 14)(q33; q32) translocation appeared at the relapse phase in a patient with acute myelogenous leukemia who exhibited a sole chromosomal translocation, t(7; 11), at initial diagnosis. After the appearance of this clone, the leukemia progressed with marked eosinophilia, and combination chemotherapy was ineffective. Southern blot analysis showed a rearrangement of the platelet-derived growth factor receptor beta (PDGFRbeta) gene at 5q33 which was not observed at initial diagnosis. This translocation resulted in a chimeric transcript fusing the PDGFRbeta gene on 5q33 with a novel gene, CEV14, located at 14q32. Expression of the 5' region of the PDGFRbeta cDNA, upstream of the breakpoint, was not detected. However, the 3' region of PDGFRbeta, which was transcribed as part of the CEV14-PDGFRbeta fusion gene, was detected. A partial cDNA for a novel gene, CEV14, includes a leucine zipper motif and putative thyroid hormone receptor interacting domain and is expressed in a wide range of tissues. The expression of a CEV14-PDGFRbeta fusion gene in association with aggressive leukemia progression suggests that this protein has oncogenic potential.
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PMID:Fusion of the platelet-derived growth factor receptor beta to a novel gene CEV14 in acute myelogenous leukemia after clonal evolution. 937 37

Chronic myelomonocytic leukemia (CMML) is a pre-leukemic syndrome that displays both myelodysplastic and myeloproliferative features. The t(5;12) chromosomal translocation, present in a subset of CMML patients with myeloproliferation fuses the amino terminal portion of the ets family member, Tel, with the transmembrane and tyrosine kinase domains of platelet-derived growth factor receptor beta (PDGFRbeta) gene. To investigate the role of this fusion protein in the pathogenesis of CMML, we expressed the Tel-PDGFRbeta fusion cDNA in hematopoietic cells of transgenic mice under the control of the human CD11a promoter. Transgenic founders and their offspring express the transgene specifically in hematopoietic tissues and develop a myeloproliferative syndrome characterized by: overproduction of mature neutrophils and megakaryocytes in the bone marrow; splenomegaly with effacement of splenic architecture by extramedullary hematopoiesis; an abnormal population of leukocytes co-expressing lymphoid and myeloid markers; and increased numbers of colonies in in vitro bone marrow CFU assays. All mice expressing the transgene exhibited at least one of these features of dysregulated myelopoiesis, and 20% progressed to a myeloid or lymphoid malignancy. This murine model of CMML parallels a myeloproliferative syndrome in humans and implicates the Tel-PDGFRbeta fusion protein in its pathogenesis.
Leukemia 1999 Nov
PMID:The Tel-PDGFRbeta fusion gene produces a chronic myeloproliferative syndrome in transgenic mice. 1055 54

TEL-JAK2 fusion proteins, which are a result of t(9;12)(p24;p13) translocations associated with human leukemia, activate Stat5 in vitro and in vivo and cause a myelo- and lymphoproliferative disease in a murine bone marrow transplant model. We report that Socs-1, a member of the SOCS family of endogenous inhibitors of JAKs and STATs, inhibits transformation of Ba/F3 cells by TEL-JAK2 but has no effect on Ba/F3 cells transformed by BCR-ABL, TEL-ABL, or TEL-platelet-derived growth factor receptor beta. TEL-JAK2, in addition to activating Stat5, associates with Shc and Grb2 and induces activation of Erk2, and expression of Socs-1 inhibits engagement of each of these signaling molecules. TEL-JAK2 kinase activity is inhibited by Socs-1, as assessed by in vitro kinase assays. In addition, Socs-1 induces proteasomal degradation of TEL-JAK2. Mutational analysis indicates that the SOCS box of Socs-1 is required for proteasomal degradation and for abrogation of growth of TEL-JAK2-transformed cells. Furthermore, murine bone marrow transplant assays demonstrate that expression of Socs-1 prolongs latency of TEL-JAK2-mediated disease in vivo. Collectively, these data indicate that Socs-1 inhibits TEL-JAK2 in vitro and in vivo through inhibition of kinase activity and induction of TEL-JAK2 protein degradation.
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PMID:Socs-1 inhibits TEL-JAK2-mediated transformation of hematopoietic cells through inhibition of JAK2 kinase activity and induction of proteasome-mediated degradation. 1131 80

Acquired reciprocal chromosomal translocations that involve chromosome bands 5q31-33 are associated with a significant minority of patients with BCR-ABL-negative chronic myeloid leukemias. The most common abnormality is the t(5;12)(q33;p13), which fuses the ETV6/TEL gene to the platelet-derived growth factor receptor-beta (PDGFRB), a receptor tyrosine kinase that maps to 5q33. PDGFRB is disrupted by other translocations and to date four additional partner genes (H4, HIP1, CEV14 and Rab5) have been reported. Clinically, most patients present with a myeloproliferative disorder (MPD) with eosinophilia, eosinophilic leukemia or chronic myelomonocytic leukemia and thus fall into the broader category of myeloproliferative disorders/myelodysplastic syndromes (MPD/MDS). With the advent of targeted signal transduction therapy, patients with rearrangement of PDGFRB might be better classified as a distinct subgroup of MPD/MDS.
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PMID:Myeloproliferative disorders with translocations of chromosome 5q31-35: role of the platelet-derived growth factor receptor Beta. 1191 93

We have previously found that the 4-[4-(N-substituted carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazolines can function as potent and selective inhibitors of platelet-derived growth factor receptor (PDGFR) phosphorylation. A series of highly potent, specific, orally active, small molecule kinase inhibitors directed against members of PDGFR receptor have been developed through modifications of the novel quinazoline template I. Systematic modifications in the A-bicyclic ring and D-rings of protype I were carried out to afford potent analogues, which display IC(50) values of <250 nM in cellular betaPDGFR phosphorylation assays. An optimized analogue in this series, 75 (CT53518), inhibits Flt-3, betaPDGFR, and c-Kit receptor phosphorylation with IC(50) values of 50-200 nM, whereas 15-20-fold less potent activity against CSF-1R was observed. This analogue also inhibits autophosphorylation of Flt-3 ligand-stimulated wild-type Flt-3 and a constitutively activated Flt-3/internal tandem duplication (ITD) with IC(50) values of 30-100 nM. Through this optimization process, 75 was found to be metabolically stable and has desirable pharmacokinetic properties in all animal species studied (F% > 50%, T(1/2) > 8 h). Oral administration of 75 promotes mice survival and significantly delayed disease progression in a Flt-3/ITD-mediated leukemia mouse model and shows efficacy in a nude mouse model of chronic myelomonocytic leukemia.
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PMID:Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family. 1216 50

Imatinib (Glivec, formerly STI571, Novartis Pharma AG, Basel, Switzerland) potently inhibits several protein tyrosine kinases, including Bcr-Abl, Kit, and the platelet-derived growth factor receptor. Phase I and II studies demonstrated that orally administered imatinib is highly effective and well tolerated in all phases of chronic myeloid leukemia (CML) at doses ranging from 400 to 600 mg. Importantly, preliminary evidence suggests that patients with advanced CML achieving hematologic or major cytogenetic responses to imatinib may have longer survival than those without such responses, whereas chronic phase patients who respond to treatment may have longer times to disease progression. Ongoing and planned studies are focused on optimizing CML treatment with imatinib, evaluating imatinib-based combination therapy, defining additional therapeutic targets and exploring the use of imatinib in children. In particular, results from several combination phase I studies are expected shortly, including an evaluation of combination imatinib-interferon-alpha therapy and imatinib-cytarabine in chronic phase CML, and a phase I study of single-agent imatinib in children with Philadelphia chromosome-positive leukemia is ongoing. A large phase III trial comparing imatinib with standard inferferon alfa plus cytarabine in first-line CML treatment is also ongoing.
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PMID:Imatinib: the first 3 years. 1252 77

Malignant mesothelioma is an aggressive malignancy that may be caused by environmental carcinogens (asbestos and erionite), viruses (SV40), and genetic predisposition. Pleural malignant mesotheliomas are far more common than the peritoneal variants. Diagnosis relies on radiographic studies as well as histology and molecular biologic analyses. The prognostic scoring systems of the Cancer and Leukemia Group B and the European Organization for Research and Treatment of Cancer are the most useful of those currently available. These systems rate performance status, age, histology, and hematologic parameters as the best prognostic factors for mesothelioma. Most patients with mesothelioma are not candidates for surgical or radiotherapy treatment, and cytotoxic agents are the only options. Historically, no classes or combinations of agents consistently yielded response rates over 20%. Recently, pemetrexed has been evaluated in phase I, II, and III clinical trials with promising results. The phase II trial showed an overall response rate of 14.1% with a 1-year survival rate of 47.8%. A phase III trial of cisplatin versus cisplatin and pemetrexed closed in February 2002 and a final analysis was presented in May 2002. Novel targeted agents are also being tested in clinical trials among mesothelioma patients and include drugs inhibiting the vascular endothelial growth factor and its receptor, the epidermal growth factor receptor, and platelet-derived growth factor receptor.
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PMID:Emerging insights into the biology and therapy of malignant mesothelioma. 1257 9

Imatinib mesylate is a 2-phenylaminopyrimidine tyrosine kinase inhibitor with specific activity for ABL, platelet-derived growth factor receptor, and c-kit receptor. The pharmacological basis of this interaction has been elucidated by crystallographic studies. Imatinib mesylate binds to the amino acids of the BCR-ABL tyrosine kinase ATP binding site and stabilizes the inactive, non-ATP-binding form of BCR-ABL, thereby preventing tyrosine autophosphorylation, and in turn, phosphorylation of its substrates. This process ultimately results in a "switch-off" of the downstream signaling pathways that promote leukemogenesis. Despite high rates of hematologic and cytogenetic responses to imatinib therapy, the emergence of resistance to imatinib has been recognized as a major problem in the treatment of Ph-positive leukemia. Considerable progress has been made in developing therapeutic agents that are effective against molecular targets specifically expressed in CML cells. It is important to emphasize that BCR-ABL is the ideal target for therapy even at relapse; at least one general mechanism of resistance involves maintenance of an active BCR-ABL kinase inside leukemic cells. It is also notable that the high frequency of BCR-ABL mutations and amplifications represents the high degree of heterogeneity in patients with advanced CML, in whom multiple leukemic clones may exist. For these reasons, a single inhibitor is unlikely to be able to block all mutants described so far.
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PMID:[Molecular-target therapy of Ph-positive leukemia by imatinib (tyrosine kinase inhibitor)]. 1293 59


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