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)

In the family of cytokines and cytokine receptors, alternative splicing of pre-mRNA is a frequently observed process that generates different protein isoforms from a single genetic locus. The splicing-derived cytokine receptor protein isoforms are mostly soluble receptors or show alterations in their cytoplasmic domain. It is possible that receptor abnormalities or a pathological ratio of different isoforms may contribute to leukaemia by circumventing normal growth factor control or altering the balance of proliferation and differentiation. IL-7 plays a critical role in early stages of both B and T cell maturation. Moreover, it stimulates the expansion of mature T cells including anti-tumour reactive cells as well as a number of T and B cell malignancies underlining its potential importance for deregulated lymphoid proliferation and leukaemogenesis. Here, we present detailed data on the expression of the interleukin 7 receptor alpha chain (IL-7Ralpha) in leukaemic cells from 210 children with acute lymphoblastic leukaemia (ALL) and describe two novel alternatively spliced transcripts of human IL-7Ralpha coding for truncated receptor proteins which are still capable of binding IL-7. IL-7Ralpha mRNA expression was more frequent in more mature pre-B ALL [91% (30/33)] than in common [81% (81/100)] or pro-B ALL [64% (18/28)], or even in T ALL [64% (29/45)]. These results are in concordance with flow cytometric analyses on the proportion of IL-7Ralpha bearing cells among total blast cell population. Our results lead us to assume that splicing derived IL-7Ralpha isoforms play a potential role in modulating IL-7 signal transduction and might be important for the pathogenesis of leukaemia.
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PMID:Expression analysis and characterization of alternatively spliced transcripts of human IL-7Ralpha chain encoding two truncated receptor proteins in relapsed childhood all. 1105 10

The inositol polyphosphate 5-phosphatase SHIP plays an important role in negative signalling in B cells and mast cells and in the down-regulation of cytokine receptor-mediated signals in myeloid cells. SHIP is expressed as a 145 kDa full-length protein and an isoform of 135 kDa due to alternative splicing. Additional smaller forms of SHIP which are truncated at the carboxy terminus have been described in bone marrow and peripheral blood mononuclear cells (PBMC). Our data demonstrate that human bone marrow cells and PBMC from healthy donors and patients with acute myeloid leukemia express the 145 kDa form of SHIP and low amounts of a 135 kDa form of SHIP in vivo whereas C-terminal-truncated SHIP proteins are generated by a PMSF-sensitive protease during the preparation of cell lysates in vitro. We have further characterized this protease and identified a proteolytic cleavage site in the human SHIP protein C-terminal to tryptophan residue 941. These data support a physiological role for the 145 and 135 kDa forms of SHIP in bone marrow and peripheral blood cells from normal donors and patients with acute myeloid leukemia.
Leukemia 2001 Jan
PMID:The inositol 5-phosphatase SHIP is expressed as 145 and 135 kDa proteins in blood and bone marrow cells in vivo, whereas carboxyl-truncated forms of SHIP are generated by proteolytic cleavage in vitro. 1124 78

Nonhuman primate model systems of autologous CD34+ cell transplant are the most effective means to assess the safety and capabilities of lentivirus vectors. Toward this end, we tested the efficiency of marking, gene expression, and transplant of bone marrow and peripheral blood CD34+ cells using a self-inactivating lentivirus vector (CS-Rh-MLV-E) bearing an internal murine leukemia virus long terminal repeat derived from a murine retrovirus adapted to replicate in rhesus macaques. In vitro cytokine stimulation was not required to achieve efficient transduction of CD34+ cells resulting in marking and gene expression of the reporter gene encoding enhanced green fluorescent protein (EGFP) following transplant of the CD34+ cells. Monkeys transplanted with mobilized peripheral blood CD34+ cells resulted in EGFP expression in 1 to 10% of multilineage peripheral blood cells, including red blood cells and platelets, stable for 15 months to date. The relative level of gene expression utilizing this vector is 2- to 10-fold greater than that utilizing a non-self-inactivating lentivirus vector bearing the cytomegalovirus immediate-early promoter. In contrast, in animals transplanted with autologous bone marrow CD34+ cells, multilineage EGFP expression was evident initially but diminished over time. We further tested our lentivirus vector system by demonstrating gene transfer of the human common gamma-chain cytokine receptor gene (gamma(c)), deficient in X-linked SCID patients and recently successfully used to treat disease. Marking was 0.42 and.001 HIV-1 vector DNA copy per 100 cells in two animals. To date, all EGFP- and gamma(c)-transplanted animals are healthy. This system may prove useful for expression of therapeutic genes in human hematopoietic cells.
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PMID:Lentivirus vector-mediated hematopoietic stem cell gene transfer of common gamma-chain cytokine receptor in rhesus macaques. 1126 44

Myelopoietins comprise a class of chimeric cytokine receptor agonists consisting of an hIL-3 (human interleukin-3) receptor agonist and an hG-CSF (human granulocyte colony-stimulating factor) receptor agonist linked head-to-tail at their respective carboxy and amino termini. The combination of an early acting cytokine (hIL-3) with a late acting one (hG-CSF) allows efficient hematopoeitic reconstruction following myeloablative insult, and drives differentiation of non-myelocytic lineages (ie thrombocytic lineages) that are inaccessible using hG-CSF alone, in both preclinical models and clinical settings. A myelopoietin species was displayed and mutagenized on filamentous bacteriophage: both component agonists of myelopoietin were presented in biologically functional conformations as each recognized its corresponding receptor. Five amino acid positions in a short region of the hG-CSF receptor agonist module of myelopoietin that had been identified as important for proliferative activity were mutagenized. Display was used because it allows very 'deep' mutagenesis at selected residues: >10(5) substitution variants were affinity-screened using the hG-CSF receptor and 130 new, active variants of myelopoietin were identified and characterized. None of the selected variants were significantly more active than the parental myelopoietin species in a hG-CSF-dependent cell proliferation assay, though many were as active. Many of these relatively high-activity variants contained parental amino acids at several positions, suggesting the parental sequence may already be optimal at these positions for the assays used, and potentially accounting for the failure to identify enhanced bioactivity variants. Analysis of substitutions of high-activity variants complements and extends previous alanine scanning, and other genetic and biochemical data for hG-CSF variants.
Leukemia 2001 Aug
PMID:Phage display mutagenesis of the chimeric dual cytokine receptor agonist myelopoietin. 1148 May 53

Thrombopoietin (TPO) and its receptor (MPL) are important regulators of megakaryopoiesis. MPL belongs to a cytokine receptor superfamily. To date, all constitutively active MPL mutants have been artificially constructed with amino acid substitutions in the transmembrane domain or extracellular domain of the protein, and they activate signal transduction pathways in Ba/F3 cells that can also be activated by the normal MPL. In this paper, we report a novel spontaneously occurring mutation of MPL, with an amino acid substitution of Trp(508) to Ser(508) in the intracellular domain of MPL, that induces the factor-independent growth of Ba/F3 cells. Examination of intracellular signaling pathways demonstrated that the mutant MPL protein constitutively activates three distinct signaling pathways, SHC-Ras-Raf-MAPK/JNK, JAK-STAT, and PI3K-Akt-Bad.
Leukemia 2002 Aug
PMID:A novel MPL point mutation resulting in thrombopoietin-independent activation. 1214 91

The human T-cell leukemia virus type 1 (HTLV) is the first isolated human retrovirus, but its receptor has yet to be identified, in part due to its ubiquitous expression. Here we report that quiescent CD4 and CD8 T lymphocytes do not express this receptor, as monitored with a soluble receptor-binding domain derived from the HTLV envelope. However, HTLV receptor is an early activation marker in neonatal and adult T lymphocytes, detected as early as 4 hours following T-cell-receptor (TCR) stimulation. This induced surface expression of the HTLV receptor requires de novo protein synthesis and results in a wide distribution on the surface of activated lymphocytes. Moreover, the distribution of the HTLV receptor is independent of TCR/CD3-capped membrane structures, as observed by confocal immunofluorescence microscopy. To determine whether HTLV receptor up-regulation specifically requires TCR-mediated signals or, alternatively, is dependent on more generalized cell cycle entry/proliferation signals, its expression was monitored in interleukin 7 (IL-7)-stimulated neonatal and adult T cells. Neonatal, but not adult, lymphocytes proliferate in response to IL-7 and HTLV receptor expression is restricted to the former population. Thus, HTLV receptor expression appears to be an early marker of cell cycle entry. Up-regulation of the HTLV receptor, via signals transmitted through the IL-7 cytokine receptor as well as the TCR, is likely to contribute to the mother-to-infant transmission and spreading of HTLV-1.
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PMID:The HTLV receptor is an early T-cell activation marker whose expression requires de novo protein synthesis. 1239 96

An inevitable trend for the development of new treatment of leukemia is to use targeted strategy. IL-6/IL-6R is important one of the cytokine receptor targeted treatment systems. Many malignant cells, including multiple myeloma, prostate carcinoma and leukemia etc., have been shown to express IL-6R. Leukemia cells, especialy in U937, TF1, KG1 cell lines highly express the high affinity IL-6R. IL-6 recombinant toxin is cytotoxic in vitro to leukemia cell expressing high affinity IL-6R; in vivo the fusion toxin can result the reduction of leukemic cell load in animal leukemia model but have no effect on normal hematopoiesis in non-leukemic animal. On the basis of these pre-clinical studies, IL-6 recombinant toxin my become novel drug for the treatment of leukemia and cancer in future.
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PMID:[A Strategy of IL-6/IL-6R System Mediates Targeted Treatment for Leukemia] 1257 31

Transactivating proteins associated with complex onco-retroviruses including human T-cell leukemia virus-1 (HTLV-1) and bovine leukemia virus (BLV) mediate transformation using poorly understood mechanisms. To gain insight into the processes that govern tumor onset and progression, we have examined the impact of BLV-Tax expression on ovine B-cells, the targets of BLV in experimentally infected sheep, using B-cell clones that are dependent on CD154 and gammac-common cytokines. Tax was capable of mediating progression of B-cells from cytokine dependence to cytokine independence, indicating that the transactivator can over-ride signaling pathways typically controlled by cytokine receptor activation in B-cells. When examined in the presence of both CD154 and interleukin-4, Tax had a clear supportive role on B-cell growth, with an impact on B-cell proliferation, cell cycle phase distribution, and survival. Apoptotic B-cell death mediated by growth factor withdrawal, physical insult, and NF-kappaB inhibition was dramatically reduced in the presence of Tax. Furthermore, the expression of Tax was associated with higher Bcl-2 protein levels, providing rationale for the rescue signals mediated by the transactivator. Finally, Tax expression in B-cells led to a dramatic increase of nuclear RelB/p50 and p50/p50 NF-kappaB dimers, indicating that cellular signaling through NF-kappaB is a major contributory mechanism in the disruption of B-cell homeostasis. Although Tax is involved in aspects of pathogenesis that are unique to complex retroviruses, the viral strategies associated with this transactivating oncoprotein may have wide-ranging effects that are relevant to other B-cell malignancies.
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PMID:Disruption of B-cell homeostatic control mediated by the BLV-Tax oncoprotein: association with the upregulation of Bcl-2 and signaling through NF-kappaB. 1288 10

Rearrangement of the FLI-1 locus and ensuing overexpression of FLI-1 protein is an early event in Friend murine leukemia virus (F-MuLV)-induced erythroleukemia. When overexpressed in primary erythroblasts, FLI-1 converts erythropoietin (Epo)-induced terminal differentiation into a proliferative response. We found that SLAP, a gene encoding a recently described negative regulator of T-cell antigen receptor function during thymocyte development, is up-regulated both at the RNA and protein levels in FLI-1-transformed erythroblasts. Src-like adaptor protein (SLAP) was found in a specific complex with erythropoietin receptor (EpoR), a cytokine receptor essential to erythroid differentiation. Constitutive expression of SLAP severely impairs hemoglobinization and late survival during Epo-induced terminal differentiation of erythroblasts. This impairment is associated with the specific inhibition of several critical Epo-dependent signaling events, including signal transducer and activator of transcription 5 (STAT5) activation and up-regulation of the expression of the antiapoptotic BCL-X gene. Our data support a model by which FLI-1 inhibits normal erythroid differentiation through the deregulation of genes encoding adaptors/effectors that modify the signaling output of cytokine receptors normally required for terminal differentiation.
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PMID:Up-regulation of SLAP in FLI-1-transformed erythroblasts interferes with EpoR signaling. 1294 94

Continuous human leukemia-lymphoma (LL) cell lines represent a rich resource of abundant, accessible and manipulable living cells contributing significantly to a better understanding of the pathophysiology of hematopoietic tumors. In particular, classical and molecular cytogenetics have benefitted enormously from the availability of LL cell lines with specific chromosomal abnormalities. Such aberrations may be the portal to the discovery of novel oncogene rearrangements for which positive cell lines provide a resource for both discovery and functional studies. The new continuous leukemia cell line MUTZ-11 was established in 1994 from the peripheral blood of a 60-year-old woman with acute myeloid leukemia (AML) M4 (following 2 years with myelodysplastic syndromes). DNA fingerprinting confirmed the authenticity and derivation of the cell line. The immunoprofile as determined by flow cytometry was as follows: positive for myelocytic markers (CD13, CD15, CD33, CD65 and CD68), negative for T-cell (except for CD4 and CD7), B-cell and erythroid-megakaryocytic markers. The cell line is constitutively cytokine-dependent and growth depends on externally added cytokines. With regard to cytokine receptor expression, the cell line was found to be positive for GM-CSFRalpha (granulocyte-macrophage colony-stimulating factor receptor, CD116), Kit (CD117) and IL-3Ralpha (interleukin-3 receptor, CD123). The cytokine response profiles as determined by [(3)H]-thymidine incorporation assay were: 2-to-12 fold growth stimulation of MUTZ-11 by GM-CSF, IFN-alpha (interferon), IFN-beta, IFN-gamma, IL-3 and SCF (stem cell factor); growth inhibition by TGF-beta1 (transforming growth factor), TNF-alpha (tumor necrosis factor) and TNF-beta. Cytogenetic analysis showed the following consensus karyotype: 46, XX, der(16)t(16;17)(p13.3;q23)x2. Previous molecular biological analysis documented that MUTZ-11 cells carry both an FLT3 internal tandem duplication (ITD) and an MLL partial tandem duplication (PTD). The scientific significance of MUTZ-11 lies (i). in the absolute cytokine-dependency and the proliferative response to various cytokines, (ii). in the unique cytogenetic (disomic t(16;17)) and (iii). molecular biological alterations (FLT3 ITD + MLL PTD). In summary, the new cytokine-dependent AML-derived cell line MUTZ-11 displays unique novel features and emphasizes the need for comprehensive analysis of new LL cell lines which may lead to the discovery of important pathogenetic alterations.
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PMID:New cytokine-dependent acute myeloid leukemia cell line MUTZ-11 with disomic chromosome rearrangement t(16;17). 1506 4


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