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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hematopoietic tyrosine kinase receptors (HGF-TKRs or class III TKRs) are essential for the growth and differentiation of hematopoietic cells. In this report we present a novel method that generates expression profiles of these receptors. The method was tested and optimized using the myeloblastic/ promyelocytic cell line KG1. The method involves PCR of cDNA using class III-specific degenerate primers and subsequent restriction enzyme digests of the 147 bp amplicons followed by fractionation on denaturing poly-acrylamide gels. This primary fingerprint of KG1 revealed equal expression of c-kit and flt3 and to a lesser extent PDGF-R alpha and c-fms. One residual band of unknown origin was seen and appeared to be the proto-oncogene RET following cloning and sequence analysis. This tyrosine kinase receptor is known to play an important role in neural development. In order to detect less abundantly expressed sequences, a secondary fingerprint was generated by pre-digestion of the receptors present in the primary expression profile and subsequent amplification of the residual band. No other tyrosine kinase receptors were observed in KG1. In conclusion, this method allows direct visualization of expression of the HGF-TKRs and has the potential to detect novel homologous receptors.
Leukemia 1996 Aug
PMID:Direct display of hematopoietic tyrosine kinase receptor expression profiles in KG1 cells by PCR using degenerate primers. 870 51

Flt3 ligand (flt3L) is a member of a small family of cytokines acting as tyrosine kinase receptor ligands that stimulate the proliferation of primitive hematopoietic progenitors in vitro. To gain insight into the physiological role of flt3L in early hematopoiesis, levels of flt3L were determined in serum of patients with multilineage bone marrow failure and related to the severity of stem cell depletion. In patients with aplastic anemia (AA) and in cancer patients with chemotherapy-induced transient suppression of hematopoiesis, flt3L fluctuated in an inverse relationship to the degree of bone marrow failure. In severe AA at diagnosis, levels of circulating soluble flt3L were highly elevated (2,653 +/- 353 pg/mL) as compared with normal blood serum values of 14 +/- 39 pg/mL. Flt3L returned to near normal levels within the first 3 months following successful bone marrow transplantation and in autologous remission induced by immunosuppressive therapy with antilymphocyte globulin (ALG; 100 +/- 31 and 183 +/- 14 pg/mL, respectively). In contrast, rejection of the graft or relapse of the disease after ALG was accompanied by an increase to high pretreatment concentrations of the circulating cytokine (3,770 +/- 2,485 and 1,788 +/- 233 pg/mL, respectively). Flt3L in serum inversely correlated with the colony-forming ability of AA bone marrow precursors in vitro (R = -.86), indicating that the concentration of the ligand reflects hematopoiesis at the progenitor cell level. Flt3L increased to 2,500 pg/mL in the serum of leukemia patients during chemoradiotherapy-induced bone marrow suppression and returned to normal values along with hematopoietic recovery. Expression of the membrane-bound form of flt3L was significantly elevated in mononuclear bone marrow and peripheral blood cells from patients with severe pancytopenia, suggesting de novo synthesis of the factor in response to bone marrow failure. The data provide a strong argument for the involvement of flt3L in the regulation of early hematopoiesis in vivo.
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PMID:Flt3 ligand level reflects hematopoietic progenitor cell function in aplastic anemia and chemotherapy-induced bone marrow aplasia. 897 41

A new cell line (LR10.6) with pre-B cell phenotype has been established from bone marrow cells obtained from a child with B lineage acute lymphoblastic leukemia in complete clinical remission. The line expresses nuclear TdT enzyme, cytoplasmic Ig lambda-chain and membrane mu-chain and other B but no T or myeloid markers. The cells also show activation antigens CD69 and CD71, adhesion molecules CD54, CD50 and CD56 and the tyrosine kinase receptor CD117. No expression of multidrug resistance phenotype MDR-1 is observed on these cells which nevertheless express the transcriptional factor p53 protein in a mutant form. Cytogenetic study shows a translocation t(5;12)(q31;p13) involving breakpoints which contain the growth factor interleukin 3 gene (5q31) and the recently identified TEL/ETV6 gene (12p13). Activation of the cells with phorbol-12 myristate 13-acetate (PMA) up-regulates the expression of the CD69 activation antigen and down-regulates the CD117 molecule. In addition, PMA fails to induce the CD20 B cell antigen.
Leukemia 1997 Jul
PMID:A new human cell line with pre-B cell phenotype and t(5;12). 920 88

The c-kit proto-oncogene encodes a transmembrane tyrosine kinase receptor. It is expressed by the primitive CD34 positive haemopoietic stem cells and interacts with the Kit ligand for signal transduction. It was reported to be expressed in over 80% of acute myelogenous leukaemia (AML) patients in North America and Japan. We analyzed 20 AML patients for c-kit expression using either Northern blot analysis or flow cytometry with the YB5.B8 anti-c-kit antibodies. Only 6 out of 20 AML patients expressed the c-kit mRNA or protein product. However, a previously unreported abnormal sized 1.7-1.9 kb transcript was detected in the blast cells of 1 AML patient, 1 acute mixed lineage leukaemia patient and 1 chronic myelogenous leukaemia (CML) patient in myeloblastic transformation. Our data suggested that in most Hong Kong Chinese AML patients, leukaemia transformation may have occurred at a c-kit negative stage. Alternatively, the abnormal sized c-kit transcript that was detected in some Chinese myeloid leukaemia patients may represent an aberrant c-kit receptor that plays an important role in leukaemogenesis.
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PMID:Low frequency of c-kit expression and detection of an aberrant Kit message among Hong Kong Chinese myelogenous leukaemia patients. 921 71

DNA differential display analysis (DD-PCR) was utilized to identify genes that are expressed in airway epithelium and are relevant to airway inflammation; cytokine-mediated induction of gene expression and inhibition of that induction by glucocorticoids were the criteria for selection. The IB3-1 cell line was cultured in the presence of tumor necrosis factor-alpha (TNF-alpha), dexamethasone, or dimethyl sulfoxide (DMSO) as a control, and analyzed via DD-PCR and Northern blot analyses. With this approach, two TNF-alpha-inducible and dexamethasone (DEX)-sensitive expressed sequence tags (EST8 and EST19) were identified. In IB3-1 cells, TNF-alpha increased messenger RNA (mRNA) expression of EST8 (34%, P < or = 0.005) and EST19 (41%, P < or = 0.01), whereas dexamethasone reduced this expression to resting levels. This pattern of mRNA expression was also observed in normal human bronchial epithelial cells (EST8: 21%, P < or = 0.009; EST19: 11%, P < or = 0.02) and in the basophil leukemia cell line KU812 (EST8: 34%, P < or = 0.01). Through basic local alignment search tool (BLAST) analysis, it was determined that these ESTs exhibited significant homology with the monomeric G protein rhoC (EST8: 100% homology, P = 1.6 x 10(-100)) and the UFO tyrosine kinase receptor (EST19: 86% homology, 5.3 x 10(-28).
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PMID:Identification of novel inducible genes in airway epithelium. 922 16

A paradox of Flt-1, a tyrosine kinase receptor for vascular endothelial growth factor (VEGF), is that the ligand cannot activate the receptor to stimulate growth of cells that exogenously overexpress the receptor. In order to find Flt-1 kinase-dependent biological systems, we obtained for the first time activated forms of the Flt-1 kinase in a ligand-independent manner. Replacement of the ABL sequences in the human leukemia oncoprotein BCR-ABL with the cytoplasmic domain of Flt-1 (BCR-FLT) followed by a retroviral random mutagenesis scheme gave constitutively active artificial chimera BCR-FLTm with mutations within the Flt-1 sequence. Like BCR-ABL it could, but not the original BCR-FLT, transform Rat1 fibroblasts, abrogate cytokine dependence in Ba/F3 cells, and induce neurite-like structures in neuronal PC12 cells. Interestingly, Rat1 cells transformed by BCR-FLTm formed tube-like structures in basement membrane matrix. BCR-FLTm retroviruses may be a very useful tool to investigate an as yet uncovered functions of the Flt-1 kinase.
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PMID:Flt-1, a receptor for vascular endothelial growth factor, has transforming and morphogenic potentials. 963 35

Recent studies have shown that hepatocyte growth factor (HGF) is a regulatory protein for the proliferation and differentiation of hematopoietic progenitors. The proto-oncogene c-met encodes a tyrosine kinase receptor that binds HGF. To obtain information about their possible involvement in the pathogenesis of hematopoietic tumors, we have examined the expression of HGF and c-met in a large panel of leukemia-lymphoma cell lines encompassing all major hematopoietic cell lineages. HGF and c-met mRNAs were detected by reverse transcriptase-polymerase chain reaction (RT-PCR) and Northern blotting. The panel of 92 cell lines analyzed comprised seven B-cell precursor, ten B-cell, six plasma cell, 13 T-cell, four natural killer (NK) cell, 16 myelocytic, 12 monocytic, 13 erythroid-megakaryocytic and 11 Hodgkin-anaplastic large cell lymphoma (ALCL) lines. In total 64 (70%) were RT-PCR-positive for HGF and 43 (47%) for c-met. The highest percentages of expression were found for HGF in the plasma cell (100%), NK (100%) and myeloid (75-92%) cell line categories, whereas c-met was found predominantly in plasma cell (100%) and Hodgkin-ALCL (91%) cell lines. The concomitant expression of HGF and c-met in plasma cell lines (100%) and Hodgkin-ALCL (73%) cell lines should be noted. The high HGF expression in myelocytic-monocytic cell lines (75 and 92%) contrasts with the low c-met expression (18 and 8%) in these cell lineages. In 50 cell lines, mRNA expression of these two genes was also examined at the Northern blot level: 12/50 (24%) and 4/48 (8%) were positive for HGF and c-met mRNA expression, respectively. Of note, three of the four c-met + lines belonged to the category Hodgkin-ALCL; the Hodgkin cell line SUP-HD-1 showed both HGF and c-met mRNA bands suggesting the possibility of an autocrine loop. In conclusion, we detected HGF expression in various types of leukemia-lymphoma cell lines, particularly in plasma cell and myeloid malignancies; c-met expression was found in plasma cell and Hodgkin-ALCL cell lines. Further detailed analysis of the role of this ligand-receptor pair in the pathogenesis of hematopoietic neoplasms is indicated; to this end the HGF + and c-met + cell lines described here represent exquisite model systems.
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PMID:Expression of hepatocyte growth factor and its receptor c-met in human leukemia-lymphoma cell lines. 971 11

The process of haemopoiesis, occurring primarily within the bone marrow, involves the proliferation and differentiation of pluripotent haemopoietic stem cells into committed, or pathway-restricted progenitors /1/. The latter further proliferate and undergo a process of maturation into circulating blood cells of myeloid and erythroid lineages /2/. Haemopoietic cell growth and differentiation is primarily regulated by the local production of various cytokines within the bone marrow micro-environment /3/, as well as by the circulating hormone, erythropoietin (EPO). The formation as well as functional activation of mature blood cells, are also modulated by a variety of hormones and growth peptides, including growth hormone (GH) and insulin-like growth factor-I (IGF-I) /4,5/. Early evidence for the role of GH in modulating haemopoiesis was provided in classical studies in rodents, which showed that removal of the pituitary gland affects blood cell formation and function /6/ and that impairment of the latter can be restored by GH administration /7/. GH exerts its effects on target cells by binding to its own receptor, which belongs to the class I cytokine receptor superfamily /8/. In humans, GH can also bind to and activate the prolactin receptor /9/. Based on the somatomedin hypothesis of Salmon and Daughaday /10/, it is now generally accepted that, in addition to the above, GH exerts many of its effects via autocrine or paracrine IGF-I, as well as via endocrine IGF-I produced in the liver. IGF-I, a small single-chain polypeptide, is one of two highly homologous peptides (IGF-I and IGF-II), that stimulate the proliferation and differentiation of a wide variety of cell types, including bone marrow cells /5,11/. Both IGF-I and IGF-II play an important role in prenatal growth and IGF-I is also essential for postnatal growth and development /12/. Two types of IGF receptors have been described. The type I IGF receptor, a tyrosine kinase receptor highly homologous to the insulin receptor, binds IGF-I and IGF-II with a high affinity. The type II/mannose 6-phosphate receptor which lacks intrinsic kinase activity, binds IGF-II with a high affinity and IGF-I with a low affinity /13,14/. Haemopoietic progenitors and mature blood cells have been shown to produce GH and IGF-I and to express receptors for these peptides. GH and IGF-I may act independently on these cells or, as more commonly observed, in a synergistic manner with primary haemopoietic cytokines. GH and IGF-I receptors are also present on freshly explanted leukemic cells and leukemic cell lines. Thus, their possible contribution to the development of leukemia should also be considered. This review summarizes our current understanding of the role of GH and IGF-I in normal and malignant haemopoiesis.
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PMID:The haematopoietic effects of growth hormone and insulin-like growth factor-I. 982 20

FLT3 ligand (FL) acting through its tyrosine kinase receptor FLT3 has pleiotropic and potent effects on hematopoietic cells. The well-described involvement of this ligand-receptor pair in physiological hematopoiesis raised the question whether FL and FLT3 also play a role in the pathobiology of leukemia. Following the early discovery of high receptor expression by myeloid leukemia cells, several investigators have focused their attention on these cells, both primary acute myeloid leukemia (AML) cells and continuous human myeloid leukemia cell lines. Regardless of the morphological FAB subtype, the vast majority of AML cases were FLT3-positive both at the mRNA and protein level; among the myeloid cell lines, predominantly the monocytic and myelocytic cell lines were FLT3-positive whereas the erythrocytic and megakaryocytic cell lines were FLT3-negative. Virtually all cell lines studied expressed FL transcripts; the finding that some cell lines displayed both ligand and receptor indicates the possibility of autocrine, intracrine or paracrine stimulatory loops. In vitro growth assays showed that FL caused a proliferative response in a high percentage of AML cases. Only constitutively growth factor-dependent myelocytic cell lines increased their proliferation upon incubation with FL whereas all growth factor-independent cell lines were refractory to FL stimulation. Combinations of FL with various cytokines (e.g. G-CSF, GM-CSF, IL-3, M-CSF, PIXY-321, SCF) had synergistic or additive mitogenic effects. Finally, FL had significant anti-apoptotic, survival-promoting effects on primary AML cells and myeloid cell lines under serum-free culture conditions. On the strength of the above findings, it can be concluded that the FL-FLT3 signaling system may play a certain, albeit probably not causal role in the development of human leukemias. Dissection of the exact molecular pathways that lead to proliferation and/or anti-apoptosis of myeloid leukemia cells as well as the detailed elucidation of the possible contribution of the FL-FLT3 genes to leukemogenesis remain future challenges.
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PMID:Effects of FLT3 ligand on proliferation and survival of myeloid leukemia cells. 1019 24

The axl tyrosine kinase receptor is aberrantly expressed on myeloid cells of many individuals afflicted with chronic myelogenous leukemia (CML) and other myeloid leukemias. Although previous studies demonstrated this kinase to have oncogenic potential, it is not known whether axl actively participates in the onset and/or progression of CML. We addressed this question by generating transgenic mice possessing constitutive ectopic expression of human axl throughout cells of the myeloid hematopoietic lineage through the use of the granulocyte colony-stimulating factor (GCSF) receptor promoter. The transgenics did not exhibit hematopoietic malignancies, but did exhibit phenotypic characteristics associated with noninsulin-dependent diabetes mellitus (NIDDM) including hyperglycemia and hyperinsulinemia, severe insulin resistance, progressive obesity, hepatic lipidosis, and pancreatic islet dysplasia. The obese-diabetes phenotype was similar to that observed in the agouti and melanocortin-4(-/-) mutants, however the axl transgenics were not hyperphagic. Axl transgenic animals expressed elevated serum tumor necrosis factor (TNF)-alpha levels that were further enhanced upon in vitro lipopolysaccharide (LPS) stimulation of peripheral blood. Administration of the axl ligand, gas6, to peripheral transgenic blood samples eliminated excessive TNF-alpha production in response to LPS stimulation. As a means to better understand axl-gas6 biology, transgenic animals were produced which systemically expressed the gas6-binding axl proteolytic cleavage product. A more severe NIDDM phenotype occurred in these mice. The observed phenotypes may be related to the axl receptor or proteolytic cleavage product competing with related axl family receptors for binding of the gas6 ligand. We conclude that axl expression in myeloid cells in itself does not lead to the onset or progression of leukemia and suggest that ectopic axl expression affects endogenous modulation of TNF-alpha production indirectly resulting in the NIDDM phenotype.
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PMID:Noninsulin-dependent diabetes mellitus occurs in mice ectopically expressing the human Axl tyrosine kinase receptor. 1052 29


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