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

In an effort to identify unique tyrosine kinases found in human leukemia cell lines, we utilized polymerase chain reaction (PCR) technology and degenerate oligonucleotide primers to produce a cDNA library of kinase catalytic domains found in the human monocytic cell line AML-193. This search yielded a member of the class 3 tyrosine kinases closely related to the murine kinase FD-22. Previous work has identified this kinase as JAK1. This class of tyrosine kinases is characterized by being ubiquitously expressed, lacking both a ligand-binding domain and a SH2 domain, while containing a second domain similar to a degenerate kinase domain. Our studies focused on the further characterization of this class 3 tyrosine kinase using Northern blot analysis to demonstrate an increase in steady-state mRNA by interferon-gamma in human monocytes. A human-hamster somatic cell hybrid panel and linkage mapping was used to assign JAK1 (aml-116) to human chromosome 1.
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PMID:Characterization of a class 3 tyrosine kinase. 137 77

The BCR/ABL oncogene in chronic myelogenous leukemia produces an activated tyrosine kinase fusion protein (p210). Like other tyrosine kinase oncogenes, BCR/ABL can abrogate the interleukin-3 (IL-3) dependence of lymphoid cell lines. To investigate the ability of BCR/ABL to generate growth factor independence in myeloid cells, the IL-3 dependent myeloid cell line NFS/N1.H7 (H7) was transfected with the p210BCR/ABL-containing plasmid, pGD210. Stable clones A54 and A74 were capable of IL-3 independent growth and tumor formation in syngeneic mice. Relief of growth factor dependence was not mediated by autocrine release of IL-3. The baseline proliferation rate of the BCR/ABL transformed cells was greater than that of the parental H7 cells maximally stimulated by IL-3. Abundant constitutive expression of c-myc, c-jun, and c-fos was observed in the p210BCR/ABL transfectants even in low serum conditions. In contrast, c-myc expression in H7 cells was dependent upon IL-3 stimulation, and neither c-jun nor c-fos was highly expressed following IL-3 stimulation in H7 cells. Thus, BCR/ABL transformation and relief of IL-3 dependence involve not only pathways that can substitute for IL-3 induced growth via tyrosine kinase mediated signals, but also pathways that recruit constitutive c-jun and c-fos expression.
Leukemia 1992 Aug
PMID:BCR/ABL confers growth factor independence upon a murine myeloid cell line. 137 13

A series of flavones has been prepared, which are variously substituted in the 3,3',4',5 and 7 positions with halo-, alkoxy-, nitro-, amino-, hydroxy-, acyloxy- and azido-groups, for evaluation of their cytotoxicity to ANN-1 cells (3T3 murine fibroblasts transformed with the Abelson murine leukaemia virus) which contain a tyrosine kinase. This cytotoxicity was compared to their non-transformed 3T3 counterparts. 3'-Amino-4'-methoxyflavone was the most cytotoxic compound (IC50 = 1.6 microM) and was less inhibitory to the non-transformed parent 3T3 cell line (IC50 = 8 microM). The compound was inactive at 50 microM in assays of the inhibition of the cell-associated Abelson protein tyrosine kinase but inhibited an epidermal growth factor (EGF) protein tyrosine kinase by 42% at 50 microM. Quercetin (3,3',4',5,7-pentahydroxyflavone) was the most potent inhibitor of the Abelson protein tyrosine kinase but showed no selective inhibition of the growth of ANN-1 cells compared to the parent 3T3 cell line. Different structure-activity relationships were observed between the results of the cytotoxicity assays and inhibition of protein tyrosine kinases. Inhibitors of the Abelson protein tyrosine kinase which were competitive with respect to ATP showed different potencies for inhibition of the EGF receptor kinase.
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PMID:Synthesis and biological evaluation of a series of flavones designed as inhibitors of protein tyrosine kinases. 138 29

The v-abl oncogene of Abelson murine leukemia virus (A-MuLV) induces two opposite phenotypes in NIH3T3 cells. In the majority of cells, v-abl causes a growth arrest at the G1 phase of the cell cycle; while in a minority of cells, v-abl abrogates the requirement for growth factors. Using temperature sensitive mutants, it can be demonstrated that v-Abl tyrosine kinase is required for growth inhibition or stimulation. The two phenotypes are not caused by mutations or differences in the expression of v-Abl, but are dependent on the cell context. Two stable subclones of NIH3T3 cells have been isolated that exhibit similar morphology and growth characteristics. However, upon infection with A-MuLV, the 'positive' cells become serum- and anchorage-independent, whereas the 'negative' cells become arrested in G1. The positive phenotype is dominant, shown by cell fusion, and treatment with 5-azacytidine converts the negative cells to the positive phenotype. Activation of v-Abl tyrosine kinase induces the serum-responsive genes in the positive but not in the negative cells. Transactivation of the c-fos promoter by v-Abl in transient assays is also restricted to the positive cells. These results show that v-Abl tyrosine kinase is not an obligatory activator of growth, but requires a permissive cellular context to manifest its mitogenic function.
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PMID:Oncogenic v-Abl tyrosine kinase can inhibit or stimulate growth, depending on the cell context. 139 87

Two sets of mutants of the Abelson murine leukemia virus, generated by linker insertion mutagenesis of a cloned proviral DNA, were tested for their ability to transform bone marrow cultures in vitro. All the viruses retained an intact tyrosine kinase domain and were competent for transformation of NIH3T3 fibroblasts in culture. One series contained 12-bp linker insertions in the regions flanking the kinase domain, and the other contained frameshift mutations that truncated the gene product downstream of the kinase domain. The majority of the 12-bp insertion mutants retained full bone marrow-transforming activity; only one insertion in the SH2 domain showed reduced activity. This mutant suggests that some aspect of the SH2 domain may be more important in transformation of lymphocytes than fibroblasts. In contrast to the first set of mutants, the bone marrow-transforming activity of the majority of the truncation mutants was significantly reduced or completely lost. We conclude that there is a broad requirement for an intact C-terminal domain of the v-abl protein for the transformation of pre-B cells, but that no single part of this domain is critical.
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PMID:Bone marrow-transforming activity of linker insertion mutants of Abelson murine leukemia virus. 143 54

Friend virus induced erythroleukaemia can be conveniently divided into a first stage and a second stage. The first stage results from the mitogenic stimulation of EPO-R by gp55. In the second stage, multiple proviral integrations appear to result in further transformation of the SFFV infected erythroblast to a leukaemogenic state. The first stage results from EPO-R activation. After retroviral entry, mediated through an unknown receptor, and after cDNA synthesis and proviral integration, viral proteins are synthesized. Gp55 binds and activates EPO-R. A small but measurable amount of gp55-EPO-R complex is transported to the cell surface (Casadewall et al, 1991). In the presence of helper virus, the defective SFFV genome is packaged and released for subsequent rounds of infection. During the first stage, erythroblasts proliferate but are not tumorigenic. During the second stage of Friend disease, subsequent infections result in further proviral integrations in the host genome. Some of these integrations result in increased Spi-1 expression, whereas others result in decreased p53 expression. These events appear to account for the leukaemogenic properties of cells at this stage, 4-6 weeks after the initial SFFV infection. The interaction between EPO-R and gp55 persists at this later stage, although its contribution to the malignant phenotype of the MEL cells is not known. The sequence of events during stage 1 and stage 2 does not appear to have absolute requirements. Starting with IL-3 dependent immortalized Ba/F3 cells, which already have some unknown proliferative mutation (Mathey-Prevot et al, 1986), gp55 and EPO-R can subsequently be introduced, resulting in tumorigenicity (Li et al, 1990). The primary focus of this review has been the early mitogenic stage of Friend disease. Several concepts have emerged regarding the interaction between gp55 and EPO-R. The interaction between the polypeptides is highly specific, occurs in the extracytoplasmic regions and the transmembrane region of the polypeptides and occurs within the same cell, not via cell-cell contact. Both EPO and gp55 activate EPO-R, via different binding sites, resulting in increased cellular tyrosine kinase activity. The first stage of Friend disease is an example of how a non-oncogene bearing retrovirus can induce leukaemia. The env gene of the SFFV is not a classical oncogene. It does not appear to be derived from a normal cellular proto-oncogene. The interaction of gp55 and EPO-R therefore supports the "receptor mediated leukaemogenesis" hypothesis (McGrath and Weissman, 1978, 1979).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The interaction of the erythropoietin receptor and gp55. 145 Nov 11

In the present study fresh leukemic cells obtained from 23 patients with acute myeloid leukemia (AML; FAB subtypes: three M1, five M2, two M3, five M4, eight M5) were investigated for the membrane expression of the CD4 molecule by cytofluorimetric analysis with an anti-CD4 monoclonal antibody (mAb). In 15 cases the presence of the CD4 mRNA was also investigated using Northern blot analysis. Membrane expression of the CD4 molecule was demonstrated in 19 out of 23 cases, and it was found to be weaker than in CD4+ lymphocytes and monocytes obtained from normal controls. Full-length CD4 mRNA was detected in 12 out of 15 (80%) cases, and AML cells positive for CD4 mRNA expression also expressed the CD4 antigen. Since the CD4 molecule expressed by T cells is associated with p56lck, a member of the src family of intracellular tyrosine kinases, we investigated whether the CD4 molecule expressed by myeloid blasts is also associated with a tyrosine kinase activity. In vitro kinase assays performed on anti-CD4 immunoprecipitates from lysates of myeloid leukemia cells from four CD4+ cases were negative for the presence of a tyrosine kinase activity. This finding was not due to the lack of expression of members of the src family since we were able to detect at least p60src and p59fyn in myeloid leukemia cells. According to our results, the CD4 molecule seems to belong to the phenotypic repertoire of most AML, irrespective of their FAB subtypes. However, in myeloid blasts this molecule is not associated with a tyrosine kinase activity as it occurs in T lymphocytes.
Leukemia 1992 Dec
PMID:The CD4 molecule belongs to the phenotypic repertoire of most cases of acute myeloid leukemia. 145 71

Chronic myeloid leukaemia (CML) is a generic term that include five apparently distinct entities. The best known form, the classical Ph-positive subtype, accounts for about 90% of all cases of CML. The morphology of its presentation blood film is highly characteristic but is also seen in about half of the remaining 10% of cases, which are Ph-negative. This classical morphological subtype, whether Ph-positive or Ph-negative I describe as 'chronic granulocytic leukaemia' to refer to the exuberant granulocytic proliferation which is its hallmark. This term is often used indiscriminately and interchangeably with 'chronic myeloid leukaemia' and similar terms, just as 'chronic lymphocytic leukaemia' was, until recently, used to cover the chronic lymphoid leukaemias in general, but is now used in a specific sense. Chronic granulocytic leukaemia (CGL), whether Ph-positive or Ph-negative, is almost always BCR-rearranged and associated with the production of a unique 210-kd protein with enhanced tyrosine kinase activity. Most of the remaining cases of Ph-negative CML are examples of either chronic myelomonocytic leukaemia (CMML), a subtype almost as homogeneous as CGL, and characterized in its presentation blood film by the presence of monocytes and neutrophils but few immature granulocytes, or atypical CML (aCML), distinct from and less homogeneous than either CGL or CMML, in which some cases also share features with CGL while others share some with CMML. CMML and aCML do not show BCR rearrangement and are not associated with the production of p210kd. CGL, CMML, and aCML, though characterized on morphological features differ in their clinical features and behaviour, response to treatment and survival.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Haematological differences between chronic granulocytic leukaemia, atypical chronic myeloid leukaemia, and chronic myelomonocytic leukaemia. 149 35

IL-4 has been shown to possess a broader spectrum of biological activities. Recently, anti-tumor activities of IL-4 on malignant tumors including hematopoietic tumors has been revealed in vitro or in vivo. We investigated the effect of recombinant human (rhIL-4) on the in vitro growth of human leukemia cells and demonstrated the inhibitory anti-tumor activity of rhIL-4 on Ph1-positive ALL cells in association with the decreased activity of cellular tyrosine kinase. This finding suggests that the clinical evaluation of rhIL-4 may offer promising therapeutic possibility for patients with Ph1-positive ALL. In this paper, we presented the IL-4-dependent inhibition of Ph1-positive ALL cells and reviewed implications for mechanism of IL-4-dependent inhibition and anti-tumor activities of IL-4.
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PMID:Inhibitory anti-tumor effects of interleukin-4 on Philadelphia chromosome-positive acute lymphocytic leukemia and other hematopoietic malignancies. 149 72

Herbimycin A, a benzoquinoid ansamycin antibiotic, was demonstrated to decrease intracellular phosphorylation by protein tyrosine kinase (PTK). In Philadelphia chromosome (Ph1)-positive leukemias such as chronic myelogenous leukemia (CML) and Ph1-positive acute lymphoblastic leukemia (ALL), both of which express bcr-abl fused gene products (P210bcr-abl or P190bcr-abl protein kinase) with augmented tyrosine kinase activities, herbimycin A markedly inhibited the in vitro growth of the Ph1-positive ALL cells and the leukemic cells derived from CML blast crisis. However, the same dose of herbimycin A did not inhibit in vitro growth of a broad spectrum of Ph1-negative human leukemia cells, and several other protein kinase antagonists also displayed no preferential inhibition. Furthermore, we demonstrated that herbimycin A has an antagonizing effect on the growth of transformed cells by a transfection of retroviral amphotrophic vector expressing P210bcr/abl into a murine interleukin (IL)-3-dependent myeloid FDC-P2 cell line. This inhibition was abrogated by the addition of sulfhydryl compounds, similar to the reaction previously described for Rous sarcoma virus transformation. The inhibitory effect of herbimycin A on the growth of Ph1-positive cells was associated with decreased bcr/abl tyrosine kinase activity, but no decrease of bcr-abl mRNA and protein, suggesting that the inactivation of bcr-abl tyrosine kinase activity by herbimycin A may be induced by its binding to the bcr-abl protein portion that is rich with sulfhydryl groups. The present study indicates that herbimycin A is a beneficial agent for the investigation of the role of the bcr-abl gene in Ph1-positive leukemias and further suggests that the development of agents inhibiting the bcr-abl gene product may offer a new therapeutic potential for Ph1-positive leukemias.
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PMID:Effect of herbimycin A, an antagonist of tyrosine kinase, on bcr/abl oncoprotein-associated cell proliferations: abrogative effect on the transformation of murine hematopoietic cells by transfection of a retroviral vector expressing oncoprotein P210bcr/abl and preferential inhibition on Ph1-positive leukemia cell growth. 151 46


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