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)

We investigated the effect of recombinant human interleukin-4 (rhIL-4) on the in vitro growth of human leukemia cells in liquid culture and 3H-thymidine incorporation and found inhibitory effects on the growth of leukemic cells from patients with Ph1-positive acute lymphoblastic leukemia (Ph1 ALL) and three Ph1 ALL cell lines. However, no inhibitory effects were seen in Ph1-positive leukemic cell lines derived from patients with chronic myelogenous leukemia in blast crisis and various types of Ph1-negative leukemia cells, including B-lineage leukemia cells. In a flow cytometry assay of IL-4 receptor (IL-4R), all three Ph1-positive ALL cell lines showed the presence of IL-4R on their cell surfaces, and the IL-4-dependent inhibition on the growth of Ph1-positive ALL cells was abrogated by the addition of either monoclonal or polyclonal antibodies against rhIL-4. Other cytokines, including IL-2, IL-3, granulocyte-macrophage colony-stimulating factor (CSF), granulocyte-CSF, and IL-6, showed no inhibitory effects on the growth of Ph1-ALL cells, but tumor necrosis factor-alpha (TNF-alpha) and interferon (IFN)-alpha, -beta, and -gamma displayed slight inhibitory effects in a high concentration. The growth inhibition induced by rhIL-4 in the Ph1-positive ALL cells was not abrogated by the addition of antibodies against either IFN-gamma or TNF-alpha. Furthermore, these cells showed no significant production of IFN-alpha, -beta, or -gamma or TNF-alpha after exposure to rhIL-4, thus indicating that the growth inhibition of Ph1-positive ALL cells by rhIL-4 is not associated with IL-4-stimulating production of these factors. rhIL-4 caused significant inhibition of the tyrosine kinase activity in these Ph1-positive ALL cells, similar to Herbimycin A, an inhibitor of tyrosine kinase that inhibited the tyrosine kinase activity in these cells. Our finding suggests that the clinical evaluation of rhIL-4 may offer promising therapeutic possibilities for patients with Ph1-positive ALL.
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PMID:Inhibitory effect of interleukin-4 on the in vitro growth of Ph1-positive acute lymphoblastic leukemia cells. 188 23

Chronic myelogenous leukemia (CML) is the best understood human cancer. The molecular basis of CML involves activation of a cellular proto-oncogene--ABL. The consequence is to increase tyrosine kinase activity. This results in a marked clonal increase in the myeloid mass. Later on, cellular maturation is blocked and the decrease eventuates in acute leukemia. Abnormalities of other proto-oncogenes or antioncogenes, like P53, may be involved in leukemia progression. Treatment of CML involves chemotherapy and, more recently, interferon. Whether this treatment prolongs survival or increases the likelihood of cure is unknown but either result seems unlikely. Bone marrow transplants which cure about 50% of persons with CML are most effective when performed in chronic phase.
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PMID:Chronic myelogenous leukemia: molecule to man. 189 3

We have isolated a cDNA encoding a novel tyrosine kinase family member, named cyl (consensus tyrosine-lacking kinase), from the K562 human leukemia cell line. The deduced cyl protein lacks signal and transmembrane sequences but contains features of known cytoplasmic tyrosine kinases, including amino-terminal SH3 and SH2 domains. However, having very short amino and carboxy termini, cyl does not seem to belong to any of the previously characterized subfamilies of cytoplasmic tyrosine kinases. Furthermore, cyl lacks the highly conserved tyrosine autophosphorylation site (Y416src) in the tyrosine kinase catalytic domain. The cyl gene is located on human chromosome 15. It is expressed ubiquitously as two independently regulated mRNA species of 2.6 and 3.4 kb in human leukemia cell lines and fetal tissues.
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PMID:cyl encodes a putative cytoplasmic tyrosine kinase lacking the conserved tyrosine autophosphorylation site (Y416src). 194 8

The effects of a ligand regulated neu tyrosine kinase were examined in NIH 3T3 cells. A chimeric construct encoding the human EGF receptor extracellular domain fused to the tyrosine kinase domain of the rat neu cDNA was expressed under the transcriptional control of the Moloney murine leukemia virus LTR promoter. This resulted in higher levels of expression of the chimeric receptor than were previously obtained from the SV40 virus early promoter in the same cells. The chimeric receptor showed strict ligand-dependent tyrosine kinase and signal transducing activities for the induction of growth-regulated biochemical activities and DNA synthesis in resting cells. The ligand-activated cells became morphologically transformed and grew in agar in the presence of EGF and TGF beta as efficiently as did the ligand-independent neu oncogene-transformed cells. Our results establish similarities between the signal pathways of the EGF receptor and the neu tyrosine kinase.
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PMID:Regulation by EGF is maintained in an overexpressed chimeric EGFR/neu receptor tyrosine kinase. 196 20

Avian c-erbB is activated to a leukemia oncogene following truncation of its amino-terminal, ligand-binding domain by retroviral insertion. The insertionally activated transcripts encode protein products that have constitutive tyrosine kinase activity and that can induce erythro-leukemia but not sarcomas. We have found that a single point mutation within the ATP-binding pocket of the tyrosine kinase domain in this truncated molecule can increase the ability of this oncogene to induce anchorage-independent growth of fibroblasts in vitro and fibrosarcoma formation in vivo. Associated with this increased transforming potential is a corresponding increase in the kinase activity of the mutant erbB protein product. The mutation, which converts a valine to isoleucine at position 157 of the insertionally activated c-erbB product, is at a residue that is highly conserved within the protein kinase family. To our knowledge, this is the first demonstration of a point mutation in the ATP-binding pocket that activates a tyrosine kinase.
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PMID:Tissue-specific transformation by epidermal growth factor receptor: a single point mutation within the ATP-binding pocket of the erbB product increases its intrinsic kinase activity and activates its sarcomagenic potential. 197 68

Expression of the 93-kd tyrosine kinase encoded by the human c-fes proto-oncogene (also known as FES) is restricted to mature hematopoietic cells of the granulocytic and monocytic lineages, suggestive of a function essential to normal myeloid differentiation. However, recent studies have shown that c-fes can transform fibroblasts if sufficient levels of gene expression are achieved. These findings indicate that strict regulation of the c-fes gene is critical to normal myeloid development, whereas elevated c-fes expression may contribute to malignant transformation. In the present study, we compared the c-fes messenger RNA (mRNA) levels in leukemia blasts from patients with myeloid or lymphoid leukemia with those of peripheral monocytes from a normal donor with the use of a quantitative ribonuclease protection assay. The presence of c-fes mRNA was readily detected in both acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) cells, but c-fes mRNA was present in low levels or was absent in lymphoid leukemia cells. The leukemia cells of two of five AML patients and four of four CML patients expressed more c-fes mRNA than monocytes from a normal donor, with more than a threefold elevation in the cells of one CML patient. No evidence of amplification or rearrangement of the c-fes gene was detectable by Southern blot analysis of myeloid leukemia DNA, suggesting that the variation in c-fes mRNA levels are related to differences in transcriptional activity and/or message stability. These results indicate that elevated c-fes expression is a common feature of myeloid leukemia cells that could potentially contribute to the leukemia phenotype.
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PMID:Elevated expression of the c-fes proto-oncogene in adult human myeloid leukemia cells in the absence of gene amplification. 198 16

More than 95% of patients with chronic myelogenous leukemia (CML) contain an abnormal chromosome termed the Philadelphia chromosome (Ph1). Ph1 and the resulting BCR-ABL fused genes are markers for this type of leukemia. The product of the fused BCR-ABL genes is a protein of about 2000 amino acids termed P210 BCR-ABL. Although the BCR-ABL protein can be routinely detected in blood cells from blast crisis CML patients by assaying for its activated tyrosine kinase activity, detection of P210 BCR-ABL in early stage CML patients (chronic phase) has not yet been possible (S. A. Maxwell et al., Cancer Res., 47: 1731, 1987). A procedure involving Western blotting with an anti-ABL monoclonal antibody was developed that allows detection of P210 BCR-ABL and P145 ABL in cells from chronic phase and blast crisis CML patients, but as expected only P145 ABL was found in normal white blood cells. Most chronic phase patients also contained one to two ABL proteins with a molecular weight of about 190,000. Interestingly, the ratio of BCR-ABL to ABL proteins increased in four blast crisis patients compared to 18 chronic phase patients. Also, one chronic phase patient analyzed on three separate occasions lacked P210 BCR-ABL and exhibited only the Mr 190,000 form. This assay should also be useful in other leukemias that express altered forms of the ABL protein.
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PMID:Detection of BCR-ABL proteins in blood cells of benign phase chronic myelogenous leukemia patients. 203 43

The T-lymphocyte-specific tyrosine kinase gene, lck, is expressed in T-lymphocyte cell lines, except for several human T-cell leukemia virus type I(HTLV-I)-transformed T-lymphocyte cell lines, which produce HTLV-I. By introducing an lck-expression vector, we found that lck product suppresses gene expression from HTLV-I promoter in a transient assay. Moreover, various other promoters of cellular genes or viruses were found to have their transcriptional activity repressed by lck.
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PMID:lck suppresses gene expression from various promoters including human T-cell leukemia virus type I promoter. 211 90

We established many immunoglobulin-null immature B cell lines transformed by tsOS-59, a temperature-sensitive mutant of Abelson murine leukemia virus. In different cell lines cell growth was depressed and cell differentiation (generation of intracytoplasmic mu-positive cells from Ig- cells) was induced by the shift of culture temperature from low (35 degrees C) to high (39 degrees C). Cell lines were categorized into four groups: (i) temperature sensitive (ts) to both cell growth and differentiation, (ii) ts to cell growth but not to cell differentiation, (iii) ts to cell differentiation but not to cell growth, and (iv) ts to neither cell growth nor differentiation. These results indicated that the depression of cell growth did not necessarily induce cell differentiation, and that cell differentiation was induced regardless of whether cell growth was depressed or not. Furthermore, the results showed that the depression of cell growth and the induction of cell differentiation occurred without the reduction of tyrosine kinase activity of P120gag-abl at high, nonpermissive temperature. Our cell growth and differentiation system described here should provide us with the interesting findings of the relation between B cell growth and differentiation.
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PMID:Unlinked regulation of cell growth and differentiation in immature B cell lines. 211 32

Colony-stimulating factor-1 (CSF-1 or M-CSF) regulates pleiotropic developmental and functional responses of macrophages and their committed bone marrow progenitors and supports the viability of cells of the mononuclear phagocyte lineage. Its actions are mediated through its binding to cell surface CSF-1 receptors (CSF-1R) that exhibit ligand-stimulated tyrosine kinase activity. CSF-1R-induced phosphorylation of intracellular protein substrates initiates a cascade of biochemical reactions that relay signals to the cell nucleus, elicit transcription of CSF-1-responsive genes and culminate in cell division. The actions of the CSF-1R kinase can be interrupted by binding of certain monoclonal antibodies to the extracellular domain of the receptor or by agents which activate protein kinase C and accelerate receptor turnover. CSF-1R is encoded by the c-fms proto-oncogene, and specific genetic alterations, which constitutively activate the receptor kinase, provide sustained signals for cell growth leading to cell transformation. Perturbations in the structure or expression of the c-fms proto-oncogene might therefore contribute to leukemia.
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PMID:Regulation of mononuclear phagocyte proliferation by colony-stimulating factor-1. 215 78


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