Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In murine leukemia virus-induced myeloid leukemias, insertional mutagenesis of the c-myb locus has been shown to occur frequently. Proto-oncogene activation is achieved in most leukemias by integration of murine leukemia virus upstream of exons 3 or 4 or by integration into exon 9 with consequent truncation of the protein. The present study investigates the effect of ectopic expression of full-length c-myb or c-myb containing amino- or carboxyl-terminal truncations (minus 47 and 248 amino acids, respectively) on granulocyte differentiation in vitro. Recombinant myb retroviruses were used to infect an interleukin 3-dependent progenitor cell line, 32Dcl3, which undergoes terminal differentiation to mature neutrophilic granulocytes in the presence of granulocyte colony-stimulating factor. Overexpression of c-myb did not abrogate the interleukin 3 dependency of the parental cell line. However, cells expressing all forms of c-myb were blocked at an intermediate stage of granulocyte differentiation and continued to proliferate in the presence of granulocyte colony-stimulating factor. After 14 days in medium with granulocyte colony-stimulating factor, myb-expressing cultures predominantly consisted of promyelocytes with some myelocytes and almost undetectable numbers of neutrophilic granulocytes. This suggested that early stages of granulocyte differentiation were not inhibited, a finding that was further supported by the induction of myeloperoxidase, a biochemical marker of promyelocytes. Interestingly, the expression of lactoferrin, known to be a marker of late stages of granulocyte differentiation, was completely inhibited in the cells infected with myb viruses. It was concluded that c-myb expression blocked granulocyte differentiation to the terminal mitotic stages and that deletion of the NH2-terminal 47 amino acids and/or the COOH-terminal 248 amino acids of c-myb neither enhanced nor diminished this effect.
 ...
PMID:Only late, nonmitotic stages of granulocyte differentiation in 32Dcl3 cells are blocked by ectopic expression of murine c-myb and its truncated forms. 753 40

The c-myb protooncogene encodes a highly conserved transcription factor that functions as both an activator and a repressor of transcription. The v-myb oncogenes of E26 leukemia virus and avian myeloblastosis virus encode proteins that are truncated at both the amino and the carboxyl terminus, deleting portions of the c-Myb DNA-binding and negative regulatory domains. This has led to speculation that the deleted regions contain important regulatory sequences. We previously reported that the 42-kDa mitogen-activated protein kinase (p42mapk) phosphorylates chicken and murine c-Myb at multiple sites in the negative regulatory domain in vitro, suggesting that phosphorylation might provide a mechanism to regulate c-Myb function. We now report that three tryptic phosphopeptides derived from in vitro phosphorylated c-Myb comigrate with three tryptic phosphopeptides derived from metabolically labeled c-Myb immunoprecipitated from murine erythroleukemia cells. At least two of these peptides are phosphorylated on serine-528. Replacement of serine-528 with alanine results in a 2- to 7-fold increase in the ability of c-Myb to transactivate a Myb-responsive promoter/reporter gene construct. These findings suggest that phosphorylation serves to regulate c-Myb activity and that loss of this phosphorylation site from the v-Myb proteins may contribute to their transforming potential.
 ...
PMID:Modulation of c-Myb-induced transcription activation by a phosphorylation site near the negative regulatory domain. 760 7

Moloney murine leukemia virus induces myeloid leukemia when inoculated intravenously into pristane-primed adult BALB/c mice. One hundred percent of these tumors show insertional activation of the c-myb proto-oncogene, and reverse transcriptase PCR assays have shown that the c-myb activation could be detected soon after infection. We tested BALB/c and NIH Swiss mice that had been inoculated as newborns with Moloney murine leukemia virus, under which conditions they develop T lymphomas exclusively. Reverse transcriptase-PCR assays indicated that c-myb activations were detectable soon after neonatal infection. However, none of the resulting T lymphomas contained c-myb activations. The implications of these results to the timing of proto-oncogene activations in leukemogenesis and the specificity of proto-oncogene activations for different diseases are discussed.
 ...
PMID:Proviral activation of the c-myb proto-oncogene is detectable in preleukemic mice infected neonatally with Moloney murine leukemia virus but not in resulting end stage T lymphomas. 760 84

Insertional mutagenesis of c-myb by Moloney murine leukemia virus occurs in 100% of promonocytic leukemias (MMLS) induced by the virus. These leukemias, which resemble acute monocytic leukemia-M5 in humans are induced only in mice undergoing a peritoneal chronic inflammatory response. We have found that two leukemia-specific gag-myb mRNAs in MML provide molecular markers for detection of preleukemic cells in hematopoietic tissue in vivo. The two aberrant RNAs result from splicing of gag to either exon 3 or 4 of c-myb, depending on the site of proviral integration. After reverse transcription-PCR with nested primers and hybridization with specific gag-myb junction probes, one cell, having aberrant c-myb message, could be detected in a minimum of 10(5) liver cells or 10(6) spleen or bone-marrow cells. This approach was used to examine hematopoietic tissues of mice after pristane injection to induce inflammation and virus inoculation. Cells with gag-myb mRNAs could be detected as early as 2 weeks after virus inoculation. In mice receiving both pristane and virus, there was evidence of preleukemic cells in 83% of the mice by 3 weeks after virus infection. Furthermore, 100% of the mice were positive for preleukemic cells by 8 weeks, even though only 50% of mice have been shown to succumb to MML (peak time for disease latency is 12-16 weeks). Cells with these aberrant c-myb messages were initially detected in the bone marrow, but during intermediate stages of disease development these cells disseminated to the spleen, liver, and granuloma. At preleukemic times, from 3 to 8 weeks after virus infection, a lower percentage of mice were positive in the group that did not receive pristane compared with mice in the group receiving pristane. However, at 18 weeks, 100% of the mice in the group receiving virus only had evidence of cells expressing gag-myb RNA in their spleens and/or bone marrow; it is of interest that mice inoculated with virus alone never develop MML. This approach for detecting preleukemic cells will now allow the study of mechanisms by which these preleukemic cells progress to a more transformed state and, perhaps, to a more differentiated state.
 ...
PMID:Activation of c-myb is an early bone-marrow event in a murine model for acute promonocytic leukemia. 767 11

Overexpression of c-myc, c-myb and c-fos proto-oncogene has been observed in many leukemia cells. However, a relation between those oncogene expressions and prognosis of the leukemia is not known in Indonesia. In order to elucidate the relation, expression of those oncogenes in leukemia cells from 52 patients in Indonesia was examined by Northern blot analysis and was compared with prognosis of the disease. The leukemia patients who survived for more than 2 years were 37% of the 52 patients. Many of the samples expressed c-myc mRNA (92%). Although strong expression of c-myb and c-fos mRNA was detected in the samples (c-myb expression in 35% of the leukemia cells and c-fos in 52%), those co-expressions with c-myc mRNA did not alter the prognosis. On the contrary, all of the 4 patients suffering from leukemia which did not express c-myc mRNA survived for more than 2 years. Therefore, c-myc expression in leukemia cells may be used as an indicator for deciding prognosis of the leukemia patients in Indonesia.
 ...
PMID:A relation between c-myc expression and prognosis of leukemia patients in Indonesia. 773 3

Retinoic acid (RA) is capable of inducing the differentiation of various myelomonocytic cell lines. During this differentiation process, the levels of c-myb expression decline, suggesting that the RA receptor (RAR) may act in part by down-regulating this proto-oncogene. We have now investigated whether the RAR can also inhibit the function of Myb proteins themselves. We have found that transcriptional activation of a Myb-responsive reporter gene can be inhibited by RA in a human monocytic cell line. This inhibition could not be overcome by the expression of exogenous Myb. The RAR did not interfere with DNA binding by Myb proteins in vitro, suggesting that the functional inhibition occurs at the level of transcriptional activation. To determine the biological relevance of the inhibition of Myb proteins by the RAR, we have used v-myb-transformed monoblasts. These cells differentiate into macrophages in the presence of phorbol ester (tetradecanoyl phorbol acetate [TPA]) but are normally unresponsive to RA treatment. The introduction of an inducible, exogenous RAR alpha into v-myb-transformed monoblasts permitted an RA-dependent differentiation into macrophage-like cells similar to those induced by TPA. These results demonstrate that transformation by v-myb is recessive to RAR alpha and imply that many types of non-RA-responsive leukemia cells may become responsive following the introduction of the RAR.
 ...
PMID:Retinoic acid receptor alpha suppresses transformation by v-myb. 773 32

In BALB/c nu/nu and sublethally irradiated DBA/2 mice, promonocytic leukemia was induced by intravenous inoculation of Friend murine leukemia virus (F-MuLV) strain C57 in conjunction with intraperitoneal injection of pristane. These tumors appear to be identical morphologically to previously reported ones induced by other MuLVs, such as Moloney, amphotropic 4070A, and F-MuLV FB29, which most commonly have provirus integrations in the 5' end of the c-myb locus. Interestingly, 2 of the 16 F-MuLV-induced tumors had viruses integrated in the distal 3' end of c-myb. To determine the precise locations of these integrations, it was necessary to clone sequences encoding the 3' c-myb exons and to prepare a physical map of this region. Exons 10 to 15 were positioned on the map, and it was found that the proviruses in the aforementioned tumors were located within narrow region in the beginning of the large (greater than 11 kb) intron 14. The predicted protein product encoded by the affected alleles is truncated by 38 amino acids. This represents a novel virus integration site which is most likely associated with oncogenic activation of the c-myb gene during leukemogenesis.
 ...
PMID:Novel integration sites at the distal 3' end of the c-myb locus in retrovirus-induced promonocytic leukemias. 774 39

The anthracycline antitumor antibiotic aclarubicin is known to induce granulocytic differentiation in the human myeloid leukemia cell line HL-60. We investigated whether this effect is accompanied by changes in the expression of the protooncogenes c-myc and c-myb. Treatment of HL-60 cells with aclarubicin, 50 nM, caused a rapid decrease in c-myc and c-myb mRNA levels within 1 h and 2 h, respectively. In parallel, we demonstrated a strong induction of superoxide-anion production on day 8 of treatment. The kinetics of the effect of aclarubicin on c-myc and c-myb expression were comparable to those associated with the dimethylsulfoxide-induced granulocytic differentiation in this cell line, or to those observed following a chase with actinomycin D, 4 microM. Since aclarubicin partially inhibited total- and poly(A)(+)-RNA synthesis, this macromolecular synthesis inhibition may be causally related to the decrease in c-myc and c-myb mRNA levels. In contrast, the conventional anthracycline doxorubicin, which did not initiate differentiation, failed to affect c-myc or c-myb mRNA levels even in high cytotoxic concentrations, indicating that the suppression of c-myc and c-myb mRNA levels may be an early differentiation-related effect of aclarubicin. On the other hand, actinomycin D, 12.5 nM, and novobiocin, 300 microM, two other known inducers of granulocytic differentiation in HL-60 cells, did not induce an early decrease in c-myb or c-myc expression. Therefore, the immediate suppression of c-myc and c-myb mRNA levels, apparently, is not an obligatory step in chemically induced myeloid differentiation in HL-60 cells, but the common phenomenon in DMSO- and aclarubicin-induced differentiation.
Leukemia 1995 Jan
PMID:DMSO-like rapid decrease in c-myc and c-myb mRNA levels and induction of differentiation in HL-60 cells by the anthracycline antitumor antibiotic aclarubicin. 784 9

For growth, ML-1 human myeloblastic leukemia cells require insulin-like growth factor 1 together with transferrin, whereas for differentiation they depend upon transforming growth factor beta in combination with transferrin. As shown in this study, growth stimulation is accompanied by c-myb expression, whereas initiation of differentiation results in the cessation of c-myb expression through premature termination of transcription in the first intron of the myb gene. Growth factor-stimulated c-myb elongation was found to correlate with an elevated level of nuclear c-ets-1 protein and with increased binding of this protein to an 18-base pair sequence in intron 1 of the c-myb gene containing the putative regulatory element PEA 3. In contrast, differentiation factor-initiated ML-1 cell maturation was accompanied by a very low level of nuclear c-ets-1 protein, by the inability to detect binding of the protein to the 18-base pair sequence, and by the cessation of c-myb expression. These results show a correlation to exist between c-ets-1 binding to intron 1 of the c-myb gene and c-myb expression. The mechanism underlying this correlation is under further study.
 ...
PMID:Differential binding of nuclear c-ets-1 protein to an intron I fragment of the c-myb gene in growth versus differentiation. 784 25

By genetically manipulating hematopoietic cells of the myeloid lineage, including both normal cells and differentiation inducible leukemic cell lines, evidence was obtained to indicate that myeloid differentiation primary response (MyD) genes and proto-oncogenes, which are known to control cell growth, function as positive and negative regulators of terminal hematopoietic cell differentiation, which is associated with inhibition of cell growth, and, ultimately programmed cell death (apoptosis). Interferon regulatory factor-1 (IRF-1), an MyD gene induced by Interleukin 6 (IL-6) or Leukemia Inhibitory factor (LIF), plays a role in growth inhibition associated with terminal differentiation. Leucine zipper transcription factors of the fos/jun family, also identified as MyD genes, function as positive regulators of hematopoietic cell differentiation, increasing the propensity of myeloblastic leukemia cells to be induced for differentiation in vitro, and reducing the aggressiveness of their leukemic phenotype in vivo. The zinc finger transcription factor EGR-1, an MyD gene specifically induced upon macrophage differentiation, was shown to be essential for and to restrict differentiation along the macrophage lineage. Finally, evidence has been accumulating to indicate that the novel MyD genes--MyD116, MyD118 and gadd45 (a member in the MyD118 gene family)--play a role in growth arrest and apoptosis of hematopoietic cells, as well as other cell types. The proto-oncogenes c-myc and c-myb, known to regulate cellular growth, were shown to function as negative regulators of terminal differentiation. Both c-myc and c-myb are normally expressed in proliferating myeloblasts and suppressed following induction of differentiation. Deregulated and continuous expression of c-myc was shown to block terminal myeloid differentiation at an intermediate stage in the progression from immature blasts to mature macrophages, whereas deregulated and continuous expression of c-myb blocked the terminal differentiation program at the immature myeloblast stage. By manipulating myc function in conditional (differentiation inducible) mutant myeloblastic leukemia cell lines, expressing a chimeric mycer transgene, it was shown that there is a window during myeloid differentiation, after the addition of the differentiation inducer, when the terminal differentiation program switches from being dependent on c-myc suppression to becoming c-myc suppression independent, and where activation of c-myc has no apparent effect on mature macrophages. These myeloblastic leukemia cell lines provide a powerful tool to increase our understanding of the role of c-myc in normal hematopoiesis and in leukemogenesis, while also providing a strategy to clone myc target genes.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Differentiation primary response genes and proto-oncogenes as positive and negative regulators of terminal hematopoietic cell differentiation. 795 Oct 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>