Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598766 (leukemogenesis)
 4,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the ras family of proto-oncogenes is supposed to be involved in leukemogenesis by point-mutational activation, we studied the effect of the activated ras gene on the growth of a murine interleukin-3 (IL-3)-dependent cell line, FDC-P2. The human activated c-H-ras gene was transfected into FDC-P2 cells by electroporation using a high-level expression vector, BMGhph, which contains a partial DNA sequence from bovine papillomavirus (BPV) and a hygromycin B (hmB)-resistant gene as a selectable marker. The transformed FDC-P2 cells showed a high incidence of IL-3-independent growth and tumorigenicity in nude mice. These clones did not express or secrete IL-3, suggesting the acquisition of IL-3 independence by a nonautocrine mechanism. The high incidence of autonomous growth may be due to the use of the BMG vector, because (1) the activated ras gene in pBR322 vector (pHs-49) was not so efficient in the induction of IL-3 independence, (2) the c-H-ras genome copies per cell increased in number up to about 50 copies by using the BMG vector, and (3) cotransfection with the activated ras gene and the BPV gene in separate plasmids partly enhanced the incidence of autonomous growth without increasing the copy number of the ras gene compared with transfection with the activated ras gene alone. The present study supports the idea that the activation of ras gene is an important step in malignant transformation of hematopoietic cells and suggests that the BPV gene products may cooperate with ras gene activation probably by affecting the cellular genes that may be involved in multistep leukemogenesis. The BMG vector may be useful to test the transforming ability of oncogenes whose oncogenic potential is relatively low.
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PMID:Acquisition of interleukin-3 independence in FDC-P2 cells after transfection with the activated c-H-ras gene using a bovine papillomavirus-based plasmid vector. 133 32

The activation of protooncogenes (ras, fms and myc genes) by point mutations in hematological malignancies are described in this review. Ras mutations are found in a variety of human malignancies at codon 12, 13, and 61. Generally, N-ras mutations are frequent in hematological malignancies. Fms mutation at codon 301 and 969, which are seen in 10 to 20% cases of AML and MDS, increase tyrosine kinase activity of the fms products. Ras and fms mutations are postulated to influence leukemogenesis at rather early stages. Burkitt lymphomas are characterized by specific chromosomal translocations between c-myc gene and one of the immunoglobulin genes. Furthermore, mutations in the 3' border of the exon 1 of c-myc are frequent, and may play an additional role in pathogenesis of Burkitt lymphoma.
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PMID:[Activation of protooncogenes by point mutations in hematological malignancies]. 151 54

In view of the potential role for ras activation in leukemogenesis, we have screened a number of children with acute non-lymphoblastic leukemia (ANLL) for activating point mutations at codons 12, 13 and 61 of the N-ras proto-oncogene using panels of oligonucleotide probes in conjunction with polymerase chain reaction (PCR) gene amplification. In contrast to the frequent occurrence (approximately 30%) of N-ras mutation reported in adult ANLL, 6 of 46 cases (13%) at the time of diagnosis had N-ras mutations involving codons 12 and 13. In these patients we also determine whether presenting clinical symptoms, cellular pathology, karyotype, or eventual outcome distinguished them from the ras-negative group. N-ras activation tended to be associated with a higher white blood cell count at diagnosis (mean of 225,000/microliters vs 91,000/microliters) and fewer remissions obtained after 28 days of therapy (3/6, 50% vs 24/32, 75%). It is possible that activation of N-ras oncogene may be involved in the progression of some cases of childhood ANLL.
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PMID:N-ras gene mutations in childhood acute non-lymphoblastic leukemia. 192 53

N-ras gene activation occurs via single base substitutions in codons 12, 13, and 61. We have developed a rapid screening method, termed allele specific restriction analysis (ASRA), for detection of N-ras mutations at these three critical codons in acute myeloid leukemia (AML). Patient DNA samples are amplified by the polymerase chain reaction (PCR) by using primers that induce restriction sites in normal but not mutant N-ras alleles. We have used ASRA to identify 5 point mutations in four out of 19 patients at initial presentation of de novo AML. Three patients had one mutation at codon 12, 13, or 61 respectively, while a fourth patient had concurrent mutations at codons 12 and 13. N-ras mutations were more common in patients over 65 years of age (P less than 0.04), but did not correlate with FAB classification, attainment of complete remission, disease free survival, or overall survival. ASRA can also be used as the first step in a more sensitive approach to the detection of ras mutations. When ASRA was combined with allele specific oligonucleotide (ASO) hybridization the sensitivity and specificity of these assays were increased. This allowed identification of additional low level mutations in two patients. The data presented here constitute the first complete analysis of N-ras mutations in leukemia by ASRA and include the first identification of three concurrent N-ras mutations in a single leukemic patient. By facilitating sensitive sequential studies, ASRA should contribute to our understanding of the role of N-ras mutations in leukemogenesis.
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PMID:Analysis of N-ras gene mutations in acute myeloid leukemia by allele specific restriction analysis. 195 19

We investigated N-ras activation in childhood acute lymphoblastic leukemia (dALL) by the polymerase chain reaction (PCR) and the oligonucleotide hybridization method. The frequency of point-mutation of the N-ras gene was not high (2 of 15), and one positive case who relapsed was analyzed in detail. Although N-ras gene activation was detected at both onset and relapse, the mutation sites were different. At onset, Gly (GGT) was changed to Ser (AGT) at codon 12, and at relapse, Gly (GGT) to Asp (GAT) was observed at the same codon. In addition, the DNA at relapse showed a remarkably higher transforming activity than the DNA at onset on two independent recipient cell lines. The identical cell surface phenotype and the same rearrangement patterns of both the immunoglobulin (Ig) heavy chain and T-cell receptor (TCR) gamma chain genes indicated that the leukemic cells at onset and those at relapse were derived from the same precursor cell. Therefore, this case supports the concept that ras activation is not the event initiating leukemogenesis, but may be involved in leukemic progression.
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PMID:Alteration of N-ras gene mutation after relapse in acute lymphoblastic leukemia. 196 19

32D C13(G) is an interleukin 3(IL3)-dependent non-tumorigenic murine hematopoietic cell line which undergoes terminal differentiation into granulocytes when exposed to granulocytic colony stimulating factor (G-CSF). Infections of 32D C13(G) cells with either Kirsten rat sarcoma virus or Balb murine sarcoma virus, both containing a v-ras oncogene, generates clones that can permanently grow in G-CSF without differentiation. 32D-Ki-ras cells show a heterogeneous morphology ranging from the promyelocytic to the myelocytic stage of differentiation, and express high levels of both myeloperoxidase (MPO) and lactoferrin (LF) mRNA. 32D-Ha-ras cells show a more immature phenotype and express MPO but no LF mRNA. The apparent differentiation block of both 32D Ki-ras and 32D Ha ras can be reversed by treatment with the chemical inducers retinoic acid, sodium butyrate or dimethylsulphoxide, which leads to terminal differentiation into granulocytes. When 32D-Ki-ras and 32D-Ha-ras cells are cultured in medium containing IL-3 they become adherent and express some monocyte-macrophage markers. Upon prolonged exposure to IL3, 32D-Ki-ras, but not 32D-Ha-ras, resume suspension growth. Both 32D-Ki-ras and 32D-Ha-ras rapidly die if grown in chemically defined medium in the absence of any growth factor and are non-tumorigenic in immunosuppressed mice. These findings indicate that ras activation may interfere with the normal response to growth and differentiation factors in cells of the granulocytic lineage. These alterations may represent a critical, although non-sufficient, step in leukemogenesis.
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PMID:Alteration of growth and differentiation factors response by Kirsten and Harvey sarcoma viruses in the IL-3-dependent murine hematopoietic cell line 32D C13(G). 246 24

Our broad aims are to delineate oncogenic events in lymphoid neoplasia and to search for genes that control haemopoietic differentiation. To explore lymphoid neoplasia, we have constructed transgenic mice bearing different oncogenes coupled to the immunoglobulin heavy chain enhancer (E mu), to force expression within lymphocytes. The prototype E mu-myc mice are highly prone to lymphomagenesis, generating pre-B and B cell lymphomas. In their pre-neoplastic phase, E mu-myc expression perturbs B cell development, accelerating the accumulation of pre-B cells. Lymphomagenesis requires additional oncogenic events, such as ras activation, and can be reconstructed in vitro. Transgenic mice bearing the N-myc, N-ras, v-abl and bcr-v-abl oncogenes are also prone to tumours. A striking demonstration that oncogenes can perturb lineage commitment has emerged. Introduction of the v-raf gene into cloned E mu-myc transgenic B cells frequently led to a switch in haemopoietic lineage: the cells became macrophages. Two clues to this remarkable metamorphosis are that the macrophage lines produce a myeloid growth factor and most bear marked karyotypic alterations, perhaps indicating that the balance between a few critical lineage control genes has been disturbed. To explore the hypothesis that genes encoding the DNA-binding homeo box domain participate in haemopoiesis, cDNA libraries from haemopoietic sources were screened, and several distinct homeo box cDNAs were isolated. They revealed a complex pattern of expression among haemopoietic cell lines. These genes are attractive candidates for regulators of haemopoietic differentiation.
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PMID:Lymphoid neoplasia and the control of haemopoietic differentiation. 256 45

While activation of the protooncogene c-N-ras is observed regularly in acute myelogenous leukemia, amplification of c-myc in AML cells or derived lines is uncommon. In particular, concurrent ras/myc activation, which has been shown to be critical in several elegant models of malignancy, has been demonstrated in a very small number of human tumors or derivative cell lines. A cell line, RED-3, is described which was derived from cells of a patient with aggressive acute leukemia which exhibits many markers of lineage infidelity. DNA from this cell line contains an activating point mutation of c-N-ras as well as 20-30-fold amplification of c-myc. After HL-60, this is the second example of ras/myc activation in AML derived cells and demonstrates that this lesion is not unique to HL-60. Rather, it may be important in leukemogenesis in a small proportion of AML patients.
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PMID:c-myc amplification coexistent with activating N-ras point mutation in the biphenotypic leukemic cell line RED-3. 265 2

We have screened a large series of primary human leukemias for activating point mutations at codons 12, 13 and 61 of the N-ras and K-ras proto-oncogenes and at codons 12 and 61 of the H-ras proto-oncogene by using panels of oligonucleotide probes in conjunction with polymerase chain reaction gene amplification. 13 of 64 (20%) acute lymphoblastic leukemia cases had ras gene mutations mostly involving N-ras codon 12/13, G-A (gly-asp) transitions. Consistent with previous studies, a comparable pattern and frequency of ras mutation was found amongst 45 cases of acute myeloid leukemia and myelodysplasia. By contrast, of 30 cases of mature B cell chronic lymphocytic leukemia, only one in terminal prolymphocytoid transformation harboured an activated ras gene. These patterns of mutation did not correlate with ras gene methylation state, a finding not obviously compatible with differential gene accessibility being an important determinant of ras gene mutation patterns in leukemogenesis. Our data suggest that activated ras is more important in tumourigenesis of immature than mature lymphocyte progenitors whilst similar mechanisms associated with aetiology and/or target cell susceptibility probably underlie the similar patterns of ras gene mutations seen in acute leukemias of both myeloid and lymphoid cell lineages.
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PMID:Analysis of ras gene mutations and methylation state in human leukemias. 266 44

The murine long-term bone marrow culture system which can support the almost infinite growth of normal B lineage cells was used to establish the experimental model for spontaneous B cell leukemogenesis. At the early phase of the culture, B cell differentiation with diversification of immunoglobulin genes was induced. However, the culture was finally captured by a single B cell clone which had the fastest growth rate. The B cell clone was strictly dependent on stromal cells for in vitro growth and did not generate leukemia when injected into syngenic mice. After up to a year of maintenance of the clone, the leukemic cells developed spontaneously. The leukemic cell line isolated in vivo retained the stromal cell-dependency, and further in vitro selection process was required to establish the stromal cell-independent leukemic cell line. These leukemic cell lines highly expressed c-myc and Ha-ras genes regardless of stromal cell-dependency. We detected no chromosomal aberrations accompanied with the process of leukemic transformation. Our results suggest that spontaneous neoplastic transformation of B cells in long-term bone marrow culture occurs in a stepwise manner.
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PMID:Stepwise progression of B cell malignancy occurred in a bone marrow stromal cell-dependent pre-B cell clone. 278 22


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