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)

High level expression of the nm23-H1 gene, which encodes for a nucleoside diphosphate kinase, has been found to correlate with diminished metastasis in some tumors but not in others. We have previously identified the protein product of the nm23-H1 gene in two-dimensional electrophoretic gels and have designated it p19/nm23. In neuroblastoma, higher levels of p19/nm23, which are associated with amplification of the N-myc oncogene, large tumor mass, and metastasis, were observed in advanced stage tumors compared with limited stage disease. Because of the variable expression of nm23-H1 in different tumors, we have investigated the relationship between amounts of the protein and cell proliferation. The levels of p19/nm23 were compared between resting and mitotically stimulated normal human PBLs and in leukemia cells. The amount of p19/nm23 increased in normal lymphocytes in response to mitotic stimulation and paralleled the increase in DNA synthesis. In leukemia cells obtained from patients with different subtypes of acute leukemia, p19/nm23 levels were also increased relative to resting normal lymphocytes. Treatment of mitotically stimulated lymphocytes with cyclosporin, which inhibits proliferation, blocked the increase in p19/nm23; treatment of the leukemia cell line HL-60 with dimethylsulfoxide, which induces terminal differentiation, resulted in diminished levels of p19/nm23. Our data therefore provide evidence that nm23-H1 expression is related to cell proliferative activity.
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PMID:Proliferation-related expression of p19/nm23 nucleoside diphosphate kinase. 131 21

Mouse plasmacytomas induced by pristane oil alone, or in combination with Abelson murine leukemia virus (A-MuLV), regularly carry one of three alternative chromosomal translocations that juxtapose c-myc to immunoglobulin heavy- or light-chain loci. E mu-c-myc transgenic mice develop translocation-free plasmacytomas after induction by pristane oil and/or A-MuLV [Sugiyama, H., Silva, S., Wang, Y., Weber, G., Babonits, M., Rosen, A., Wiener, F. & Klein, G. (1990). Int. J. Cancer, 46, 845-852]. In order to test whether another member of the myc family, N-myc, could play a similar role as c-myc, we treated E mu-N-myc transgenic mice with pristane and helper-free A-MuLV. Of 20 mice that received a single pristane injection followed by A-MuLV, 17 developed plasmacytomas with a mean latency period of 54 +/- 20 days. In a corresponding group that only received a single pristane injection, five out of six transgenic mice developed plasmacytomas with a mean latency period of 142 +/- 32 days. However, after three monthly injections of pristane, all 15 transgenic mice developed plasmacytomas with a mean latency period of 128 +/- 20 days. All plasmacytomas expressed the N-myc transgene, while none of them expressed either c-myc or endogenous N-myc. None of the tumors carried the usual plasmacytoma-associated translocations.
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PMID:Functional homology between N-myc and c-myc in murine plasmacytomagenesis: plasmacytoma development in N-myc transgenic mice. 137 20

Tremendous advances in our understanding of acute leukemia have been made through the development of new technologies and close collaboration between immunologists, molecular biologists, and clinical oncologists. These technological advances have included the development of monoclonal antibodies (MoAb) reactive with surface antigens on leukemic cells which can help confirm the lineage and diagnosis of acute leukemia. More importantly, MoAb in conjunction with morphology and cytochemical stains have led to the identification of FAB-MO and the more common recognition of FAB-M7. MoAbs have also helped define prognostic groups, e.g., T-cell leukemia, mature B-cell leukemia, and rare groups such as CD7+ AML. However, the greatest advances in our understanding of acute leukemia has occurred with the application of genetic techniques. Disregulation of genes responsible for normal growth and differentiation initiates the molecular events that lead to the transformation and proliferation of cells recognized clinically as leukemia. Non-random cytogenetic abnormalities apparently contribute to this gene disregulation and specific abnormalities are associated with clinically important subgroups. In acute lymphoblastic leukemia (ALL), the t(9;22), t(1;19), and t(4;11) appear to have a poor prognosis. In acute myeloblastic leukemia (AML), -7/7q-;-5/5q-, 11q23 abnormalities have poor outcomes while t(15;17) and in some series t(9;11), t(8;21), and inv(16) have a good response to therapy. Molecular studies of somatic cell (immunoglobulin and T-cell receptor) gene rearrangements have assisted in the diagnosis and classification of ALL. The application of the polymerase chain reaction technique to specific gene rearrangements has provided a useful approach to minimal residual disease. Specific gene activation (N-myc, evi-1) or fusion genes such as the alpha retinoic acid receptor (alpha RAR) and pml have been identified as the specific cause of some cases of leukemia. The cloning of specific chromosomal breakpoints identified in leukemia (as has been done for CML) will result in specific probes which can be used to make the diagnosis rapidly at the molecular level. Because of the tremendous number of recent developments, this paper will focus only on major developments that will soon have a clinical impact.
Leukemia 1992 Nov
PMID:Pathology and immunology of acute leukemia. 143 16

MuLV-integration sites were analyzed on seventeen thymic leukemia cell lines which have been established from spontaneous thymic leukemias in AKR mice and bone marrow chimeras. Three proviral integration sites were identified; near c-myc, N-myc and pim-1. Among them the integrations near the N-myc were analyzed. Two cell lines from AKR and a cell line from [(BALB/c x B6) F1-->AKR] bone marrow chimera contained the proviral integration near N-myc. In all three cell lines the integration of the provirus was found 18 to 20 bp downstream of the translational termination codon. The partial sequence analysis of the integrated LTR cell line established from AKR thymic lymphomas was the same as AKV. In contrast, the LTR integrated in a cell line from a bone marrow chimera was different from that of MuLV so far reported.
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PMID:[Activation of N-myc gene in leukemia cell lines derived from spontaneous murine lymphomas]. 148 82

Transgenic mice bearing a mutant, activated N-ras oncogene directed to express within hematopoietic cells by an immunoglobulin enhancer (E mu) sporadically develop T-cell lymphomas and non-lymphoid tumors that may be of macrophage origin. To identify genes that can collaborate with N-ras in hematopoietic neoplasia, Moloney murine leukemia virus was used as an insertional mutagen. Infection of newborn E mu-N-ras mice with the virus greatly accelerated tumorigenesis, and nearly all the tumors proved to be T-cell lymphomas. Their variable surface phenotype (CD4+CD8-, CD4+CD8+ and CD4-CD8-) suggested that cells at several stages of T-cell development were susceptible to tumorigenesis. Southern blot analysis revealed that 68% of the tumors bore a proviral insert 5' to the c-myc gene, while 13% had an insert within the 3' untranslated region of the N-myc gene. Insertion was associated with elevated expression of these genes. Hence, activation of a myc gene appears to be the dominant pathway to tumorigenesis by insertional mutagenesis in lymphoid cells expressing a mutant ras gene. However, since many of the tumors were not transplantable, even the partnership of myc and ras may not suffice for full lymphoid malignancy.
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PMID:Retroviral infection accelerates T lymphomagenesis in E mu-N-ras transgenic mice by activating c-myc or N-myc. 157 Jan 58

N-myc expression has been reported in neuroblastoma, retinoblastoma and small cell lung carcinoma. Increased expression associated with gene amplification in neuroblastoma correlates with disease stage and prognosis. N-myc expression has been observed in diverse murine tissues during early stages of development with loss of expression in later stages. Abelson murine leukemia virus (A-MuLV)-transformed pre-B cells express N-myc, whereas mature B cells do not. To determine whether human B-lymphocyte precursors also have increased N-myc expression, we extracted DNA and RNA from representative cell lines, prepared Southern and Northern blots and examined them with the N-myc probe, pNB-1. RNA from the following B-cell developmental stages were examined. One null, 1 pre-pre-B, 3 pre-B (including pre-B-lymphoblastic leukemia, a poor prognostic category) and 5 mature B. Neuroblastoma cells and tissues served as positive controls; negative controls included human muscle, placenta, epithelial cell lines, monocytic, promyelocytic, and T-cell lines. N-myc expression was detected in neuroblastoma cells, but in none of the mature human B or B-lymphocyte precursor cells. Additional immunocytochemical studies performed for N-myc nuclear protein likewise failed to detect this gene product. We conclude that human pre-B cells, unlike murine B-cell precursors, do not express increased levels of N-myc RNA. Expression of this oncogene in human neoplastic B cells does not appear to correlate with developmental stage or prognostic group.
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PMID:Human B-lymphocyte precursors do not express the N-myc gene. 157 Oct 96

Transgenic mice that contain the L-myc gene under the control of the immunoglobulin heavy-chain enhancer (E mu) express the transgene preferentially in T cells, develop thymic hyperplasia and are predisposed to T-cell lymphomas. An analogous E mu N-myc transgene is expressed preferentially in pre-B and B cells and provokes the development of B-cell neoplasias. Animals with an E mu pim-1 construct express the transgene in both B and T cells, but succumb to T-cell lymphomas. Complementation of the E mu N- and L-myc transgenic mice by breeding with E mu pim-1 animals leads to much more rapid development and a dramatically higher incidence of lymphoid malignancies, but the lineage specificity prescribed by the E mu N- and L-myc transgenes is maintained. The different oncogenic potential of myc genes is illustrated by the average latency period of tumor manifestation in double transgenics. Whereas c-myc/pim-1 animals develop pre-B-cell leukemia prenatally, the mean latency period for N-myc/pim-1 and L-myc/pim-1 mice is 36 and 94 days respectively. The N- and L-myc transgenes are expressed at high levels in tumors from double transgenic mice, but expression of the endogenous c- and N-myc genes is undetectable, directly implicating the myc transgenes in the tumor formation process.
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PMID:E mu N- and E mu L-myc cooperate with E mu pim-1 to generate lymphoid tumors at high frequency in double-transgenic mice. 165 5

Among 18 thymic leukemia cell lines which have been established from spontaneous thymic lymphomas in AKR mice as well as in bone marrow chimeras which were constructed by transplanting allogeneic bone marrow cells into irradiated AKR mice, three proviral integration sites were identified; near c-myc, N-myc and pim-1 loci. No integration site specific for chimeric leukemia cell lines was found. In three thymic leukemia cell lines which contained rearranged N-myc genes, insertions of long terminal repeats (LTRs) of murine leukemia viruses were detected at 18 or 20 bp downstream of the translational termination codon. These results demonstrate that the 3' region of the N-myc gene is one of the integration targets for murine leukemia viruses in spontaneous thymic lymphomas. In these three cell lines, N-myc mRNA was stably transcribed and transcription of c-myc mRNA was down-regulated. The integrated murine leukemia viruses in AKR thymic leukemia were most likely AKV, though the DNA sequence of the LTR inserted in the genome of a leukemic cell line from [(BALB/c x B6)F1----AKR], CAK20, was different from LTRs of murine leukemia viruses so far reported.
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PMID:Provirus integration at the 3' region of N-myc in cell lines established from thymic lymphomas spontaneously formed in AKR mice and a [(BALB/c x B6)F1----AKR] bone marrow chimera. 190 Aug 22

The myc proto-oncogenes encode nuclear phosphoproteins, which are believed to participate in the control of cell proliferation and differentiation. Deregulated expression of c-myc has been implicated in several human hematopoietic malignancies. We have studied the expression and mRNA processing of human L-myc, N-myc, and c-myc genes in a panel of human leukemias, leukemia cell lines, and normal hematopoietic cells. L-myc mRNA was expressed in three acute myeloid leukemias (AML) studied and in several myeloid leukemia cell lines. Only low expression levels were observed in adult bone marrow and in fetal spleen and thymus. The K562 and Dami leukemia cell lines showed a unique pattern of L-myc mRNA processing, with approximately 40% of L-myc mRNA lacking exon III and intron I. N-myc was expressed in five of six AML cases studied, in one of nine acute lymphocytic leukemia (ALL) cases, and in several leukemia cell lines, while c-myc mRNA was detected in all leukemias and leukemia cell lines studied. Coexpression of all three myc genes was observed in Dami and MOLT-4 cell lines and in two AMLs, and either L-myc or N-myc was coexpressed with c-myc in several other cases. These results show that in addition to c-myc, the L-myc and N-myc genes are expressed in some human leukemias and leukemia cell lines, and suggest a lack of mutually exclusive cross-regulation of the myc genes in human leukemia cells.
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PMID:Expression of L-myc and N-myc proto-oncogenes in human leukemias and leukemia cell lines. 195 86

Transgenic mouse lines carrying the N-myc oncogene deregulated by the immunoglobulin heavy-chain enhancer spontaneously develop B-lymphoid tumors (R. Dildrop, A. Ma, K. Zimmerman, E. Hsu, A. Tesfaye, R. DePinho, and F. W. Alt, EMBO J. 8:1121-1128, 1989; H. Rosenbaum, E. Webb, J. M. Adams, S. Cory, and A. W. Harris, EMBO J. 8:749-755). Permanent cell lines derived from these tumors (E mu-N-myc cell lines) express extremely high levels of the N-myc transgene but little or no detectable endogenous N-myc or c-myc. We have employed nuclear run-on assays to show that down-regulation of endogenous N- and c-myc expression occurs at the transcriptional level. To determine whether the lack of endogenous myc gene transcription is a direct effect of high-level N-myc transgene expression, we have generated Abelson murine leukemia virus (A-MuLV)-transformed cell lines from prelymphomatous E mu-N-myc mice (A-MuLV/E mu-N-myc cell lines). Although these A-MuLV/E mu-N-myc lines express very high levels of the N-myc transgene, they continue to transcribe the endogenous c-myc gene. These findings demonstrate that high-level N-myc gene expression alone does not necessarily lead to down-regulation of endogenous myc gene expression and suggest that events associated with transformation by N-myc may be critical to this process.
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PMID:Mechanism of endogenous myc gene down-regulation in E mu-N-myc tumors. 198 38


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