RESUMEN
The Janus family of tyrosine kinases (JAK) plays an essential role in development and in coupling cytokine receptors to downstream intracellular signaling events. A t(9;12)(p24;p13) chromosomal translocation in a T cell childhood acute lymphoblastic leukemia patient was characterized and shown to fuse the 3' portion of JAK2 to the 5' region of TEL, a gene encoding a member of the ETS transcription factor family. The TEL-JAK2 fusion protein includes the catalytic domain of JAK2 and the TEL-specific oligomerization domain. TEL-induced oligomerization of TEL-JAK2 resulted in the constitutive activation of its tyrosine kinase activity and conferred cytokine-independent proliferation to the interleukin-3-dependent Ba/F3 hematopoietic cell line.
Asunto(s)
Leucemia-Linfoma de Células T del Adulto/metabolismo , Proteínas de la Leche , Proteínas de Fusión Oncogénica/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas , Proteínas Represoras , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Biopolímeros , División Celular , Línea Celular , Preescolar , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Activación Enzimática , Humanos , Interleucina-3/fisiología , Janus Quinasa 2 , Leucemia-Linfoma de Células T del Adulto/genética , Masculino , Ratones , Datos de Secuencia Molecular , Proteínas de Fusión Oncogénica/química , Proteínas de Fusión Oncogénica/genética , Fosforilación , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas c-ets , Factor de Transcripción STAT5 , Transducción de Señal , Transactivadores/metabolismo , Factores de Transcripción/química , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transfección , Translocación Genética , Proteína ETS de Variante de Translocación 6RESUMEN
The transcription factor hypoxia inducible factor 1 (HIF1), an HIF1alpha-aryl hydrocarbon receptor nuclear translocator (ARNT) dimeric factor, is essential to the cellular response to hypoxia. We described a t(1;12)(q21;p13) chromosomal translocation in human acute myeloblastic leukemia that involves the translocated Ets leukemia (TEL/ETV6) and the ARNT genes and results in the expression of a TEL-ARNT fusion protein. Functional studies show that TEL-ARNT interacts with HIF1alpha and the complex binds to consensus hypoxia response element. In low oxygen tension conditions, the HIF1alpha/TEL-ARNT complex does not activate transcription but exerts a dominant-negative effect on normal HIF1 activity. Differentiation of normal human CD34+ progenitors cells along all the erythrocytic, megakaryocytic and granulocytic pathways was accelerated in low versus high oxygen tension conditions. Murine 32Dcl3 myeloid cells also show accelerated granulocytic differentiation in low oxygen tension in response to granulocyte colony-stimulating factor. Interestingly, stable expression of the TEL-ARNT in 32Dcl3 subclones resulted in impaired HIF1-mediated transcriptional response and inhibition of differentiation enhancement in hypoxic conditions. Taken together, our results underscore the role of oxygen tension in the modulation of normal hematopoietic differentiation, whose targeting can participate in human malignancies.
Asunto(s)
Translocador Nuclear del Receptor de Aril Hidrocarburo/fisiología , Hematopoyesis/genética , Oxígeno/sangre , Proteínas Proto-Oncogénicas c-ets/fisiología , Proteínas Recombinantes de Fusión/fisiología , Proteínas Represoras/fisiología , Animales , Translocador Nuclear del Receptor de Aril Hidrocarburo/genética , Diferenciación Celular/genética , Línea Celular , Células HeLa , Humanos , Ratones , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Represoras/genética , Proteína ETS de Variante de Translocación 6RESUMEN
Most of the translocations affecting the chromosome band 11q23, frequently seen in human acute leukemias, involve a restricted area of the HRX gene. We have characterized two t(1;11)(p32;q11) translocations which fuse the HRX gene to a novel gene, AF-1p on chromosome 1p32, in two myeloid leukemias. The der (11) chromosome expresses the 1368 N-terminal amino acids of HRX, including the AT-hook, snRNP and methyltransferase similarities, fused to almost all the AF-1p product. The predicted wild type AF-1p product is a 98 kDa acidic protein which does not exhibit similarity to the AF-4, AF-9 and ENL gene products. It is highly similar to the murine eps 15 gene product, which encodes a cytoplasmic phosphoprotein. Our data indicate that AF-1p defines another class of genes fused to HRX in 11q23 abnormalities.
Asunto(s)
Proteínas de Unión al Calcio , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 1 , Proteínas de Unión al ADN/genética , Leucemia Monocítica Aguda/genética , Leucemia Mieloide/genética , Fosfoproteínas , Proto-Oncogenes , Factores de Transcripción , Translocación Genética , Proteínas Adaptadoras Transductoras de Señales , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Northern Blotting , Preescolar , Clonación Molecular , Secuencia de Consenso , Femenino , N-Metiltransferasa de Histona-Lisina , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Datos de Secuencia Molecular , Proteína de la Leucemia Mieloide-Linfoide , Reacción en Cadena de la Polimerasa , Mapeo Restrictivo , Dedos de ZincRESUMEN
We have recently described a t(8;14)(q24;q11) translocation which appeared secondarily in a non-established acute T-cell leukaemia and involved the 3' region of c-myc proto-oncogene and the alpha chain of the T-cell receptor gene (TcR-alpha). In order to elucidate the mechanism of the translocation, we have isolated breakpoint regions from normal and recombinant chromosomes. Our results show that the translocation occurred at the 3' end of a V alpha segment in the proximity of recombination signal sequences (5'-heptamer-23bp spacer-nonamer-3'). Interestingly, an inverted heptamer internal to the V alpha segment was found at two nucleotides 5' of the break. Nucleotide sequence analysis also revealed the presence of homologous signal sequences on chromosome 8, suggesting that the recombination enzymatic system played an important role in the generation of the translocation. This hypothesis is supported by the addition of N nucleotides and the loss of only three nucleotides during the rejoining process. These data established the involvement of a V alpha segment and its recombination signals in the mechanisms of t(8;14) translocations in T-cell leukaemias.
Asunto(s)
Cromosomas Humanos Par 14 , Cromosomas Humanos Par 8 , Leucemia/genética , Proteínas Proto-Oncogénicas/genética , Receptores de Antígenos de Linfocitos T/genética , Translocación Genética , Secuencia de Aminoácidos , Secuencia de Bases , Clonación Molecular , ADN de Neoplasias/genética , Genes , Humanos , Datos de Secuencia Molecular , Conformación de Ácido Nucleico , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-myc , Receptores de Antígenos de Linfocitos T alfa-beta , Recombinación Genética , Linfocitos TRESUMEN
The TEL/ETV6 gene is located at 12p13 and is frequently involved in chromosomal translocations in human malignancies usually resulting in the expression of fusion proteins between the amino terminal part of TEL, and either unrelated transcription factors or protein tyrosine kinases. We report here a novel gene named TELB which is located on human chromosomal band 6p21 and encodes a protein highly related to TEL. TELB is widely expressed in different tissues and, similarly to TEL encodes a sequence-specific transcriptional repressor.
Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas de Drosophila , Genes , Leucemia/genética , Proteínas Proto-Oncogénicas , Factores de Transcripción/genética , Secuencia de Aminoácidos , Animales , Linfoma de Burkitt/genética , Cromosomas Humanos Par 6/genética , Cromosomas Humanos Par 6/ultraestructura , Subunidad alfa 2 del Factor de Unión al Sitio Principal , ADN Complementario/genética , ADN de Neoplasias/genética , Proteínas de Unión al ADN/biosíntesis , Drosophila melanogaster/genética , Exones/genética , Etiquetas de Secuencia Expresada , Proteínas del Ojo/genética , Regulación Leucémica de la Expresión Génica , Células HeLa , Humanos , Datos de Secuencia Molecular , Familia de Multigenes , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas c-ets , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Represoras/genética , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Especificidad de la Especie , Factores de Transcripción/biosíntesis , Transcripción Genética , Transfección , Translocación Genética , Proteína ETS de Variante de Translocación 6RESUMEN
Analysis of several cases of t(1:14)(p32;q11) translocation present in 3% of T-cell acute leukemias (T-ALL) has revealed the tal-1 gene. This gene encodes a helix-loop-helix protein. It has been found to be expressed in normal bone marrow and in leukemic T-cell and erythroleukemia cell lines, but not in normal T cells. Recently, a site-specific deletion, tald, renamed tald1 in this paper, has been detected in a high proportion of pediatric T-ALL, which arose by a site-specific DNA recombination between tal-1 and a new locus termed SIL. In this study we searched for structural rearrangements within tal-1 in a panel of 134 non-selected leukemic patients (including 66 with T-ALL). Only 6% of patients with T-ALL harbored the tald1 deletion. A second specific deletion termed tald2 was observed in another 6% of T-ALL patients; it involves another site within tal-1 plus the same site as tald1 in the SIL locus. Similarly to tald1 deletion, tald2 junctions harbor structural characteristics that are reminiscent of aberrant recombinase activity. Moreover, we report a detailed analysis of the tal-1 gene structure. Transcription analysis and in vitro translation data are consistent with the differential expression of several TAL-1 protein species containing the HLH motif but differing in their amino terminus. Taken together, our data indicate that t(1;14) translocations and both tald deletions disrupt the 5' part of the tal-1 gene, placing its entire coding sequences under the control of the regulatory elements of the TCR-delta gene or the SIL gene, both of which are normally expressed in T-cell lineage.
Asunto(s)
Deleción Cromosómica , Leucemia-Linfoma de Células T del Adulto/genética , Translocación Genética/genética , Secuencia de Aminoácidos , Secuencia de Bases , Médula Ósea/metabolismo , Médula Ósea/patología , Médula Ósea/ultraestructura , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 14 , ADN de Neoplasias/genética , ADN de Neoplasias/aislamiento & purificación , Genes Reguladores/genética , Humanos , Leucemia-Linfoma de Células T del Adulto/metabolismo , Leucemia-Linfoma de Células T del Adulto/patología , Datos de Secuencia Molecular , Estructura Molecular , Regiones Promotoras Genéticas/genética , Biosíntesis de Proteínas/genética , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Transcripción Genética/genética , Células Tumorales CultivadasRESUMEN
The human TEL gene is involved in several 12p13 chromosomal abnormalities present in various human hematological malignancies, the most frequent being the t(12;21)(p13;q22), specific for childhood acute lymphoblastic leukemia. The predicted product of TEL harbours an amino acid region similar to the ETS DNA binding domain. We now report the isolation of the murine TEL cDNA and the characterization of the human TEL proteins. Human and murine TEL proteins are particularly homologous within their aminoterminal regions and their ETS domains. TEL proteins are nuclear and display specific DNA binding activity toward classical ETS binding sites. In addition, we show that TEL mRNAs initiate translation at either of the two first inframe ATGs (codon 1 and 43) to encode 50 kDa and 57 kDa TEL proteins. In vivo, each of these primary translational products is modified by multiple phosphorylation events.
Asunto(s)
ADN Complementario/genética , Proteínas de Unión al ADN/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , Proteínas Represoras , Factores de Transcripción/genética , Animales , Secuencia de Bases , Western Blotting , Células COS , Cromosomas Humanos Par 12 , Cromosomas Humanos Par 21 , Clonación Molecular , ADN/metabolismo , ADN Complementario/aislamiento & purificación , Proteínas de Unión al ADN/aislamiento & purificación , Humanos , Hibridación Fluorescente in Situ , Leucemia de Células B/genética , Ratones , Datos de Secuencia Molecular , Proteínas Nucleares/aislamiento & purificación , Fosfoproteínas/aislamiento & purificación , Fosforilación , Proteínas Proto-Oncogénicas c-ets , ARN Mensajero/aislamiento & purificación , Factores de Transcripción/aislamiento & purificación , Translocación Genética , Células Tumorales Cultivadas , Proteína ETS de Variante de Translocación 6RESUMEN
The leukemia-associated TEL-Jak2 fusion protein possesses a constitutive tyrosine kinase activity and transforming properties in hematopoietic cell lines and animal models. In the murine pro-B Ba/F3 cell line, this fusion constitutively activates the Signal Transducer and Activator of Transcription 5 (Stat5) factors and, as a consequence, induces the sustained expression of various Stat5-target genes including the Cytokine Inducible SH2-containing protein (Cis) gene, which codes for a member of the Suppressor of Cytokine Signaling (Socs) protein family. In TEL-Jak2-transformed Ba/F3 cells, we also observed the upregulation of the Socs1 gene, whose product has been reported to negatively regulate the Jak kinase activity. In transient transfection experiments, Socs1 physically interacts with TEL-Jak2 and interferes with the TEL-Jak2-induced phosphorylation and activation of Stat5 factors, probably through the Socs1-induced proteasome-mediated degradation of the fusion protein. Interestingly, TEL-Jak2-expressing Ba/F3 cells were found to be resistant to the anti-proliferative activities of gamma interferon (IFN-gamma) seemingly as a consequence of Socs1 constitutive expression. These results indicate that the Socs1-dependent cytokine feedback loop, although active, is bypassed by the TEL-Jak2 fusion, but may play a role in the leukemogenic process by altering the cytokine responses of the leukemic cells. Our results also suggest that Socs1 plays a role in shutting down the signaling from the normally activated Jak2 kinase by inducing its proteasome-dependent degradation.
Asunto(s)
Proteínas Portadoras/biosíntesis , Citocinas/biosíntesis , Proteínas de Fusión Oncogénica/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas , Proteínas Represoras/biosíntesis , Animales , Linfocitos B/metabolismo , Línea Celular Transformada , Células Cultivadas , Cisteína Endopeptidasas/metabolismo , Regulación Leucémica de la Expresión Génica , Células Madre Hematopoyéticas/metabolismo , Janus Quinasa 2 , Ratones , Complejos Multienzimáticos/metabolismo , Complejo de la Endopetidasa Proteasomal , Unión Proteica , Receptores de Interferón/metabolismo , Transducción de Señal , Proteína 1 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas , Ubiquitinas/metabolismo , Receptor de Interferón gammaRESUMEN
Chromosomal translocations involving the human 12p13 band frequently affect the TEL gene, usually resulting in gene fusion between TEL and genes encoding proteins of various types. The most frequent 12p13 translocation is the t(12;21)(p13;q22), which recombines TEL with the AML1 gene on chromosome 21 and is frequently associated with deletion of the untranslocated TEL allele. Using antisera against different parts of TEL and against the AML1 proteins, we undertook Western blot and immunofluorescence analyses of leukemic samples with and without 12p13 abnormalities. In t(12;21) samples, TEL-AML1 was detected as several protein species in the nuclei, whereas the AML1-TEL protein, was inconsistently expressed. AML1 was found to be expressed but no normal TEL proteins were detected. A survey of the TEL proteins in a panel of human leukemic samples without t(12;21) revealed a variation in the ratio of TEL protein isoforms. We also analysed a leukemic cell line bearing a t(12;22)(p13;q11) that was found to affect the 5' untranslated (UT) region of TEL and to be associated with inactivation of the untranslocated TEL allele. No MN1-TEL fusion could be detected upon RT-PCR analysis, in contrast to the previously investigated t(12;22). Strikingly, extremely low levels of apparently normal TEL proteins, expressed from the translocated allele, were detected by Western blot analysis. These results suggest that the level of TEL expression can be important for leukemogenesis.
Asunto(s)
Cromosomas Humanos Par 12 , Cromosomas Humanos Par 21 , Proteínas de Unión al ADN/metabolismo , Leucemia Mielomonocítica Aguda/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Fusión Oncogénica , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogénicas , Proteínas Represoras , Factores de Transcripción/metabolismo , Adulto , Animales , Niño , Preescolar , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Células HL-60 , Células HeLa , Humanos , Isomerismo , Leucemia Mielomonocítica Aguda/patología , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Proteínas Proto-Oncogénicas c-ets , Conejos , Fracciones Subcelulares , Translocación Genética , Células Tumorales Cultivadas , Proteína ETS de Variante de Translocación 6RESUMEN
The HRX gene has recently been shown to be involved in most of the chromosomal abnormalities of band 11q23 frequently present in human hematological malignancies. Rearrangements are strikingly diverse, but most affect a restricted area of the HRX gene and lead to gene fusion between HRX and a gene located on the partner chromosome. Another kind of HRX alteration seen in human acute leukemia is a partial duplication of the NH2 part of the HRX locus. We have characterized two cases of partial HRX duplication in acute leukemias bearing trisomy 11 as the sole chromosomal abnormality. In one patient analyzed at the genomic level, an Alu repeat was involved within exon 6 but not within intron 1. Splicing of exon 6 to exon 2 was observed in this patient while splicing of exon 8 to exon 2 was observed in the other. Our data indicated that HRX duplication is highly similar to the translocation affecting the HRX locus both in the restricted diversity of the fusion points and the involvement of Alu repeats within the breakpoint cluster region (exon 5 to 10).
Asunto(s)
Anemia Refractaria con Exceso de Blastos/genética , Aberraciones Cromosómicas/genética , Cromosomas Humanos Par 11/genética , Leucemia Mieloide/genética , Leucemia Prolinfocítica/genética , Trisomía , Enfermedad Aguda , Anciano , Secuencia de Bases , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Transcripción GenéticaRESUMEN
The TEL gene is involved in several chromosomal abnormalities of human hematopoietic malignancies. The chromosome 12 breakpoints frequently lie within the fifth intron of the gene, particularly in the most frequent translocation involving TEL, the t(12;21)(p13;q22). In order to search for a peculiar mechanism involved in the genesis of these translocations, we have established the sequence of two t(12;21) and a t(9;12)(q24;p13) breakpoints. Our data do not reveal the involvement of VDJ recombinase activity or Alu sequences but favor the occurrence of staggered breaks and DNA repair activity in the genesis of these translocations.
Asunto(s)
Linfoma de Burkitt/genética , Rotura Cromosómica/genética , Cromosomas Humanos Par 12/genética , Proteínas de Unión al ADN/genética , Leucemia-Linfoma de Células T del Adulto/genética , Proteínas Represoras , Factores de Transcripción/genética , Translocación Genética/genética , Alelos , Elementos Alu/genética , Secuencia de Bases , Niño , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 9/genética , Análisis Mutacional de ADN , ADN Nucleotidiltransferasas/metabolismo , Reparación del ADN/genética , Exones/genética , Humanos , Intrones/genética , Leucemia-Linfoma de Células T del Adulto/patología , Mapeo Físico de Cromosoma , Proteínas Proto-Oncogénicas c-ets , Recurrencia , VDJ Recombinasas , Proteína ETS de Variante de Translocación 6RESUMEN
FISH identified a cryptic t(5;14)(q35;q32) in T acute lymphoblastic leukemia (ALL), whereas it was not observed in B ALL samples. This translocation is present in five out of 23 (22%) children and adolescents with T ALL tested. RanBP17, a gene coding for a member of the importin beta protein family, and Hox11Like2, an orphan homeobox gene were mapped close to the chromosome 5 breakpoints and CTIP2, which is highly expressed during normal T cell differentiation, was localized in the vicinity of the chromosome 14 breakpoints. The Hox11L2 gene was found to be transcriptionally activated as a result of the translocation, probably under the influence of CTIP2 transcriptional regulation elements. These data establish the t(5;14)(q35;q32) as a major abnormality, and Hox11 family member activation as an important pathway in T ALL leukemogenesis.
Asunto(s)
Cromosomas Humanos Par 14 , Cromosomas Humanos Par 5 , Proteínas de Homeodominio/genética , Leucemia-Linfoma de Células T del Adulto/genética , Proteínas Oncogénicas/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocación Genética/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Estudios de Casos y Controles , Transformación Celular Neoplásica , Niño , Preescolar , Rotura Cromosómica , Análisis Citogenético , Femenino , Humanos , Leucemia-Linfoma de Células T del Adulto/etiología , Masculino , Datos de Secuencia Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Proteínas Proto-Oncogénicas , Alineación de Secuencia , Proteína de Unión al GTP ran/genéticaRESUMEN
Toyocamycin (TMC), an adenosine analog has been previously reported to inhibit both number and infectivity of retrovirus particles released by chronically infected cells (Bonar et al., 1970; Riman, 1971; Mauchauffé et al., 1979). We have previously shown that loss of infectivity could result from the incorporation of TMC in place of adenosine in the genomic 35S RNA (Larsen et al., 1979). This phenomenon is likely to impair the structure of the viral genome in such a way that reverse transcriptase cannot properly copy the template. Another consequence of the Toyocamycin action on the retrovirus particles released by analog-treated cells was their reduced content in envelope glycoprotein or gp70 (Mathieu - Mahul et al., 1979). In order to find the origin of this defect, which could also explain the loss of infectivity, viral polypeptides present in the cytoplasm of Toyocamycin-treated cells were analyzed by immunoprecipitation with specific antisera. The results indicated a diminution of the biosynthesis of the envelope glycoprotein and other GAG gene-related polypeptides. However, the gpr85env precursor was normally synthesized and processed into its final products (gp70 + p15E), which accumulated in the cells. These result make it likely that Toyocamycin has no specific effect on the virus replicative process in chronically infected cells but acts by deteriorating cellular functions, which are necessary to virus assembly. Indeed, it was found that a membrane fraction corresponding to smooth endoplasmic reticulum and Golgi apparatus was severely reduced if not totally suppressed in TMC-treated cells.
Asunto(s)
Virus de la Leucemia Murina de Friend/metabolismo , Glicoproteínas/biosíntesis , Ribonucleósidos/farmacología , Toyocamicina/farmacología , Proteínas Virales/biosíntesis , Animales , Línea Celular , Membranas/metabolismo , RatonesRESUMEN
This paper summarizes the results of a study on human breast cancers performed mainly at the Centre René Huguenin in collaboration with other American and French groups, and supported in part by a Grant from the Association pour la Recherche sur le Cancer (ARC) Villejuif. During this work, the following conclusions emerged: c-myc proto-oncogene amplification is a common alteration in ductal invasive tumors, more frequently found in recurrent and metastatic tumors, suggesting a role for c-myc in tumor progression. However, in the current state of our study, it does not appear to be linked to prognosis; parts of the short arm of chromosome 11 are deleted in 20% of tumors resulting in hemizygosity for several genes (c-ha-ras, beta globin, pTH, calcitonin, catalase). These deletions seem to be linked with aggressiveness of tumors; a restriction fragment length polymorphism (RFLP) study of c-ha-ras has shown a significant association of the frequency of rare ha-ras alleles in cancer patients compared to that of normal individuals. Although this result is currently a matter of controversy, further studies must be independently repeated to be conclusive; -- another RFLP was found in c-mos proto-oncogene, which is detected only in patients with breast cancers or other types of tumors. The molecular basis for this RFLP has been elucidated. The significance of this association is unknown.
Asunto(s)
Neoplasias de la Mama/genética , Proto-Oncogenes , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/patología , Deleción Cromosómica , Femenino , Amplificación de Genes , Genes ras , Humanos , Polimorfismo de Longitud del Fragmento de Restricción , Pronóstico , Proto-Oncogenes Mas , Factores de RiesgoAsunto(s)
Cromosomas Humanos Par 14 , Cromosomas Humanos Par 8 , Leucemia Linfoide/genética , Translocación Genética , Secuencia de Bases , Femenino , Antígenos HLA/genética , Humanos , Masculino , Datos de Secuencia Molecular , Receptores de Antígenos de Linfocitos T/genética , Células Tumorales CultivadasAsunto(s)
Adenosina Monofosfato , Polinucleótidos , ARN/aislamiento & purificación , Animales , Secuencia de Bases , Línea Celular , Celulosa , Cromatografía de Afinidad , Gammaretrovirus , Hidrólisis , Radioisótopos de Fósforo , Polinucleótidos/síntesis química , Polirribosomas , ARN/análisis , ARN Mensajero/aislamiento & purificación , ARN Ribosómico , Ratas , Ribonucleasas , UltracentrifugaciónAsunto(s)
Antibióticos Antineoplásicos/farmacología , Virus de la Leucemia Murina de Friend/metabolismo , ARN Viral/metabolismo , Toyocamicina/farmacología , Citoplasma/metabolismo , ADN Viral , Virus de la Leucemia Murina de Friend/efectos de los fármacos , Hibridación de Ácido Nucleico , ARN/metabolismo , Toyocamicina/metabolismoRESUMEN
The presence of a rearrangement of the proto-oncogene c-myc was investigated in the DNA of fresh cells isolated from the blood of two patients with Burkitt's leukemia (L3), and from the node biopsy of a patient with Burkitt's lymphoma. Both samples from the L3 leukemia patients had the characteristic t(8;14) translocation, while the lymphoma specimen presented no abnormality of chromosome 8. Only one of the leukemic DNA's presented a rearranged c-myc pattern, with the breakpoint region located between the first and the second exon. The c-myc pattern of the two other patients appeared normal. The finding of a rearranged c-myc oncogene in fresh cells from a Burkitt's leukemia is direct evidence for the implication of c-myc in the disease whereas most of the rearrangements previously described have been found in cell lines established in culture.
Asunto(s)
Leucemia Linfoide/genética , Translocación Genética , Secuencia de Bases , Linfoma de Burkitt/genética , Cromosomas Humanos 6-12 y X , ADN/genética , Enzimas de Restricción del ADN , Humanos , Hibridación de Ácido Nucleico , Proto-Oncogenes Mas , Proto-OncogenesRESUMEN
The presence of a gp66 closely related to the Friend ecotropic murine leukemia virus gp70 (F-MuLV) has recently been reported (D. Mathieu-Mahul, J. M. Heard, S. Fichelson, S. Gisselbrecht, B. Sola, and C. J. Larsen (1982) virology 119, 59-67). In the present work, characterization of this gp66 was continued. First, immunoprecipitation tests, using cytoplasmic membrane subfractions from one of the myelomonocytic cell lines in which gp66 was first detected, indicated that most of it was associated with rough endoplasmic reticulum. Second, to define the limits of gp66 expression, a variety of hemopoietic cell lines were analyzed for gp66 content. These lines were obtained (a) from various tumors (including erythroleukemias, chloroleukemias, and lymphatic leukemias) induced in susceptible mice by F-MuLV and (b) from long-term bone marrow cultures (LTBMC) infected with F-MuLV. In the latter case, lines of adherent fibroblastoid cells and nonadherent cells with myelomonocytic and mastocytic characteristics were obtained. Although several F-MuLV isolates were used, gp66 was only expressed in myelomonocytic and mastocytic cells. This did not result from in vitro culture conditions as gp66 was also found in fresh cells. These data suggested that a particular processing of the env gene product may exist in both myelomonocytic and mastocytic cell lines. In agreement with this hypothesis, a metabolically unstable gp62 related to MCF gp70 was found in one myelomonocytic cell line expressing MCF virus.
Asunto(s)
Virus de la Leucemia Murina de Friend/genética , Regulación de la Expresión Génica , Leucemia Experimental/microbiología , Leucemia Mieloide/microbiología , Proteínas Virales/biosíntesis , Animales , Adhesión Celular , Línea Celular , Hematopoyesis , Mastocitos , RatonesRESUMEN
Toyocamycin (TMC), an adenosine analog, impairs qualitatively and quantitatively virus production in a cellular system chronically infected by Friend Virus. Viral particles released by cell cultures treated with 0.2 microgram/ml of the drug have lost most of their glycoprotein (gp 70) content. This phenomenon is likely to modify the viral envelope and could explain the loss of infectivity of the virus.