RESUMEN
Although it has been clear for more than a century that the chromosomes in human tumour cells are often wildly abnormal, there has been controversy as to whether these changes are primary events or are merely secondary epiphenomena that reflect the genomic instability of these cells. The prevailing view for most of this period was that chromosome changes were secondary events. What happened to change this view?
Asunto(s)
Neoplasias/genética , Translocación Genética , Transformación Celular Neoplásica/genética , Citogenética/historia , Predicción , Historia del Siglo XIX , Historia del Siglo XX , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/historia , Cromosoma FiladelfiaRESUMEN
Cytogenetic analysis provides critical information of diagnostic and prognostic importance for haematological malignancies. In fact, the identification of recurring chromosomal breakpoints in leukaemias and lymphomas has expedited the cloning of genes whose translocation-induced deregulation causes malignant transformation. The pillar of karyotype analysis rests on chromosome banding techniques that have the distinct advantage that the entire genome can be analysed in a single experiment. However, poorly spread or contracted metaphase chromosomes and highly rearranged karyotypes with numerous marker chromosomes, common in tumour cell preparations, are often difficult to interpret unambiguously and subtle chromosomal aberrations, in particular the exchange of telomeric chromatin or small insertions remain elusive. Fluorescence in situ hybridization (FISH) overcomes some of these limitations, but is mainly utilized to confirm the presence of previously characterized or suspected aberrations. We have developed a novel approach, termed spectral karyotyping or SKY based on the hybridization of 24 fluorescently labelled chromosome painting probes that allows the simultaneous and differential colour display of all human chromosomes. We have used SKY to complement conventional banding techniques in haematological malignancies by analysing 15 cases with unidentified chromosome aberrations. In all instances SKY provided additional cytogenetic information, including the identification of marker chromosomes, the detection of subtle chromosomal translocations and the clarification of complex chromosomal rearrangements. Thus, SKY in combination with standard chromosome banding allows the characterization of chromosomal aberrations in leukaemia with unprecedented accuracy.
Asunto(s)
Aberraciones Cromosómicas/genética , Hibridación Fluorescente in Situ/métodos , Cariotipificación/métodos , Leucemia/genética , Linfoma/genética , Adulto , Anciano , Preescolar , Aberraciones Cromosómicas/diagnóstico , Bandeo Cromosómico , Trastornos de los Cromosomas , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Optical rectification is demonstrated in (110)-cut ZnGeP(2) (ZGP) providing broadband terahertz (THz) generation. The source is compared to both GaP and GaAs over a wavelength range of 1150 nm to 1600 nm and peak-intensity range of 0.5 GW/cm(2) to 40 GW/cm(2). ZGP peak-to-peak field amplitude is larger than in the other materials due to either lower nonlinear absorption or larger second-order nonlinearity. This material is well suited for broadband THz generation across a wide range of infrared excitation wavelengths.
RESUMEN
Specific consistent chromosome translocations are regularly observed in certain human leukemias and lymphomas. For the myeloid leukemias, the constant recombinants are: the long arm of 9 to chromosome 22 in chronic myeloid leukemia, the long arm of 21 to chromosome 8 in acute myeloblastic leukemia, and the long arm of 17 to chromosome 15 in acute promyelocytic leukemia. Three related translocations are seen in Burkitt lymphoma and B cell acute lymphocytic leukemia; in each one, chromosome 8 is involved with chromosome 2, 14, or 22. Analysis of a complex translocation affecting chromosomes 8 and 14 indicates that the translocation of chromosome 8 to chromosome 14 is the critical constant rearrangement. The analysis of the DNA at the translocation sites of these chromosomes, rather than the reciprocal of each translocation, appears to be the most productive focus for initial study. The various immunoglobulin loci are located in chromosomes 2, 14, and 22, the chromosomes regularly involved in translocations in Burkitt lymphoma and B cell acute lymphocytic leukemia.
Asunto(s)
Aberraciones Cromosómicas , Inmunoglobulinas/genética , Leucemia/genética , Linfoma/genética , Cromosomas Humanos 13-15 , Cromosomas Humanos 16-18 , Cromosomas Humanos 21-22 e Y , Cromosomas Humanos 6-12 y X , Genes , Humanos , Translocación GenéticaRESUMEN
Gene probes for interferons alpha and beta 1 and v-ets were hybridized to metaphase chromosomes from three patients with acute monocytic leukemia who had a chromosomal translocation, t(9;11)(p22;q23). The break in the short arm of chromosome 9 split the interferon genes, and the interferon-beta 1 gene was translocated to chromosome 11. The c-ets-1 gene was translocated from chromosome 11 to the short arm of chromosome 9 adjacent to the interferon genes. No DNA rearrangement was observed when these probes were hybridized to genomic DNA from leukemic cells of two of the patients. The results suggest that the juxtaposition of the interferon and c-ets-1 genes may be involved in the pathogenesis of human monocytic leukemia.
Asunto(s)
Interferón Tipo I/genética , Leucemia Monocítica Aguda/genética , Proto-Oncogenes , Translocación Genética , Mapeo Cromosómico , Cromosomas Humanos 6-12 y X , ADN de Neoplasias/genética , Humanos , Hibridación de Ácido NucleicoRESUMEN
The human c-mos proto-oncogene is located on chromosome 8 at band q22, close to the breakpoint in the t(8;21) (q22;q22) chromosome rearrangement. This translocation is associated with acute myeloblastic leukemia, subgroup M2. The c-myc gene, another proto-oncogene, has been mapped to 8q24. The breakpoint at 8q22 separates these genes, as determined by in situ hybridization of c-mos and c-myc probes. The c-mos gene remains on the 8q-chromosome and the c-myc gene is translocated to the 21q+ chromosome. Southern blot analysis of DNA from bone marrow cells of four patients with this translocation showed no rearrangement of c-mos.
Asunto(s)
Cromosomas Humanos 21-22 e Y , Cromosomas Humanos 6-12 y X , Leucemia Mieloide Aguda/genética , Oncogenes , Translocación Genética , Mapeo Cromosómico , Humanos , Hibridación de Ácido Nucleico , Proto-Oncogenes MasRESUMEN
By in situ chromosomal hybridization, the GM-CSF and FMS genes were localized to human chromosome 5 at bands q23 to q31, and at band 5q33, respectively. These genes encode proteins involved in the regulation of hematopoiesis, and are located within a chromosome region frequently deleted in patients with neoplastic myeloid disorders. Both genes were deleted in the 5q-chromosome from bone marrow cells of two patients with refractory anemia and a del(5)(q15q33.3). The GM-CSF gene alone was deleted in a third patient with acute nonlymphocytic leukemia (ANLL) who has a smaller deletion, del(5)(q22q33.1). Leukemia cells from a fourth patient who has ANLL and does not have a del(5q), but who has a rearranged chromosome 5 that is missing bands q31.3 to q33.1 [ins(21;5)(q22;q31.3q33.1)] were used to sublocalize these genes; both genes were present on the rearranged chromosome 5. Thus, the deletion of one or both of these genes may be important in the pathogenesis of myelodysplastic syndromes or of ANLL.
Asunto(s)
Enfermedades de la Médula Ósea/genética , Deleción Cromosómica , Cromosomas Humanos 4-5 , Factores Estimulantes de Colonias/genética , Proto-Oncogenes , Anemia Refractaria/genética , Mapeo Cromosómico , Humanos , Leucemia/genéticaRESUMEN
We have isolated cDNAs representing a previously unrecognized human gene that apparently encodes a protein-tyrosine kinase. We have designated the gene as HCK (hemopoietic cell kinase) because its expression is prominent in the lymphoid and myeloid lineages of hemopoiesis. Expression in granulocytic and monocytic leukemia cells increases after the cells have been induced to differentiate. The 57-kilodalton protein encoded by HCK resembles the product of the proto-oncogene c-src and is therefore likely to be a peripheral membrane protein. HCK is located on human chromosome 20 at bands q11-12, a region that is affected by interstitial deletions in some acute myeloid leukemias and myeloproliferative disorders. Our findings add to the diversity of protein-tyrosine kinases that may serve specialized functions in hemopoietic cells, and they raise the possibility that damage to HCK may contribute to the pathogenesis of some human leukemias.
Asunto(s)
Cromosomas Humanos Par 20 , Genes , Leucocitos/enzimología , Proteínas Tirosina Quinasas/genética , Secuencia de Aminoácidos , Linfocitos B/enzimología , Secuencia de Bases , Línea Celular , Bandeo Cromosómico , Mapeo Cromosómico , ADN/aislamiento & purificación , Humanos , Leucemia/enzimología , Leucemia/genética , Peso Molecular , Proto-Oncogenes Mas , Proto-Oncogenes , Homología de Secuencia de Ácido NucleicoRESUMEN
TEL is a member of the Ets family of transcription factors which are frequently rearranged in human leukemia. The mechanism of TEL-mediated transformation, however, is unknown. We report the cloning and characterization of a chromosomal translocation associated with acute myeloid leukemia which fuses TEL to the ABL tyrosine kinase. The TEL-ABL fusion confers growth factor-independent growth to the marine hematopoietic cell line Ba/F3 and transforms Rat-1 fibroblasts and primary murine bone marrow cells. TEL-ABL is constitutively tyrosine phosphorylated and localizes to the cytoskeleton. A TEL-ABL mutant containing an ABL kinase-inactivating mutation is not constitutively phosphorylated and is nontransforming but retains cytoskeletal localization. However, constitutive phosphorylation, cytoskeletal localization, and transformation are all dependent upon a highly conserved region of TEL termed the helix-loop-helix (HLH) domain. TEL-ABL formed HLH-dependent homo-oligomers in vitro, a process critical for tyrosine kinase activation. These experiments suggest that oligomerization of TEL-ABL mediated by the TEL HLH domain is required for tyrosine kinase activation, cytoskeletal localization, and transformation. These data also suggest that oligomerization of Ets proteins through the highly conserved HLH domain may represent a previously unrecognized phenomenon.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Leucemia Mieloide/metabolismo , Proteínas Proto-Oncogénicas c-abl/metabolismo , Proteínas Represoras , Factores de Transcripción/metabolismo , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Secuencia de Bases , Mapeo Cromosómico , Cromosomas Humanos Par 12 , Proteínas del Citoesqueleto/metabolismo , Cartilla de ADN/química , Regulación Neoplásica de la Expresión Génica , Secuencias Hélice-Asa-Hélice , Humanos , Masculino , Datos de Secuencia Molecular , Fosfoproteínas/metabolismo , Unión Proteica , Proteínas Proto-Oncogénicas c-ets , ARN Mensajero/genética , ARN Neoplásico/genética , Proteínas Recombinantes de Fusión , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Translocación Genética , Proteína ETS de Variante de Translocación 6Asunto(s)
Proteínas de Unión al ADN/genética , Leucemia/genética , Proto-Oncogenes , Factores de Transcripción , Translocación Genética , Enfermedad Aguda , Preescolar , Enfermedades en Gemelos , Femenino , Sangre Fetal , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Recién Nacido , Proteína de la Leucemia Mieloide-Linfoide , Reacción en Cadena de la Polimerasa , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Embarazo , Efectos Tardíos de la Exposición PrenatalRESUMEN
Complete data regarding age, sex, karyotype, and French-American-British Cooperative Group classification were available for 239 unselected patients with acute nonlymphocytic leukemia. Of these, 128 were classified as having acute myeloblastic leukemia (M1 or M2); within the acute myeloblastic leukemia group, 83 (65%) of the patients were chromosomally abnormal. Except for 16 patients with a t(8;21), the percentage of patients with an abnormal karyotype increased with age, particularly above the age of 50 years. Besides the patients with t(8;21), there were 29 patients with loss of part or all of chromosomes 5 and/or 7, 11 patients with +8, and 27 patients with other abnormalities. Of 70 patients with acute myelomonocytic leukemia (M4), on the other hand, 28 (40%) were chromosomally abnormal, only three had loss of chromosomes 5 or 7, one was -7, +8, and our were +8, whereas 20 had other abnormalities. This difference may reflect different etiological factors in these two types of leukemia.
Asunto(s)
Aberraciones Cromosómicas/clasificación , Leucemia/clasificación , Adolescente , Adulto , Factores de Edad , Anciano , Niño , Preescolar , Trastornos de los Cromosomas , Cromosomas Humanos 21-22 e Y , Cromosomas Humanos 4-5 , Cromosomas Humanos 6-12 y X , Femenino , Humanos , Fragmentos Fab de Inmunoglobulinas , Lactante , Cariotipificación , Leucemia/ultraestructura , Leucemia Mieloide Aguda/clasificación , Masculino , Persona de Mediana Edad , Factores SexualesRESUMEN
An interstitial deletion of the short arm of a chromosome 11 was found in Wilms' tumor cells of a patient without aniridia. The chromosomes in her peripheral blood lymphocytes were normal. The karyotype of the tumor cells is similar to that reported for the somatic cells of patients with aniridia-Wilms' tumor association. We showed that the same cytogenetic change as that seen in patients with this condition, namely, an interstitial deletion of 11p13, can occur in patients without aniridia as a mutation that is confined to tumor cells.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos 6-12 y X/ultraestructura , Tumor de Wilms/genética , Preescolar , Femenino , Humanos , Enfermedades del Iris/complicaciones , Enfermedades del Iris/genética , Cariotipificación , Linfocitos/ultraestructura , Tumor de Wilms/complicacionesRESUMEN
DNA-based cytophotometry was used to analyze metaphase chromosomes in four patients with chronic myelogenous leukemia. In three of these patients, both Philadelphia chromosome (Ph1)-positive and Ph1-negative cells were measured. On the basis of these three patients, the characteristic 9q+/22q- translocation of chronic myelogenous leukemia involves the net transfer of 0.325% of the autosomal genome; there is no evidence of net gain or loss of DNA (apart from duplication of the Ph1 chromosome in one patient), and no significant difference is found in the amount of DNA transferred in different patients. Significant differences are found among patients in the derived Chromosomes 9 and the Ph1 chromosomes and are ascribed to preexisting variations in the Ph1-negative cells of these patients. There is no evidence in these patients of any further cytogenetic lesion associated with chronic myelogenous leukemia.
Asunto(s)
Cromosomas Humanos 21-22 e Y , Cromosomas Humanos 6-12 y X , ADN de Neoplasias/análisis , Leucemia Mieloide/genética , Translocación Genética , Adolescente , Adulto , Cromosomas Humanos , Femenino , Humanos , Leucemia Mieloide/análisis , Masculino , Metafase , Persona de Mediana EdadRESUMEN
The karyotype of nine of 11 Wilms' tumors was successfully analyzed using chromosome banding techniques. Peripheral lymphocytes had a normal karyotype in all six analyzed cases. Cultured cells from one tumor had a normal karyotype; however, they appeared to be fibroblasts. A chromosome 11 deletion, del(11)(p13p14), similar to that seen in patients with sporadic aniridia, was found as the sole abnormality in cells from one tumor. Abnormalities of chromosome 1 resulting in trisomy for the long arm (q21-q31) were found in five cases. Two of them had a translocation involving 1q and 16q, although the breakpoints in each chromosome appeared to differ in the two cases. Two patients had an isochromosome of the long arm, i(1q), and a fifth case had a duplication of the long arm as a result of karyotypic evolution. Chromosome 16 abnormalities were found in three cases, resulting in the partial monosomy of the long arm, sharing q22 as a common deletion. The same three cases also had trisomy 1q due to an unbalanced translocation of 1q or an i(1q). Trisomy for both chromosomes 9 and 12 were present in three cases. Two patients each had whole or partial trisomy of chromosomes 6, 7, 8, 17, and 18. Our data show that although an 11p deletion can occur as a mutation confined to tumor cells, the most common changes are trisomy for 1q, and less often a deletion of 16q.
Asunto(s)
Aberraciones Cromosómicas , Trastornos de los Cromosomas , Neoplasias Renales/genética , Tumor de Wilms/genética , Adolescente , Adulto , Bandeo Cromosómico , Femenino , Humanos , Cariotipificación , Masculino , Translocación GenéticaRESUMEN
DNA cytophotometry was used to quantify the chromosomal alterations in the bone marrow and blood of three patients with nonspecific myeloid disorders. All patients possessed a population of cells with a morphologically abnormal chromosome 20, del(20)(qll). In two of the patients, the abnormal chromosome 20 showed nearly identical DNA measurements with a net loss of 0.37% of the total autosomal DNA in one patient and 0.38% in the second. The third patient had a net loss of only 0.25% of the autosomal DNA. Analysis of the DNA content of the long arm and short arm of the abnormal No. 20 indicated that all three cases had chromosomal material added to the short arm (0.10 to 0.14% of the autosomal DNA). About 0.50% of the autosomal DNA was deleted from the long arm in two of the patients; only 0.35% of the autosomal DNA was deleted from the long arm in the third case. Within the limit of resolution, there is no evidence that the material lost has been translocated intact to another chromosome. The origin of the 20q- chromosome as the result of an incomplete pericentric inversion is suggested.
Asunto(s)
Enfermedades de la Médula Ósea/genética , Deleción Cromosómica , Cromosomas Humanos 19-20 , ADN de Neoplasias/análisis , Anciano , Anemia Sideroblástica/genética , Enfermedades de la Médula Ósea/metabolismo , Femenino , Humanos , Masculino , Métodos , Persona de Mediana Edad , Policitemia Vera/genéticaRESUMEN
We studied the clinical and karyotypic features of 50 patients with acute lymphoblastic leukemia, including 33 American and 17 Japanese patients, at two institutions. Clonal chromosome abnormalities were found in 39 of the 50 patients (78%) at diagnosis. Eleven patients had diploidy (N patients). Among the 39 aneuploid patients, 17 had pseudodiploidy (A1 patients), eight had hyperdiploidy with 47 to 49 chromosomes (A2 patients), nine had hyperdiploidy with 50 to 59 chromosomes (A3 patients), and five had other chromosome abnormalities. Of 14 patients whose chromosomes were also studied at relapse, eight had karyotypic progression, five had abnormalities identical or similar to those observed at diagnosis, and one had a change of karyotype from diploidy to aneuploidy. The median age and the median WBC of A1 patients were higher than those of any other group of patients, although one-third of the patients had WBC below 20 x 10(3)/microliters, and they often had leukemic cells of T-cell or B-cell lineage. The A2 patients were relatively old and tended to have higher WBC. The N patients were relatively young and tended to have low WBC, although these tendencies were not as marked as those in A3 patients. The A3 patients had longer survival times than the A1 (p = 0.003) or A2 (p = 0.002) patients. Also, N patients had longer survival times than A1 (p = 0.03) or A2 (p = 0.05) patients. The difference in survival times between A3 and N patients was not significant. Our study demonstrated that the karyotype is correlated with survival and with other recognized prognostic factors. However, in some A1 and A2 patients, the karyotype was a more reliable factor in indicating a poor prognosis than was the WBC or age.
Asunto(s)
Aberraciones Cromosómicas , Cariotipificación , Leucemia Linfoide/diagnóstico , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Leucemia Linfoide/genética , Leucemia Linfoide/mortalidad , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
Karyotypes were analyzed by routine Giemsa and quinacrine fluorescence for 16 patients with acute lymphocytic leukemia [ten adults (18 to 51 years) and six children (3 to 15 years)]. Four patients had received previous therapy, but all 16 had active disease when they were first studied. Eight patients (five untreated) had a normal karyotype initially; however, three of these developed a chromosomal abnormality during relapse. Eight patients had a chromosomal abnormality in their initial samples. Each of the 11 patients had different abnormalities. All chromosomes except Nos. 3, 5, 15, 16, and Y were involved in the various aneuploidies. One patient had a Ph1 chromosome due to a translocation with No. 21: t(21;22)(q22;q11). A patient with B-cell acute lymphocytic leukemia had a 14q+ marker in addition to other abnormalities. The median survival of patients with initially normal karyotypes may be longer than that of patients whose karyotypes are abnormal initially.
Asunto(s)
Aberraciones Cromosómicas , Leucemia Linfoide/genética , Enfermedad Aguda , Adolescente , Adulto , Antineoplásicos/uso terapéutico , Niño , Preescolar , Cromosomas Humanos 21-22 e Y , Ensayos Clínicos como Asunto , Femenino , Humanos , Leucemia/genética , Leucemia Linfoide/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Recurrencia , Remisión Espontánea , Factores de TiempoRESUMEN
Previous studies have suggested that structural abnormalities involving the short arm of chromosome 9 are frequently associated with gliomas. The alpha-, beta-, and omega-interferon (IFNA, IFNB1, and IFNW, respectively) and the methylthioadenosine phosphorylase (MTAP) genes have been mapped to the short arm of chromosome 9, band p22. Homozygous deletions of these genes have been reported in many leukemia- and glioma-derived cell lines. In this report, we present a detailed analysis of partial and complete homozygous or hemizygous deletions of DNA sequences on 9p in human cell lines and primary tumor samples of glioma patients. Ten of 15 (67%) glioma-derived cell lines had hemizygous or homozygous deletion of IFN genes or rearrangement of sequences around these genes, while 13 of 35 (37%) primary glioma tumor samples had hemizygous (8 tumors) or homozygous (5 tumors) deletion of the IFN genes. The shortest region of overlap of these deletions maps in the interval between the centromeric end of the IFN gene cluster and the MTAP gene. In the cell lines and primary tumors examined, these gross genomic alterations were seen only in association with high grade or recurrent gliomas. Our observations confirm that loss of DNA sequences on 9p, particularly the IFN genes, occurs at a significant frequency in gliomas, and may represent an important step in the progression of these tumors. These results are consistent with a model of tumorigenesis in which the development or progression of cancer involves the loss or inactivation of a gene or several genes that normally act to suppress tumorigenesis. One such gene may be located on 9p; this gene may be closely linked to the IFN genes. Nevertheless, loss of the IFN genes, when it occurs, may play an additional role in the progression of these tumors.
Asunto(s)
Neoplasias Encefálicas/genética , Deleción Cromosómica , Cromosomas Humanos Par 9 , Glioma/genética , Reordenamiento Génico , Humanos , Cariotipificación , Mapeo Restrictivo , Células Tumorales CultivadasRESUMEN
We analyzed the karyotype of 27 B-cell lymphomas of human origin that developed in mice with severe combined immunodeficiency disease following the injection of peripheral blood leukocytes from Epstein-Barr virus-seropositive donors. Three tumors had clonal abnormalities detected with conventional techniques, 2 had trisomy 11, and 1 had a del(6)(q21q25). One other tumor had trisomy 11 detected with fluorescence in situ hybridization. Twelve tumors had a normal karyotype, 11 tumors had nonclonal abnormalities (which included trisomy 9 or 12 in 3 or 2 tumors, respectively), and one tumor had a karyotype of 92,XXXX(75%)/46,XX(25%) by conventional cytogenetic analysis. Trisomy for chromosomes, 9, 11, and 12 are recurring abnormalities that have been observed in lymphomas associated with an immunocompromised state. Clonal or nonclonal abnormalities were observed in 8 of 11 tumors derived from 3 donors whose peripheral lymphocytes induced a high incidence of tumors in mice with severe combined immunodeficiency disease compared with a clonal abnormality and 2 nonclonal abnormal cells in 2 of 5 tumors derived from 3 donors whose lymphocytes induced an intermediate to low incidence. These observations suggest an association between a higher incidence of karyotypically abnormal cells in lymphomas and the increased tumorigenic potential of the lymphocytes that induced these tumors.