RESUMEN
Fluorescence in situ hybridization (FISH) studies were performed in three cases of acute lymphoblastic leukemia (ALL) with marker chromosomes to analyze the contribution of chromosome 21 in these markers. FISH with a chromosome 21 painting probe confirmed that chromosome 21 was involved in all three cases. FISH with YAC probes showed that the number of extra copies varied according to their location on chromosome 21. Attention was focused on the AML1 gene, which was present as five copies in most of the cells exhibiting the marker chromosomes. As controls, 11 cases of childhood ALL were studied with PAC probes covering AML1. The results agreed with the banded karyotypes in 10 patients. FISH uncovered a clone with four copies of AML1 which were only observed by FISH analysis of interphase nuclei in one patient. No point mutation was detected in exons 3-5, encoding the runt domain of AML1, in the three cases, suggesting an oncogenic role of wild-type AML1 amplification.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 21/genética , Proteínas de Unión al ADN/genética , Amplificación de Genes/genética , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogénicas , Factores de Transcripción/genética , Adolescente , Niño , Preescolar , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Análisis Mutacional de ADN , Femenino , Humanos , Cariotipificación , MasculinoRESUMEN
A patient with acute myeloblastic leukemia (AML) and karyotypic abnormality mimicking t(8;21) is reported. Because of the uncommon morphology of blasts for AML with t(8;21), and absence of AML1-ETO fusion in the RT-PCR analysis, fluorescence in situ hybridization (FISH) was applied to precise the abnormality. FISH revealed a complex rearrangement involving chromosomes 7, 21 and 8, and involvement of the AML1 gene without evidence of AML1-ETO fusion. This case of unusual AML illustrates the necessity of collecting all hematologic, cytogenetic, and eventual FISH and RT-PCR data to analyse genetic rearrangements in leukemic patients.
Asunto(s)
Aberraciones Cromosómicas , Trastornos de los Cromosomas , Cromosomas Humanos Par 21 , Cromosomas Humanos Par 8 , Leucemia Mieloide Aguda/genética , Translocación Genética , Adulto , Aberraciones Cromosómicas/genética , Mapeo Cromosómico , Cromosomas Humanos Par 7 , Femenino , Humanos , Hibridación Fluorescente in Situ , CariotipificaciónRESUMEN
Cytogenetic study of a young child with acute megakaryocytic leukaemia (AML-M7) has shown a karyotype with 49-50 chromosomes with one and two acquired extra chromosomes 21. Fluorescence in situ hybridization detected a minor clone with translocation t(1;21) and loss of a part of chromosome band 1p36. Trisomy and polysomy 21 are not uncommon in AML-M7. A more systematic search for chromosome 21 rearrangements in AML-M7 using FISH techniques is proposed.
Asunto(s)
Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 21/genética , Síndrome de Down , Leucemia Megacarioblástica Aguda/genética , Translocación Genética/genética , Médula Ósea/patología , Médula Ósea/ultraestructura , Aberraciones Cromosómicas/genética , Bandeo Cromosómico , Análisis Citogenético , Humanos , Hibridación Fluorescente in Situ/métodos , Lactante , Cariotipificación , MasculinoRESUMEN
Cytogenetic and fluorescence in situ hybridization studies have shown the presence of telomeric repeats in translocation present in three patients with hematopoietic malignancies. One had jumping translocations, involving 1q12 and 2q, 16p, and 19q. These sequences were detected by FISH only in derivative chromosomes t(1;16) and t(1;19) in the first patient, and t(1;7) in the second. They were not seen in derivative t(1;2) and t(7;8), respectively. Interstitial telomeric sequences were observed in der(2)t(1;2) in about half of the metaphases in the third patient. The instability of interstitial telomeric DNA repeats in translocations is shown by the present findings. Moreover it supports the hypothesis that the presence of interstitial telomere repeats is not sufficient to make it functional.
Asunto(s)
Neoplasias Hematológicas/genética , Telómero/genética , Translocación Genética , Anciano , Anciano de 80 o más Años , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 16 , Cromosomas Humanos Par 19 , Cromosomas Humanos Par 2 , Femenino , Humanos , Cariotipificación , Masculino , Secuencias Repetitivas de Ácidos Nucleicos/genéticaAsunto(s)
Cromosomas Humanos Par 16 , Cromosomas Humanos Par 21 , Leucemia Mieloide/genética , Proteínas de Fusión Oncogénica/genética , Factores de Transcripción/genética , Translocación Genética/genética , Enfermedad Aguda , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Femenino , Humanos , Cariotipificación , Datos de Secuencia MolecularRESUMEN
The TEL/ETV6 gene is located at 12p13 and encodes a member of the ETS family of transcription factors. Translocated ETS leukemia (TEL) 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 have characterized a t(1;12)(q21;p13) translocation in an acute myeloblastic leukemia (AML-M2). At the protein level, the untranslocated TEL copy and, as a result of the t(1;12) translocation, a fusion protein between TEL and essentially all of aryl hydrocarbon receptor nuclear translocator (ARNT) are expressed. The involvement of ARNT in human leukemogenesis has not been previously described. The ARNT protein belongs to a subfamily of the "basic region helix-loop-helix" (bHLH) protein that shares an additional region of similarity called the PAS (Per, ARNT, SIM) domain. ARNT is the central partner of several heterodimeric transcription factors, including those containing the aryl hydrocarbon (dioxin) receptor (AhR) and the hypoxia-inducible factor 1alpha (HIF1alpha). Our results show that the TEL-ARNT fusion protein is the crucial product of the translocation and suggest that interference with the activity of AhR or HIF1alpha can contribute to leukemogenesis.
Asunto(s)
Cromosomas Humanos Par 12 , Cromosomas Humanos Par 1 , Proteínas de Unión al ADN/genética , Leucemia Mieloide Aguda/genética , Receptores de Hidrocarburo de Aril , Proteínas Represoras , Factores de Transcripción/genética , Translocación Genética , Fusión Artificial Génica , Translocador Nuclear del Receptor de Aril Hidrocarburo , Preescolar , Humanos , Masculino , Proteínas Proto-Oncogénicas c-ets , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína ETS de Variante de Translocación 6RESUMEN
Using fluorescence in situ hybridization analysis, breakpoints involving the long arm of chromosome 1 (1q) were localized in 36 patients with various hematopoietic disorders and rearrangements of the proximal part of 1q, as ascertained with banding techniques. The breakpoint was localized within the satellite II (sat II) domain in 14 patients with various abnormalities, between the sat II domain and the BCL9 locus in eight, between the BCL9 and ARNT loci in two, between sat II and ARNT in two others, and distal to ARNT in seven. A dicentric chromosome 1 was present in two patients. A high incidence of heterochromatin heteromorphism of chromosome 1 was present in this series. Two recurrent translocations were identified, t(1;2)(q12;q37) in three patients suffering from three different acute leukemia subtypes, and t(1;16)(q12;q24) in two patients with different diseases. Two patients had jumping translocations. Most of the rearrangements of 1q were secondary abnormalities, included in complex karyotypes. The roles of methylation, interactions with the proteins interfering with heterochromatin and possible gene silencing due to heterochromatin rearrangements are discussed.
Asunto(s)
Cromosomas Humanos Par 1 , ADN Satélite , Reordenamiento Génico , Hibridación Fluorescente in Situ , Translocación Genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , RecurrenciaRESUMEN
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
Cytogenetic and fluorescence in situ hybridization (FISH) analysis of 10 patients with various hematopoietic malignancies revealed the presence of dicentric chromosomes or pericentric chromosome rearrangements. Dicentrics were only ascertained by FISH studies in six patients. Two types of pericentric chromosome rearrangements have been observed: 'classical' dicentrics with two clearly separated centromeric regions, and more unusual rearrangements with a breakpoint within the centromeric or heterochromatic area, but outside the alphoid domain. FISH analysis of partial chromosome 1 q duplications present in three Burkitt lymphoma cell lines confirmed the partial involvement of the non-alphoid centromeric domain in the duplicated chromosome segment. The incidence of centromeric and pericentromeric rearrangements in hematopoietic malignancies may be higher than hitherto admitted. The chromosomal localization of these rearrangements suggests several mechanisms possibly involved in the malignant process and deserves more systematic study.
Asunto(s)
Aberraciones Cromosómicas , Neoplasias Hematológicas/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Masculino , Persona de Mediana Edad , Células Tumorales CultivadasRESUMEN
Two patients with acute myeloid leukemia (AML-M7 and AML-M4) and trisomy 10 as the sole chromosome abnormality are reported. In the first patient, all karyotypes were abnormal. A karyotypically normal cell population was present in the second patient and the trisomic cells were less numerous than the normal ones at diagnosis. A review of the literature shows the rarity of isolated trisomy 10 in hematopoietic disorders and the diversity of the involved diseases. Moreover, in some patients, the trisomic cell population was less numerous than the normal one. These data are discussed in relation with the hypothesis that cells with trisomy 10 can belong to nonmalignant clones, at least in some cases, as previously shown for trisomy 7 in other conditions.
Asunto(s)
Cromosomas Humanos Par 10 , Leucemia Megacarioblástica Aguda/genética , Leucemia Mielomonocítica Aguda/genética , Trisomía , Anciano , Femenino , Humanos , Cariotipificación , MasculinoRESUMEN
The MLL gene, located on chromosome band 11q23 is fused to different partner genes as a result of various chromosomal translocations in hematopoietic malignancies. A t(1;11) (q21;q23) resulting in a MLL-AF1q fusion gene has previously been reported. Cytogenetic studies on six cases are reported, including one three-way translocation. FISH analysis using a YAC encompassing the MLL gene and a YAC encompassing the AF1q locus showed splitting in three cases and two patients, respectively. PCR analysis of two cases confirmed that AF1q is specifically associated with t(1;11)(q21;q23). The MLL-AF1q fusion mRNA was similar to that previously described in one case and involved MLL exon 7 in the other. This study confirms the specific involvement of AF1q in t(1;11) (q21;q23)-positive acute leukemia with monocytic involvement.