Asunto(s)
Proteínas de Ciclo Celular/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Niño , Femenino , Haplotipos , N-Metiltransferasa de Histona-Lisina , Humanos , Hibridación Fluorescente in Situ , LactanteRESUMEN
Chromosomal rearrangements of the human MLL gene are a hallmark for aggressive (high-risk) pediatric, adult and therapy-associated acute leukemias. These patients need to be identified in order to subject these patients to appropriate therapy regimen. A recently developed long-distance inverse PCR method was applied to genomic DNA isolated from individual acute leukemia patients in order to identify chromosomal rearrangements of the human MLL gene. We present data of the molecular characterization of 414 samples obtained from 272 pediatric and 142 adult leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) was determined and several new TPGs were identified. The combined data of our study and published data revealed a total of 87 different MLL rearrangements of which 51 TPGs are now characterized at the molecular level. Interestingly, the four most frequently found TPGs (AF4, AF9, ENL and AF10) encode nuclear proteins that are part of a protein network involved in histone H3K79 methylation. Thus, translocations of the MLL gene, by itself coding for a histone H3K4 methyltransferase, are presumably not randomly chosen, rather functionally selected.
Asunto(s)
Leucemia/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Fusión Oncogénica/genética , Translocación Genética/genética , Enfermedad Aguda , Adulto , Niño , Aberraciones Cromosómicas , Mapeo Cromosómico , ADN/genética , ADN/aislamiento & purificación , N-Metiltransferasa de Histona-Lisina , Histonas/metabolismo , Humanos , MetilaciónRESUMEN
Solid pseudopapillary neoplasm of the pancreas (SPNP) is a rare tumor with low malignant potential found in adolescent girls and young women. The pathogenesis of SPNP remains uncertain and its management is controversial. Genetic changes associated with SPNP have seldom been reported. We describe here the cytogenetic investigation of a case of SPNP in a 13-year-old girl whose tumor cells revealed two unrelated clones: one clone characterized by complex karyotypic changes, including breakpoints in two common fragile sites at chromosome 2, band q33, and chromosome 4, band q31, and the second clone defined by partial monosomy for chromosome X. Loss of heterozygosity for HRAS was also identified by array comparative genomic hybridization (a-CGH). These cumulative changes seem insufficient for activation of cell transformation, but could possibly play a role in priming the cell for future mutagenic events.
Asunto(s)
Aberraciones Cromosómicas , Neoplasias Pancreáticas/genética , Adolescente , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Pérdida de Heterocigocidad , Hibridación de Ácido NucleicoAsunto(s)
Células Clonales/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/patología , Inmunización , Leucemia Mielomonocítica Crónica/patología , Antígenos CD/metabolismo , Diferenciación Celular/inmunología , Niño , Células Clonales/metabolismo , Células Clonales/patología , Células Dendríticas/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Antígenos HLA-DR/metabolismo , Humanos , Interleucina-4 , Leucemia Mielomonocítica Crónica/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Células Tumorales CultivadasRESUMEN
The clinical features, cytogenetics and response to treatment have been examined in 180 infants (aged <1 year) with acute leukaemia; 118 with acute lymphoblastic leukaemia (ALL) and 62 with acute myeloid leukaemia (AML). Comparison of clinical features showed no difference in age or sex distribution between infants with ALL and AML but infants with ALL tended to have higher leucocyte counts at presentation. Cytogenetic abnormalities involving 11q23 were found in 66% of ALL and 35% of AML cases, the commonest, t(4;11) being found only in ALL. The other recognised 11q23 translocations were found in both types of leukaemia. Few patients had the common cytogenetic abnormalities associated with ALL in older children and few with AML had good risk abnormalities. Four year event-free survival 60% cf 30% (P = 0.001) and survival 65% cf 41% (P = 0.007) were significantly better in AML than ALL. These results were due to a lower risk of relapse 27% cf 62% at four years. Superior event-free survival was also seen in the subgroup of patients with 11q23 abnormalities and AML (55% cf 23%). The reasons for superior response in AML are unknown but may be related to the intensity of treatment, lineage of the leukaemia or other as yet unidentified factors.
Asunto(s)
Leucemia Mieloide/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Enfermedad Aguda , Factores de Edad , Médula Ósea/patología , Aberraciones Cromosómicas , Cromosomas Humanos Par 11 , Análisis Citogenético , Femenino , Humanos , Lactante , Recién Nacido , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/genética , Recuento de Leucocitos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Factores Sexuales , Análisis de Supervivencia , Translocación Genética , Resultado del TratamientoRESUMEN
Concordance for neuroblastoma in monozygotic twins has been reported only rarely, and the cause of the shared pathology has not been established. We describe a case of infant monozygotic twins developing tumours that were morphologically, clinically and molecularly indistinguishable, but with a delay of 6 months between times of presentation. Both tumours were metastatic and had amplification of MYCN and deletion at 1p36. Twin 1, who developed neuroblastoma first, had constitutional karyotype abnormalities in at least 5% of peripheral blood mononuclear cells involving 1p and 3p, and a deletion of 1q44 in 21% of cells. Twin 2 had a normal constitutional karyotype and lacked rearrangement or deletion of these regions. We propose an acquired neuroblastoma predisposition specific for twin 1, and in utero metastatic spread of tumour cells to twin 2 via the shared placental circulation.
Asunto(s)
Metástasis de la Neoplasia , Neuroblastoma/patología , Gemelos Monocigóticos , ADN de Neoplasias/análisis , Femenino , Humanos , Lactante , Recién Nacido , Cariotipificación , Neuroblastoma/genéticaRESUMEN
The ETV6 gene is rearranged as a result of translocations involving a wide variety of chromosomal partners. To date, 12 partner genes for ETV6 have been cloned, and a further 23 chromosomal regions have been described. We previously identified a cryptic t(7;12) with ETV6 involvement in two cases of infant leukemia. The finding of a third case of t(7;12), also in an infant, prompted a more focussed search based on the common features found in these patients and those reported in the literature. The selection criteria were age at diagnosis < 20 months and the presence of +19 and/or +8 in the karyotype; cases with abnormalities of 7q and/or 12p were also considered. FISH studies using whole chromosome paints and probes for the ETV6 gene revealed a t(7;12) in 10 out of 23 cases studied. Seven of these had evidence of ETV6 rearrangement. Of those with ETV6 involvement, six had a 7q36 and one a 7q22 breakpoint. Importantly, in three cases the 7q36 breakpoint was within the same PAC, suggesting the existence of a new nonrandom translocation. However, in at least one patient the 7q36 breakpoint was different. The identification of the 7q partner genes will determine whether it is the disruption of ETV6 alone, or the formation of fusion genes, that is important for leukemogenesis in these patients. As both 7q36 and 7q22 are critical regions of gene loss in del(7q) leukemias, the identification of partner genes from these regions may also be important in understanding the pathogenesis of these diseases.
Asunto(s)
Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 7/genética , Proteínas de Unión al ADN/genética , Leucemia/genética , Proteínas Represoras , Factores de Transcripción/genética , Translocación Genética/genética , Rotura Cromosómica/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Masculino , Proteínas Proto-Oncogénicas c-ets , Proteína ETS de Variante de Translocación 6RESUMEN
A newborn infant with spontaneous remission of congenital leukemia cutis is described and a literature review of this uncommon phenomenon is provided. In view of the unusual and unpredictable behavior of this disease, chemotherapy should be withheld unless there is evidence of an 11q23 translocation or progressive disease. Otherwise, overall survival does not appear to be affected by adopting a conservative approach. Because of occasional late relapses, long-term follow-up is recommended. The biologic basis underlying spontaneous remission of congenital leukemia is unknown; therefore, molecular or molecular cytogenetic analysis of DNA obtained from a skin biopsy is recommended.
Asunto(s)
Leucemia Mieloide/congénito , Biomarcadores de Tumor , Médula Ósea/patología , Progresión de la Enfermedad , Humanos , Recién Nacido , Cariotipificación , Leucemia Mieloide/genética , Leucemia Mieloide/patología , Leucemia Mieloide/terapia , Infiltración Leucémica , Masculino , Células Madre Neoplásicas/patología , Remisión Espontánea , Piel/patologíaRESUMEN
The TEL-AML1 fusion which results from the t(12;21) rearrangement in childhood B-precursor acute lymphoblastic leukaemia (B-precursor ALL) is often accompanied by loss of the untranslocated TEL allele. From 32/109 children with B-precursor ALL screened for these abnormalities, we found evidence for del 12p, including the loss of the untranslocated TEL allele, to be the secondary event to take place in the leukaemic cells from those patients positive for these abnormalities. This suggests that the initial or predisposing event is the generation of a TEL-AML1 fusion, followed by the promoting event of a deletion of a gene(s) on 12p. A striking characteristic of the leukaemic cells in 61% of the patients showing t(12:21). was the substantial evolution of the primary clonal line containing the reciprocal TEL-AML1 fusion. We were able to show loss of normal TEL in the same patients by interphase fluorescence in situ hybridisation (FISH) analysis and reverse-transcriptase polymerase chain reaction (RT-PCR).
Asunto(s)
Eliminación de Gen , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Alelos , Niño , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Proteínas de Unión al ADN/genética , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Proteínas Proto-Oncogénicas c-ets , Proteínas Represoras/genética , Proteína ETS de Variante de Translocación 6RESUMEN
Rearrangements involving the MLL gene at chromosome 11q23 are associated with leukemia and are present in up to 70% of infant leukemias. Loss of heterozygosity (LOH) has been shown for anonymous polymorphic markers at 11q23 in adult leukemias. To study LOH at the MLL locus, we have identified two new polymorphic microsatellite markers: a GAA repeat (mllGAAn) in intron 6 of the MLL gene and a GA (mllGAn) repeat in the 5' flanking region of the gene, approximately 2 kb upstream of the translation initiation codon. The heterozygosity index of mllGAAn is 0.54, which renders it useful for analyzing LOH. We screened two groups of leukemia patients to study LOH at the mllGAAn marker. Group A (n = 18) was selected on the basis of presentation before 18 months. Cytogenetic and reverse transcription-polymerase chain reaction analysis showed that 9 of these 18 children had translocations involving MLL. No LOH was observed. Group B (n = 36) were randomly selected children who had presented with leukemia between 1993 and 1994. Cytogenetic analysis of this group showed a variety of different chromosomal abnormalities. LOH was shown in 9 of 20 individuals (45%) who were informative. Microsatellite instability (MSI) was demonstrated in 1 of 18 individuals in group A and 5 of 36 individuals (13.9%) in group B. MSI and LOH were observed simultaneously in three individuals. Loss of an allele was confirmed in one individual by fluorescence in situ hybridization. Individuals with MSI or LOH at mllGAAn were selected for analysis at anonymous polymorphic markers D11S1364 and D11S1356, which flank the MLL gene. No LOH or MSI was observed at these markers in those individuals who were informative. These results show that LOH at the MLL gene locus is a common event during leukemogenesis. Furthermore, the presence of MSI at this locus suggests that the region is a hotspot for genetic instability.
Asunto(s)
Cromosomas Humanos Par 11 , Proteínas de Unión al ADN/genética , Leucemia/genética , Pérdida de Heterocigocidad , Proto-Oncogenes , Factores de Transcripción , Enfermedad Aguda , Adulto , Factores de Edad , Niño , Preescolar , ADN Satélite/genética , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Leucemia/fisiopatología , Proteína de la Leucemia Mieloide-Linfoide , Polimorfismo GenéticoRESUMEN
The t(12;21) is the commonest recurrent translocation in childhood acute lymphoblastic leukaemia (ALL), the presence of which has been suggested to be a good prognostic feature. We have studied 22 childhood cases of B-precursor ALL with this rearrangement, and have found no significant differences in event-free survival between these and a control group of patients with similar phenotypes. Using a variety of cytogenetic and molecular techniques, we have confirmed a strong association with co-expression of myeloid markers, frequent deletions of the short-arm of the untranslocated chromosome 12 homologue and duplication of the derivative chromosome 21. Intragenic deletion of the untranslocated ETV6 gene in 3/12 informative patients points to the likelihood of this gene being a target for deletion.
Asunto(s)
Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 21/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocación Genética/genética , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Reordenamiento Génico , Humanos , Cariotipificación , Pérdida de Heterocigocidad , Masculino , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodosRESUMEN
A case of transient abnormal myelopoiesis in a normal newborn without features of Down syndrome is described. The majority of bone marrow cells analysed belonged to a chromosomally abnormal clone with trisomy for chromosomes 18 and 21. Complex intrachromosomal rearrangements of one chromosome 21, demonstrated by fluorescence in situ hybridization using locus-specific probes, were found in a minor population of the clonal cells. These rearrangements involved loci previously shown to be rearranged in the leukaemic cells from patients with Down syndrome and leukaemia. However, the child's myeloproliferation resolved rapidly, with disappearance of the abnormal clone, and 3.5 years later she remains well.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 21 , Leucopoyesis , Trastornos Mieloproliferativos/genética , Síndrome de Down/genética , Femenino , Estudios de Seguimiento , Humanos , Hibridación Fluorescente in Situ , Recién Nacido , FenotipoRESUMEN
Detection of residual disease after completion of therapy or following bone marrow transplantation (BMT) in patients with acute promyelocytic leukaemia (APL) predicts relapse and is associated with a poor prognosis. Here we describe the successful treatment of residual disease post-transplant in APL using prolonged all-trans retinoic acid (ATRA) therapy in two children in whom autologous BMT (ABMT) had been performed in second complete remission (CR). ATRA treatment was well tolerated and found to be beneficial despite its prior use as a component of the initial induction protocol. ATRA therapy post-transplant led to molecular remission as determined by fluorescence in situ hybridization (FISH) as well as reverse transcriptase-polymerase chain reaction (RT-PCR) analyses and remission now exceeds 3.5 years in both patients. Overall, this study not only demonstrates that ATRA may successfully salvage APL patients with residual disease post-transplant, but also suggests a potential role for retinoids post-consolidation as a means of eliminating residual disease which could be beneficial even in patients previously exposed to ATRA as a component of the induction protocol.
Asunto(s)
Antineoplásicos/uso terapéutico , Trasplante de Médula Ósea , Leucemia Promielocítica Aguda/tratamiento farmacológico , Tretinoina/uso terapéutico , Niño , Preescolar , Femenino , Humanos , Leucemia Promielocítica Aguda/terapia , Neoplasia Residual , Terapia Recuperativa/métodosRESUMEN
Down syndrome (DS) is associated with an increased risk of developing hematological malignancies, but the basis for this predisposition is so far unknown. Using fluorescence in situ hybridization with a panel of locus-specific probes on normal and leukemic metaphases, we have found long-arm interstitial deletions of one of the chromosome 21s in the leukemic cells from five patients with DS and leukemia. This finding provides strong evidence for a gene or genes present on chromosome 21 having an important function in the development of leukemia in individuals with Down syndrome.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 21/genética , Síndrome de Down/complicaciones , Leucemia/complicaciones , Leucemia/genética , Preescolar , Síndrome de Down/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Cariotipificación , MasculinoRESUMEN
ABSTARCT: Cytogenetic changes are important in understanding the pathogenesis of disease. Karyotypic analysis is particularly useful when investigatmg conditions such as human malignancies, where aneuploidy and structural chromosome rearrangements are commonly found, as in the human leukemias. In these, karyotypes can show a wide range of different structural rearrangements, with highly specific chromosome abnormalities that are used in the classification of leukemras (1), which, in turn, are related to specific clinical features.
RESUMEN
Monosomy 7 (Mo7) and leukaemia predisposition are associated with Kostmann's disease (KD). The recent introduction of long-term recombinant HuG-CSF treatment in patients with KD, whilst showing significant reductions in infectious complications and improved quality of life, might also be associated with an increased risk of developing karyotypic abnormalities, myelodysplasia (MDS) and acute myeloid leukaemia (AML). We describe a case of an identical twin with probable autosomal dominant KD who developed anaemia, Mo7/MDS and AML at 18, 30 and 50 months respectively from starting r-metHuG-CSF (filgrastim) treatment. Further patient analyses are required to establish the natural history of KD and to determine what role, if any, filgrastim plays in altering the pathobiology of this disorder.
Asunto(s)
Agranulocitosis/congénito , Cromosomas Humanos Par 7 , Enfermedades en Gemelos , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Leucemia Mielomonocítica Aguda/etiología , Monosomía , Agranulocitosis/complicaciones , Agranulocitosis/terapia , Preescolar , Filgrastim , Estudios de Seguimiento , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Masculino , Síndromes Mielodisplásicos/etiología , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéutico , Gemelos MonocigóticosRESUMEN
Karyotype analysis of a case of acute megakaryoblastic leukaemia revealed an X;6 translocation as the sole abnormality. Using fluorescence in situ hybridisation on leukaemic metaphases we demonstrated that the breakpoint on the X-chromosome occurred at p11.21, within a region spanned by a YAC probe which has also been found to be disrupted in synovial sarcomas and some papillary renal cell carcinomas.
Asunto(s)
Leucemia Megacarioblástica Aguda/genética , Translocación Genética , Mapeo Cromosómico , Cromosomas Humanos Par 6 , Humanos , Hibridación Fluorescente in Situ , Lactante , Cariotipificación , Masculino , Cromosoma XRESUMEN
There are five reported cases of an atypical myeloproliferative disorder in which the leukemia cells have a consistent t(8;13)(p11;q12) translocation. We analyzed the breakpoint in metaphases from two of these patients by fluorescence in situ hybridization using a series of yeast artificial chromosomes (YACs) derived from the 13q12 region. We found that a YAC containing the FLT1 and FLT3 oncogenes was localized distal to the 13q12 breakpoint and was not rearranged. YAC66, a YAC that lies immediately adjacent to the chromosome 13 centromere, was localized proximal to the 13q12 breakpoint and was not rearranged. A third YAC, which is located between FLT1 and YAC66, was unrearranged in normal metaphase chromosomes, but showed hybridization signals on both derivative chromosomes in both cases. Thus, the breakpoints in these two cases are localized to the same 1.5 Mbp region of 13q12. This may be the site of an unidentified gene involved in the pathogenesis of some types of leukemia.
Asunto(s)
Cromosomas Humanos Par 13 , Cromosomas Humanos Par 8 , Trastornos Mieloproliferativos/genética , Translocación Genética , Médula Ósea/patología , Mapeo Cromosómico , Cromosomas Artificiales de Levadura , Marcadores Genéticos , Humanos , Hibridación Fluorescente in Situ , Trastornos Mieloproliferativos/patología , Reacción en Cadena de la Polimerasa , Estudios RetrospectivosRESUMEN
Molecular analysis of a new series of synovial sarcomas confirms that t(X;18)(p11.2;q11.2) breakpoints occur at two distinct regions on Xp designated SS1 and SS2. Breakpoint position correlates with tumor phenotype. Monophasic tumors with no evidence of glandular components have breakpoints within the SS2 region in Xp11.21, and biphasic tumors with a focal poorly differentiated or extensive glandular structure have breakpoints within the SS1 region in Xp11.23.
Asunto(s)
Sarcoma Sinovial/genética , Translocación Genética , Cromosoma X , Adolescente , Adulto , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Persona de Mediana Edad , Sarcoma Sinovial/clasificación , Sarcoma Sinovial/patología , Células Tumorales CultivadasRESUMEN
A chromosomally abnormal clone characterized by a translocation, t(5;12)(q31;q13), was detected in the marrow of a child with myelodysplasia and associated eosinophilia which included a generalized skin infiltration. Combined immunophenotyping and fluorescence in situ hybridization on interphase bone marrow cells showed that the chromosomal rearrangement was restricted to the granulocyte lineage but was not present in the eosinophils. If the chromosome rearrangement is important in the overproduction of eosinophils in this case, the lineage restriction found suggests that its effect must be indirect.