RESUMEN
The European Organisation for Research and Treatment of Cancer 58951 trial for children with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) addressed 3 randomized questions, including the evaluation of dexamethasone (DEX) versus prednisolone (PRED) in induction and, for average-risk patients, the evaluation of vincristine and corticosteroid pulses during continuation therapy. The corticosteroid used in the pulses was that assigned at induction. Overall, 411 patients were randomly assigned: 202 initially randomly assigned to PRED (60 mg/m(2)/d), 201 to DEX (6 mg/m(2)/d), and 8 nonrandomly assigned to PRED. At a median follow-up of 6.3 years, there were 19 versus 34 events for pulses versus no pulses; 6-year disease-free survival (DFS) rate was 90.6% (standard error [SE], 2.1%) and 82.8% (SE, 2.8%), respectively (hazard ratio [HR] = 0.54; 95% confidence interval, 0.31-0.94; P = .027). The effect of pulses was similar in the PRED (HR = 0.56) and DEX groups (HR = 0.59) but more pronounced in girls (HR = 0.24) than in boys (HR = 0.71). Grade 3 to 4 hepatic toxicity was 30% versus 40% in pulses versus no pulses group and grade 2 to 3 osteonecrosis was 4.4% versus 2%. For average-risk patients treated according to Berlin-Frankfurt-Muenster-based protocols, pulses should become a standard component of therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma no Hodgkin/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Corticoesteroides/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Niño , Preescolar , Dexametasona/administración & dosificación , Femenino , Humanos , Lactante , Linfoma no Hodgkin/diagnóstico , Linfoma no Hodgkin/mortalidad , Masculino , Osteonecrosis/inducido químicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Prednisolona/administración & dosificación , Análisis de Supervivencia , Tasa de Supervivencia , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
BACKGROUND: Abnormalities of 11q23 involving the MLL gene are found in approximately 10% of human leukemias. To date, nearly 100 different chromosome bands have been described in rearrangements involving 11q23 and 64 fusion genes have been cloned and characterized at the molecular level. In this work we present the identification of a novel MLL fusion partner in a pediatric patient with de novo biphenotypic acute leukemia. METHODS: Cytogenetics, fluorescence in situ hybridization (FISH), molecular studies (RT-PCR and LDI-PCR), and bioinformatic sequence analysis were used to characterize the CT45A2 gene as novel MLL fusion partner in pediatric acute leukemia. RESULTS: Fluorescence in situ hybridization of bone marrow G-banded metaphases demonstrated a cryptic insertion of 11q23 in Xq26.3 involving the MLL gene. Breakpoint fusion analysis revealed that a DNA fragment of 653 kb from 11q23, containing MLL exons 1-9 in addition to 16 other 11q23 genes, was inserted into the upstream region of the CT45A2 gene located at Xq26.3. In addition, a deletion at Xq26.3 encompassing the 3' region of the DDX26B gene (exons 9-16) and the entire CT45A1 gene was identified. RNA analysis revealed the presence of a novel MLL-CT45A2 fusion transcript in which the first 9 exons of the MLL gene were fused in-frame to exon 2 of the CT45A2 gene, resulting in a spliced MLL fusion transcript with an intact open reading frame. The resulting chimeric transcript predicts a fusion protein where the N-terminus of MLL is fused to the entire open reading frame of CT45A2. Finally, we demonstrate that all breakpoint regions are rich in long repetitive motifs, namely LINE/L1 and SINE/Alu sequences, but all breakpoints were exclusively identified outside these repetitive DNA sequences. CONCLUSION: We have identified CT45A2 as a novel spliced MLL fusion partner in a pediatric patient with de novo biphenotypic acute leukemia, as a result of a cryptic insertion of 11q23 in Xq26.3. Since CT45A2 is the first Cancer/Testis antigen family gene found fused with MLL in acute leukemia, future studies addressing its biologic relevance for leukemogenesis are warranted.
Asunto(s)
Antígenos de Neoplasias/genética , Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Fusión Oncogénica/genética , Antígenos de Neoplasias/química , Niño , Bandeo Cromosómico , Cromosomas Humanos Par 11/ultraestructura , Cromosomas Humanos X/ultraestructura , Exones , Resultado Fatal , Eliminación de Gen , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Leucemia Mieloide Aguda/terapia , Masculino , Proteína de la Leucemia Mieloide-Linfoide/química , Sistemas de Lectura AbiertaRESUMEN
BACKGROUND: A relevant role of septins in leukemogenesis has been uncovered by their involvement as fusion partners in MLL-related leukemia. Recently, we have established the MLL-SEPT2 gene fusion as the molecular abnormality subjacent to the translocation t(2;11)(q37;q23) in therapy-related acute myeloid leukemia. In this work we quantified MLL and SEPT2 gene expression in 58 acute myeloid leukemia patients selected to represent the major AML genetic subgroups, as well as in all three cases of MLL-SEPT2-associated myeloid neoplasms so far described in the literature. METHODS: Cytogenetics, fluorescence in situ hybridization (FISH) and molecular studies (RT-PCR, qRT-PCR and qMSP) were used to characterize 58 acute myeloid leukemia patients (AML) at diagnosis selected to represent the major AML genetic subgroups: CBFB-MYH11 (n = 13), PML-RARA (n = 12); RUNX1-RUNX1T1 (n = 12), normal karyotype (n = 11), and MLL gene fusions other than MLL-SEPT2 (n = 10). We also studied all three MLL-SEPT2 myeloid neoplasia cases reported in the literature, namely two AML patients and a t-MDS patient. RESULTS: When compared with normal controls, we found a 12.8-fold reduction of wild-type SEPT2 and MLL-SEPT2 combined expression in cases with the MLL-SEPT2 gene fusion (p = 0.007), which is accompanied by a 12.4-fold down-regulation of wild-type MLL and MLL-SEPT2 combined expression (p = 0.028). The down-regulation of SEPT2 in MLL-SEPT2 myeloid neoplasias was statistically significant when compared with all other leukemia genetic subgroups (including those with other MLL gene fusions). In addition, MLL expression was also down-regulated in the group of MLL fusions other than MLL-SEPT2, when compared with the normal control group (p = 0.023) CONCLUSION: We found a significant down-regulation of both SEPT2 and MLL in MLL-SEPT2 myeloid neoplasias. In addition, we also found that MLL is under-expressed in AML patients with MLL fusions other than MLL-SEPT2.
Asunto(s)
Regulación hacia Abajo , Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Neoplasias Primarias Secundarias/genética , Monoéster Fosfórico Hidrolasas/genética , Regulación Neoplásica de la Expresión Génica , N-Metiltransferasa de Histona-Lisina , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Neoplasias Primarias Secundarias/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismoRESUMEN
Anaplastic large cell lymphoma (ALCL) is a relatively rare and highly malignant form of non-Hodgkin lymphoma (NHL) which accounts for 10-15% of these childhood lymphomas. Current treatment protocols for ALCL in children consist of a short course of high intensity polychemotherapy. Here we describe an 8-year-old female with relapsed ALCL who achieved good response with anti-CD25 monoclonal antibody daclizumab. Daclizumab appears to offer a safe treatment option, but further research needs to be conducted in order to define its role in children with ALCL who do not respond to intensive chemotherapy.
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Anticuerpos Monoclonales/uso terapéutico , Inmunoglobulina G/uso terapéutico , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Daclizumab , Femenino , Humanos , Inmunosupresores/uso terapéutico , Terapia Recuperativa , Resultado del TratamientoRESUMEN
One of the MLL fusion partners in leukemia is the SEPT6 gene, which belongs to the evolutionarily conserved family of genes of septins. In this work we aimed to characterize at both the RNA and DNA levels three acute myeloid leukemias with cytogenetic evidence of a rearrangement between 11q23 and Xq24. Molecular analysis led to the identification of several MLL-SEPT6 fusion transcripts in all cases, including a novel MLL-SEPT6 rearrangement (MLL exon 6 fused with SEPT6 exon 2). Genomic DNA breakpoints were found inside or near Alu or LINE repeats in the MLL breakpoint cluster region, whereas the breakpoint junctions in the SEPT6 intron 1 mapped to the vicinity of GC-rich low-complexity repeats, Alu repeats, and a topoisomerase II consensus cleavage site. These data suggest that a non-homologous end-joining repair mechanism may be involved in the generation of MLL-SEPT6 rearrangements in acute myeloid leukemia.
Asunto(s)
Leucemia Mieloide Aguda/genética , Proteínas de Fusión Oncogénica/genética , Adolescente , Adulto , Niño , Preescolar , Rotura Cromosómica , Clonación Molecular , Femenino , Regulación Leucémica de la Expresión Génica , Humanos , Lactante , Cariotipificación , Leucemia Mieloide Aguda/patología , MasculinoRESUMEN
Alveolar rhabdomyosarcoma (ARMS) is characterized by two pathognomonic translocations, both involving the FOXO1 gene. We describe a case of a 10-year-old child with multiple lytic lesions involving all the vertebral bodies, sternum and femur and a bone marrow biopsy compatible with a small round cell neoplasia, but no evidence of a primary tumor. Interphase FISH analysis with specific probes evidenced a rearrangement involving the FOXO1 gene and RT-PCR identified the PAX7-FOXO1 fusion transcript. These data show a case of ARMS with no evidence of primary tumor presenting the PAX7-FOXO1 fusion gene.
Asunto(s)
Neoplasias de la Médula Ósea/diagnóstico , Neoplasias de la Médula Ósea/genética , Rabdomiosarcoma Alveolar/diagnóstico , Rabdomiosarcoma Alveolar/genética , Biopsia , Neoplasias de la Médula Ósea/metabolismo , Neoplasias de la Médula Ósea/cirugía , Forma de la Célula , Niño , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Rabdomiosarcoma Alveolar/metabolismo , Rabdomiosarcoma Alveolar/cirugíaRESUMEN
Methotrexate (MTX) is an antimetabolite with a major role in the treatment of acute lymphoblastic leukaemia (ALL). The authors report the management of a 9-year-old boy who developed an anaphylactoid reaction to high-dose MTX infusion, after a first challenge with intrathecal administration, during induction therapy for ALL. A desensitization protocol was followed and MTX tolerance has been successfully achieved, allowing this patient to complete the needed chemotherapy.
Asunto(s)
Anafilaxia/inducido químicamente , Anafilaxia/terapia , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Desensibilización Inmunológica , Hipersensibilidad a las Drogas/terapia , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Niño , Humanos , Inyecciones Espinales , Leucemia-Linfoma de Células T del Adulto/complicaciones , MasculinoRESUMEN
The t(4;11)(q21;q23) involving the genes MLL and AF4 (alias for AFF1) is detected in 50-70% of infant leukemia. We characterize at both the DNA and RNA level a rare MLL-AF4 fusion transcript identified in a 15-month-old girl with acute lymphoblastic leukemia. Direct sequence analysis of the reverse transcriptase-polymerase chain reaction product showed an in-frame fusion between MLL exon 9 and AF4 exon 6. We further demonstrated that the genomic breakpoints were located 1,553 bp downstream of MLL exon 9 and 1,239 bp upstream of AF4 exon 6. Four Alu repeats were detected in MLL intron 9 and two Alu repeats and one LINE1 repetitive element were identified downstream of AF4 exon 5. Finally, a 9-bp polypurine (A) tract and an 8-bp polypyrimidine (T) tract were found flanking the translocation breakpoint. In summary, we have characterized at both the RNA and the DNA level a rare MLL-AF4 fusion variant that was presumably mediated by Alu repeats or polypurine and polypyrimidine tracts located in the vicinity of genomic breakpoints.
Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/fisiología , Leucemia/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteína de la Leucemia Mieloide-Linfoide/fisiología , Proteínas Nucleares/genética , Proteínas Nucleares/fisiología , Proteínas de Fusión Oncogénica/genética , Secuencia de Bases , ADN/metabolismo , Exones , Femenino , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Datos de Secuencia Molecular , Purinas/química , Pirimidinas/química , ARN/metabolismo , Análisis de Secuencia de ADN , Factores de Elongación TranscripcionalRESUMEN
AIM OF THE STUDY: To evaluate the prognostic significance of the initial cerebro-spinal fluid (CSF) involvement of children with ALL enrolled from 1989 to 1996 in the EORTC 58881 trial. PATIENTS AND METHODS: Patients (2025) were categorised according to initial central nervous system (CNS) status: CNS-1 (CNS negative, n=1866), CNS-2 (<5 leucocytes/mm(3), CSF with blasts, n=50), CNS-3 (CNS positive, n=49), TLP+ (TLP with blasts, n=60). CNS-directed therapy consisted in intravenous (i.v.) methotrexate (5 g/sqm) in 4-10 courses, and intrathecal methotrexate injections (10-20), according to CNS status. Cranial irradiation was omitted in all patients. RESULTS: In the CNS1, TLP+, CNS2 and CNS3 group the 8-year EFS rate (SE%) was 69.7% (1.1%), 68.8% (6.2%), 71.3% (6.5%) and 68.3% (6.2%), respectively. The 8-year incidence of isolated CNS relapse (SE%) was 3.4% (0.4%), 1.7% (1.7%), 6.1% (3.5%) and 9.4% (4.5%), respectively, whereas the 8-year isolated or combined CNS relapse incidence was 7.6% (0.6%), 3.5% (2.4%), 10.2% (4.4%) and 11.7% (5.0%), respectively. Patients with CSF blasts had a higher rate of initial bad risk features. Multivariate analysis indicated that presence of blasts in the CSF had no prognostic value: (i) for EFS and OS; (ii) for isolated and isolated or combined CNS relapse; WBC count<25 × 10(9)/L and Medac E-coli asparaginase treatment were each related to a lower CNS relapse risk. CONCLUSIONS: The presence of initial CNS involvement has no prognostic significance in EORTC 58881. Intensification of CNS-directed chemotherapy, without CNS radiation, is an effective treatment of initial meningeal leukaemic involvement.
Asunto(s)
Neoplasias del Sistema Nervioso Central/líquido cefalorraquídeo , Leucocitos , Leucemia-Linfoma Linfoblástico de Células Precursoras/líquido cefalorraquídeo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/mortalidad , Líquido Cefalorraquídeo/citología , Niño , Preescolar , Femenino , Humanos , Lactante , Estimación de Kaplan-Meier , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Pronóstico , Recurrencia , Estudios Retrospectivos , Trasplante de Células Madre/métodosRESUMEN
Septins are proteins associated with crucial steps in cell division and cellular integrity. In humans, 14 septin genes have been identified, of which five (SEPT2, SEPT5, SEPT6, SEPT9, and SEPT11) are known to participate in reciprocal translocations with the MLL gene in myeloid neoplasias. We have recently shown a significant down-regulation of both SEPT2 and MLL in myeloid neoplasias with the MLL-SEPT2 fusion gene. In this study, we examined the expression pattern of the other 13 known septin genes in altogether 67 cases of myeloid neoplasia, including three patients with the MLL-SEPT2 fusion gene, four with MLL-SEPT6 fusion, and three patients with the MLL-SEPT9 fusion gene. When compared with normal controls, a statistically significant down-regulation was observed for the expression of both MLL (6.4-fold; p=0.008) and SEPT6 (1.7-fold; p=0.002) in MLL-SEPT6 leukemia. Significant down-regulation of MLL was also found in MLL-MLLT3 leukemias. In addition, there was a trend for SEPT9 down-regulation in MLL-SEPT9 leukemias (4.6-fold; p=0.077). Using hierarchical clustering analysis to compare acute myeloid leukemia genetic subgroups based on their similarity of septin expression changes, we found that MLL-SEPT2 and MLL-SEPT6 neoplasias cluster together apart from the remaining subgroups and that PML-RARA leukemia presents under-expression of most septin family genes.
Asunto(s)
Proteínas del Citoesqueleto/genética , Proteínas de Unión al GTP/genética , Expresión Génica , Leucemia Mieloide Aguda/genética , Proteínas de Fusión Oncogénica/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Análisis por Conglomerados , Humanos , Lactante , Persona de Mediana Edad , Proteína de la Leucemia Mieloide-Linfoide/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Adulto JovenRESUMEN
Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in folate metabolism and in DNA methylation and synthesis. The role of two common polymorphisms at the MTHFR gene, C677T and A1298C, in the etiology of childhood or adult acute lymphoblastic leukemia (ALL) has been previously investigated. Although a protective effect of MTHFR*677T against ALL was systematically reported, the magnitude of the effect appeared to be influenced by population-specific gene-environmental interactions. The evidence of the role of MTHFR*1298C in ALL susceptibility was less consistent, emphasizing the need for enlarging molecular epidemiologic studies to independent trials from different populations. The authors analyzed in North Portugal the association between variations at the two MTHFR positions and risk of ALL by comparing genotypes and gene frequencies in 103 affected children with those in 111 healthy controls. None of the variations was found to significantly affect the risk of developing childhood ALL in North Portugal, and this finding per se is of relevance in further studies aimed at assessing the etiology of the pathology in this specific population. Despite the absence of statistical significance, these data revealed that the frequency of MTHFR*677T was lower in patients than in controls, a result that is congruent with other reports and with the functional model usually invoked to explain its ALL protective effect. Concerning MTHFR1298*C, this study failed to corroborate previous findings of decreased risk of ALL in the presence of the variant.