RESUMEN
Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5'-KMT2A, two patients had a 5'-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.
Asunto(s)
N-Metiltransferasa de Histona-Lisina , Leucemia Mieloide Aguda , Proteína de la Leucemia Mieloide-Linfoide , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Lactante , Preescolar , Niño , Adolescente , Adulto , Persona de Mediana Edad , Anciano , Leucemia Mieloide Aguda/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , N-Metiltransferasa de Histona-Lisina/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Fusión GénicaRESUMEN
The human mixed lineage leukemia (MLL) gene is frequently involved in genetic rearrangements with more than 55 different translocation partner genes, all associated with acute leukemia. Reciprocal chromosomal translocations generate two MLL fusion alleles, where 5'- and 3'-portions of MLL are fused to gene segments of given fusion partners. In case of t(4;11) patients, about 80% of all patients exhibit both reciprocal fusion alleles, MLL.AF4 and AF4.MLL, respectively. By contrast, 20% of all t(4;11) patients seem to encode only the MLL.AF4 fusion allele. Here, we analyzed these 'MLL.AF4(+)/AF4.MLL(-)' patients at the genomic DNA level to unravel their genetic situation. Cryptic translocations and three-way translocations were found in this group of t(4;11) patients. Reciprocal MLL fusions with novel translocation partner genes, for example NF-KB1 and RABGAP1L, were identified and actively transcribed in leukemic cells. In other patients, the reciprocal 3'-MLL gene segment was fused out-of-frame to PBX1, ELF2, DSCAML1 and FXYD6. The latter rearrangements caused haploinsufficiency of genes that are normally expressed in hematopoietic cells. Finally, patients were identified that encode only solitary 3'-MLL gene segments on the reciprocal allele. Based on these data, we propose that all t(4;11) patients exhibit reciprocal MLL alleles, but due to the individual recombination events, provide different pathological disease mechanisms.
Asunto(s)
Reordenamiento Génico , Leucemia/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Translocación Genética , Alelos , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 4 , Humanos , Proteína de la Leucemia Mieloide-Linfoide/análisis , Proteínas de Fusión Oncogénica/análisisRESUMEN
Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients.
Asunto(s)
N-Metiltransferasa de Histona-Lisina/genética , Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Adulto , Niño , Aberraciones Cromosómicas , Rotura Cromosómica , Femenino , Reordenamiento Génico/genética , Humanos , Lactante , Masculino , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocación Genética/genéticaRESUMEN
An estimated 10% of acute leukemias carry mixed-lineage leukemia (MLL) fusion genes. Approximately 50 different fusion partners of the MLL gene have already been molecularly identified. These leukemias are commonly regarded as high-risk cases and are treated accordingly with intensified therapy regimens, including hematopoietic stem cell transplantation. However, a subset of patients may achieve long-term remissions with conventional therapy. Monitoring minimal residual disease (MRD) is undoubtedly of great value in clinical decision making, also in the pre- and post-transplant setting. Here, we describe a novel method for detecting MRD in leukemias with MLL aberrations. The method is based on monitoring patient-specific chromosomal breakpoint DNA sequences. This has several advantages over other methods that are based either on detecting specific RNA molecules of MLL fusion genes or on surrogate markers. An accurate and absolute quantification of the MRD level is possible. No reference to housekeeping genes is necessary and the target structure is much more stable than any mRNA fusion transcript.
Asunto(s)
Sitios Frágiles del Cromosoma , Leucemia/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Neoplasia Residual/genética , Enfermedad Aguda , Secuencia de Bases , Cartilla de ADN , Sondas de ADN , N-Metiltransferasa de Histona-Lisina , Humanos , InmunofenotipificaciónRESUMEN
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
TCF3-PBX1 (E2A-PBX1) is a recurrent gene fusion in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), which is caused by the translocation t(1;19)(q23;p13). TCF3-PBX1 BCP-ALL patients typically benefit from chemotherapy; however, many relapse and subsequently develop resistant disease with few effective treatment options. Mechanisms driving disease progression and therapy resistance have not been studied in TCF3-PBX1 BCP-ALL. Here, we aimed to identify novel treatment options for TCF3-PBX1 BCP-ALL by profiling leukemia cells from a relapsed patient, and determine molecular mechanisms underlying disease pathogenesis and progression. By drug-sensitivity testing of leukemic blasts from the index patient, control samples and TCF3-PBX1 positive and negative BCP-ALL cell lines, we identified the phosphatidylinositide 3-kinase delta (p110δ) inhibitor idelalisib as an effective treatment for TCF3-PBX1 BCP-ALL. This was further supported by evidence showing TCF3-PBX1 directly regulates expression of PIK3CD, the gene encoding p110δ. Other somatic mutations to TP53 and MTOR, as well as aberrant expression of CXCR4, may influence additional drug sensitivities specific to the index patient and accompanied progression of the disease. Our results suggest that idelalisib is a promising treatment option for patients with TCF3-PBX1 BCP-ALL, whereas other drugs could be useful depending on the genetic context of individual patients.
Asunto(s)
Proteínas de Fusión Oncogénica , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Purinas/farmacología , Quinazolinonas/farmacología , Adulto , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase Ia/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Proteínas de Fusión Oncogénica/fisiología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Purinas/uso terapéutico , Quinazolinonas/uso terapéutico , RecurrenciaRESUMEN
Chromosomal translocations involving the MYC oncogene are a hallmark of Burkitt lymphoma but they are only found in a varying frequency in mature Burkitt-type acute lymphoblastic leukemia (B-ALL). We have investigated samples of 56 sporadic Burkitt leukemia/lymphoma patients for the translocations t(8;14)(q24;q32), t(2;8)(p11;q24) and t(8;22)(q24;q11). Long PCR was used for detecting the immunoglobulin heavy chain (IgH) translocation and cytogenetics and/or fluorescence in situ hybridization for detecting the 'variant' MYC translocations. A total of 29 samples (51.8%) were t(8;14)-positive by long PCR. Approximately one-third had a chromosomal breakpoint in the IgH joining region while the others had breakpoints in the IgH switch regions. Among them were two cases with a previously unreported MYC translocation into the IgE switch region. Long PCR was more reliable compared to conventional cytogenetics for detecting the t(8;14). Epstein-Barr virus was detected in high copy number in two (3.6%) t(8;14)-positive cases by real-time quantitative PCR. Human herpesvirus 8 was not detected in any case by nested PCR. A typical L3 or L3-compatible cytomorphology was highly predictive (>80%) but not specific of a MYC translocation. A total of 34 patients were treated according to the GMALL B-ALL therapy protocols and there was no significant difference in overall survival between patients with or without t(8;14).
Asunto(s)
Linfoma de Burkitt/genética , Heterogeneidad Genética , Translocación Genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Linfoma de Burkitt/inmunología , Linfoma de Burkitt/patología , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 8 , Análisis Citogenético , Femenino , Genes myc , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Tasa de SupervivenciaRESUMEN
The expression of the chondroitin sulfate proteoglycan neuron-glial antigen 2 (NG2) has been demonstrated in association with rearrangement of the mixed lineage leukemia (MLL) gene in acute leukemia, but the frequency of NG2 expression in adult acute lymphoblastic leukemia (ALL) is yet unknown. We evaluated NG2 expression in 313 adult ALL patients by flow cytometry and simultaneously determined MLL rearrangement in 120 adult patients out of them with B-precursor ALL by reverse transcription-polymerase chain reaction and fluorescence in situ hybridization. A total of 57% of pro-B ALL, 2% of common ALL and 20% of pre-B ALL were NG2 positive, but NG2 was absent in T-ALL and mature B-ALL. In B-precursor ALL, NG2 expression was significantly associated with a CD10(-)/CD34(-)/CD24(-)/CD65s(+)/CD15(+)/CD13(-)/CD33(-) phenotype and showed a sensitivity, specificity and positive predictive value of 0.89, 0.89, and 0.93 for MLL rearrangement, respectively. NG2 was positive in three patients without detectable MLL rearrangement and negative in eight patients with MLL-AF4 transcripts. However, NG2 predicted with a 100% accuracy MLL rearrangement among patients disclosing a CD65s(+) and/or CD15(+) immunophenotype. In summary, NG2 adds to a more precise identification of high-risk adult ALL and should therefore be included into diagnostic marker panels. As NG2 is negative in non-malignant hematopoietic cells, this novel antigen might also serve in future studies as a powerful marker in monitoring minimal residual disease.
Asunto(s)
Antígenos CD/análisis , Antígenos/análisis , Proteínas de Unión al ADN/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Proteoglicanos/análisis , Proto-Oncogenes , Factores de Transcripción , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Linfocitos B/patología , Biomarcadores/análisis , Femenino , Reordenamiento Génico , N-Metiltransferasa de Histona-Lisina , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Proteína de la Leucemia Mieloide-Linfoide , Proteínas de Fusión Oncogénica/genética , Valor Predictivo de las Pruebas , Pronóstico , ARN Mensajero/análisis , Ratas , Medición de Riesgo , Sensibilidad y Especificidad , Homología de SecuenciaRESUMEN
Here we describe the results of an interlaboratory test for RT-PCR-based BCR/ABL analysis. The test was organized in two parts. The number of participating laboratories in the first and second part was 27 and 20, respectively. In the first part samples containing various concentrations of plasmids with the ela2, b2a2 or b3a2 BCR/ABL transcripts were analyzed by PCR. In the second part of the test, cell samples containing various concentrations of BCR/ABL-positive cells were analyzed by RT-PCR. Overall PCR sensitivity was sufficient in approximately 90% of the tests, but a significant number of false positive results were obtained. There were significant differences in sensitivity in the cell-based analysis between the various participants. The results are discussed, and proposals are made regarding the choice of primers, controls, conditions for RNA extraction and reverse transcription.
Asunto(s)
Proteínas de Fusión bcr-abl , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Secuencia de Bases , Biomarcadores de Tumor , Cartilla de ADN , Proteínas de Fusión bcr-abl/normas , Humanos , Control de CalidadRESUMEN
The application of molecular biological techniques in malignant hematologic diseases, particularly leukemias, has led to a rapid increase in knowledge and a deeper insight into the pathobiology of these diseases. Leukemia is a very heterogeneous disease on the molecular level. Clonal chromosomal abnormalities can be found in the vast majority of cases. A broader understanding of the underlying molecular changes has enabled the development of risk-adapted therapy regimens with improved outcome. One example is the application of molecular genetic techniques for detecting small numbers of leukemia cells after therapy ("minimal residual disease"). This allows the early preclinical recognition and prevention of relapse. This study gives a short overview of the current status of molecular genetics in human leukemias and its implications for the therapy and prognosis of these diseases. The following topics are covered: generation of oncogenic fusion genes or dysregulation of protooncogenes by chromosomal translocations, detection of minimal residual disease based on clonally rearranged immunoglobulin or T-cell receptor genes or on leukemia-specific fusion genes, monitoring bone marrow chimerism after allogeneic transplantation by molecular genetic techniques, and the role of oncogenic herpesviruses and retroviruses in human hematologic malignancies.
Asunto(s)
Aberraciones Cromosómicas/genética , Leucemia/genética , Retroviridae , Enfermedad Aguda , Trastornos de los Cromosomas , Enfermedad Crónica , Terapia Genética , Herpesvirus Humano 4 , Herpesvirus Humano 8 , Virus Linfotrópico T Tipo 1 Humano , Humanos , Leucemia/terapia , Leucemia/virología , Biología Molecular , Translocación Genética , Infecciones Tumorales por Virus/complicacionesAsunto(s)
Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 19/genética , Leucemia/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , ARN Mensajero/genética , ARN Neoplásico/genética , Trans-Empalme/genética , Factores de Transcripción/genética , Transcripción Genética , Translocación Genética/genética , Enfermedad Aguda , Adulto , Animales , Niño , Rotura Cromosómica , Cromosomas Humanos Par 11/ultraestructura , Cromosomas Humanos Par 19/ultraestructura , ADN de Neoplasias/genética , Exones/genética , N-Metiltransferasa de Histona-Lisina , Humanos , Intrones/genética , Ratones , Proteína de la Leucemia Mieloide-Linfoide/química , ARN Mensajero/biosíntesis , ARN Neoplásico/biosíntesisRESUMEN
Minimal residual disease (MRD) after allogeneic stem cell transplantation (SCT) for Ph+ acute lymphoblastic leukemia (ALL) is predictive of relapse. Imatinib administration subsequent to SCT may prevent relapse, but the role of scheduling and its impact on outcome are not known. In a prospective, randomized multicenter trial, we compared the tolerability and efficacy of post-transplant imatinib administered either prophylactically (arm A; n=26) or following detection of MRD (arm B; n=29). Prophylactic imatinib significantly reduced the incidence of molecular recurrence after SCT compared with MRD-triggered imatinib (40% vs 69%; P=0.046). Median duration of PCR negativity was 26.5 and 6.8 months, respectively (P=0.065). Five-year survival in both interventional groups was high (80 and 74.5%), despite premature discontinuation of imatinib in the majority of patients because of poor tolerability. Relapse probability was significantly higher in patients who became MRD positive (P=0.017). In conclusion, post-transplant imatinib results in a low relapse rate, durable remissions and excellent long-term outcome in patients with BCR-ABL1-positive ALL irrespective of whether it is given prophylactically or MRD-triggered. Reappearance of BCR-ABL1 transcripts early after SCT or at higher levels identifies a small subset of patients who do not benefit sufficiently from imatinib, and in whom alternative approaches should be explored.
Asunto(s)
Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Neoplasia Residual , Piperazinas/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pirimidinas/uso terapéutico , Trasplante de Células Madre , Adolescente , Adulto , Antineoplásicos/efectos adversos , Benzamidas/efectos adversos , Terapia Combinada , Femenino , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Cooperación del Paciente , Piperazinas/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pirimidinas/efectos adversos , Análisis de Supervivencia , Adulto JovenRESUMEN
Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (≈ 90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements.
Asunto(s)
Rotura Cromosómica , Reordenamiento Génico , Leucemia/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Fusión Oncogénica/genética , Translocación Genética/genética , Enfermedad Aguda , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Animales , Niño , Preescolar , Femenino , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Recién Nacido , Leucemia/clasificación , Masculino , Ratones , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Pronóstico , Adulto JovenRESUMEN
A subgroup of pediatric acute T-lymphoblastic leukemia (T-ALL) was characterized by a gene expression profile comparable to that of early T-cell precursors (ETPs) with a highly unfavorable outcome. We have investigated clinical and molecular characteristics of the ETP-ALL subgroup in adult T-ALL. As ETP-ALL represents a subgroup of early T-ALL we particularly focused on this cohort and identified 178 adult patients enrolled in the German Acute Lymphoblastic Leukemia Multicenter studies (05/93-07/03). Of these, 32% (57/178) were classified as ETP-ALL based on their characteristic immunophenotype. The outcome of adults with ETP-ALL was poor with an overall survival of only 35% at 10 years, comparable to the inferior outcome of early T-ALL with 38%. The molecular characterization of adult ETP-ALL revealed distinct alterations with overexpression of stem cell-related genes (BAALC, IGFBP7, MN1, WT1). Interestingly, we found a low rate of NOTCH1 mutations and no FBXW7 mutations in adult ETP-ALL. In contrast, FLT3 mutations, rare in the overall cohort of T-ALL, were very frequent and nearly exclusively found in ETP-ALL characterized by a specific immunophenotype. These molecular characteristics provide biologic insights and implications with respect to innovative treatment strategies (for example, tyrosine kinase inhibitors) for this high-risk subgroup of adult ETP-ALL.
Asunto(s)
Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resultado Fatal , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Mutación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Trasplante Homólogo , Adulto JovenAsunto(s)
Mutación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Factor de Transcripción STAT5/genética , Adolescente , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteína bcl-X/genéticaRESUMEN
Chromosomal rearrangements of the human MLL gene are associated with high-risk pediatric, adult and therapy-associated acute leukemias. These patients need to be identified, treated appropriately and minimal residual disease was monitored by quantitative PCR techniques. Genomic DNA was isolated from individual acute leukemia patients to identify and characterize chromosomal rearrangements involving the human MLL gene. A total of 760 MLL-rearranged biopsy samples obtained from 384 pediatric and 376 adult leukemia patients were characterized at the molecular level. The distribution of MLL breakpoints for clinical subtypes (acute lymphoblastic leukemia, acute myeloid leukemia, pediatric and adult) and fused translocation partner genes (TPGs) will be presented, including novel MLL fusion genes. Combined data of our study and recently published data revealed 104 different MLL rearrangements of which 64 TPGs are now characterized on the molecular level. Nine TPGs seem to be predominantly involved in genetic recombinations of MLL: AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, MLLT4/AF6, ELL, EPS15/AF1P, MLLT6/AF17 and SEPT6, respectively. Moreover, we describe for the first time the genetic network of reciprocal MLL gene fusions deriving from complex rearrangements.
Asunto(s)
Leucemia/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Proteínas de Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Recombinación Genética , Translocación Genética , Enfermedad Aguda , Adulto , Biopsia , Médula Ósea/química , Médula Ósea/patología , Niño , Rotura Cromosómica , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 11/ultraestructura , Biología Computacional , ADN de Neoplasias/sangre , ADN de Neoplasias/genética , Duplicación de Gen , N-Metiltransferasa de Histona-Lisina , Humanos , Reacción en Cadena de la PolimerasaRESUMEN
Adult T-cell acute lymphoblastic leukemia (T-ALL) continues to represent an unfavorable disease. Molecularly based treatment stratifications could help improve outcome. The prognostic impact of HOX11 and HOX11L2 expression has been an area of controversy. We have investigated 286 adult T-ALL patients enrolled into the German Multicenter ALL (GMALL) therapy protocols by comparative real-time RT-PCR. High HOX11 expression and HOX11L2 expression were predominantly seen in thymic T-ALL (PAsunto(s)
Proteínas de Homeodominio/genética
, Leucemia-Linfoma de Células T del Adulto/genética
, Proteínas Proto-Oncogénicas/genética
, Timo/patología
, Adolescente
, Adulto
, Anciano
, Femenino
, Proteínas de Homeodominio/metabolismo
, Humanos
, Leucemia-Linfoma de Células T del Adulto/metabolismo
, Leucemia-Linfoma de Células T del Adulto/patología
, Masculino
, Persona de Mediana Edad
, Pronóstico
, Proteínas Proto-Oncogénicas/metabolismo
, ARN Mensajero/genética
, ARN Mensajero/metabolismo
, Estudios Retrospectivos
, Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
, Factores de Riesgo
, Tasa de Supervivencia
, Timo/metabolismo
, Resultado del Tratamiento
RESUMEN
Persistent polyclonal B-cell lymphocytosis (PPBL) is an extremely rare disorder, which occurs almost exclusively in smoking women and is characterized by a lymphocytosis with circulating binucleated lymphocytes. We analyzed 25 PPBL patients with respect to immunophenotype and by adaptive cluster analysis system (ACAS). Furthermore, HLA type, presence of Epstein-Barr virus (EBV) DNA in B cells, and clinical data were evaluated. Overall, the median percentages of B cells in PPBL patients with expression of CD5(dim), CD23(dim), CD25, CD27, and FMC7 were 21%, 38%, 16%, 74%, and 93%. Compared to normal controls, ACAS revealed a subset of nucleic-acid-rich lymphocytes located between the regular lymphocyte and regular monocyte region. Sixteen (64%) of 25 patients carried a HLA DR7 phenotype. Quantitative real-time polymerase chain reaction analysis did not detect relevant amounts of EBV DNA in circulating B cells of any patient. During a median follow-up of 5 years, a single patient developed lymphoplasmacytic lymphoma. The abnormal morphology and frequent, albeit dim, expression of CD5 and CD23 in PPBL may result in erratic diagnostic assignment of this benign disorder. However, incorporation of immunophenotyping and ACAS into the diagnostic algorithm allows recognition of PPBL in routine analysis and its differentiation from malignant B cell lymphoproliferative diseases. We found that an infection of a significant percentage of PPBL cells by EBV is unlikely. The observation of malignant lymphoma in a single patient implicates that evolution into a clonal malignant transformation may occasionally occur in PPBL.
Asunto(s)
Linfocitos B , Citometría de Flujo/métodos , Linfocitosis , Adulto , Linfocitos B/inmunología , Linfocitos B/patología , Femenino , Citometría de Flujo/instrumentación , Herpesvirus Humano 4/genética , Humanos , Inmunofenotipificación , Linfocitosis/diagnóstico , Linfocitosis/inmunología , Linfocitosis/patología , Masculino , Persona de Mediana EdadRESUMEN
Retrovirology emerged as a branch of science at the beginning of the last century. However, a deeper insight into the pathology of retroviruses and retrovirus-induced cancers could only be gained after the advent of modern biochemical and molecular biological techniques in the 1970s and 1980s. This study gives an overview of the known and well-characterised exogenous oncogenic animal retroviruses and the only human oncoretrovirus discovered thus far, HTLV-1. It briefly reviews retrovirus genetics, mechanisms of oncogenic transformation and malignant diseases caused by retroviruses.