RESUMEN
A retrospective cytogenetic study of acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS) was conducted by the Groupe Francophone de Cytogénétique Hématologique (GFCH) to evaluate the structural abnormalities of chromosome 5 associated with other chromosomal abnormalities, in particular of chromosome 7, in these pathologies. In all, 110 cases of AML/MDS were recruited based on the presence of chromosome 5 abnormalities under conventional cytogenetics and supplemented by a systematic fluorescence in situ hybridization study of chromosomes 5 and 7. The abnormalities of the long arm of chromosome 5 (5q) were deletions of various sizes and sometimes cryptic. The 5q abnormalities were associated with translocations in 54% of cases and were simple deletions in 46%. In 68% of cases, 5q deletions were associated with chromosome 7 abnormalities, and 90% of these presented a complex karyotype. Of the 110 patients, 28 had a hematopoietic disorder secondary to chemotherapy, radiotherapy, or both. Among 82 patients with de novo AML/MDS, 63 were older than 60 years. Chromosomal abnormalities often associated hypodiploidy and chromosome 5 and 7 abnormalities in complex karyotypes, features resembling those of secondary hemopathies. Systematic investigation of the exposure to mutagens and oncogenes is thus essential to specify the factors potentially involved in MDS/AML with 5q abnormalities.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 5 , Cromosomas Humanos Par 7 , Leucemia Mieloide/genética , Síndromes Mielodisplásicos/genética , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Deleción Cromosómica , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Neoplasias Inducidas por Radiación , Translocación GenéticaRESUMEN
Pediatric acute myeloid leukemia (AML) is a rare disease whose prognosis is highly variable according to factors such as chromosomal abnormalities. Recurrent genomic rearrangements are detected in half of pediatric AML by karyotype. NUcleoPorin 98 (NUP98) gene is rearranged with 31 different fusion partner genes. These rearrangements are frequently undetected by conventional cytogenetics, as the NUP98 gene is located at the end of the chromosome 11 short arm (11p15). By screening a series of 574 pediatric AML, we detected a NUP98 rearrangement in 22 cases (3.8%), a frequency similar to CBFB-MYH11 fusion gene (4.0%). The most frequent NUP98 fusion gene partner is NSD1. These cases are homogeneous regarding their biological and clinical characteristics, and associated with bad prognosis only improved by bone marrow transplantation. We detailed the biological characteristics of these AML by exome sequencing which demonstrated few recurrent mutations (FLT3 ITD, WT1, CEBPA, NBPF14, BCR and ODF1). The analysis of the clonal structure in these cases suggests that the mutation order in the NUP98-rearranged pediatric AML begins with the NUP98 rearrangement leading to epigenetic dysregulations then followed by mutations of critical hematopoietic transcription factors and finally, activation of the FLT3 signaling pathway.
Asunto(s)
Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Proteínas de Complejo Poro Nuclear/genética , Translocación Genética , Alelos , Biomarcadores de Tumor , Proteínas Potenciadoras de Unión a CCAAT/genética , Niño , Preescolar , Epigénesis Genética , Exoma , Femenino , Regulación Leucémica de la Expresión Génica , Frecuencia de los Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/mortalidad , Masculino , Mutación , Proteínas de Fusión Oncogénica/genética , Pronóstico , Transducción de Señal , Proteínas WT1/genética , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
Chromosomal abnormalities of erythroleukemia (EL) are often described as complex and unspecific. A retrospective study of 75 EL defined following the WHO classification was performed by the Groupe Francophone de Cytogénétique Hématologique (GFCH) in order to reexamine the cytogenetics of this infrequent leukemia subtype. Clonal chromosomal abnormalities were found in 57 patients (76%), distributed in 4 subgroups according to their ploidy status: pseudodiploid (16%), hypodiploid (47%), hyperdiploid (19%), and 18% mixed cases associating 2 different clones (hypodiploid+hyperdiploid) or (pseudodiploid+hyperdiploid). Complex rearrangements and hypodiploid chromosome number were widely dominant (50%). Partial or entire monosomies represented 56% of abnormalities. Chromosomes 5 and 7 were the most frequently involved (41 and 33 times, respectively), followed by chromosomes 8, 16, and 21 (19 times each). Unbalanced abnormalities were more frequent than balanced. All these kinds of abnormalities were observed in de novo as well as in secondary EL. Four out of 7 cases of "pure erythroid" leukemia were associated with a BCR-ABL fusion. Lastly, no chromosome abnormality specific to EL could be established. However, the large overlap of chromosomal abnormality patterns of EL (pure erythroid form excepted) and refractory anemia with excess of blasts in transformation (RAEB-t) favors the hypothesis of similarities between these 2 hematologic disorders.
Asunto(s)
Aberraciones Cromosómicas , Leucemia Eritroblástica Aguda/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Cromosomas Humanos , Humanos , Persona de Mediana Edad , Ploidias , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
Myeloproliferative neoplasms are frequently associated with aberrant constitutive tyrosine kinase (TK) activity resulting from chimaeric fusion genes or point mutations such as BCR-ABL1 or JAK2 V617F. We report here the cloning and functional characterization of two novel fusion genes BCR-RET and FGFR1OP-RET in chronic myelomonocytic leukemia (CMML) cases generated by two balanced translocations t(10;22)(q11;q11) and t(6;10)(q27;q11), respectively. The two RET fusion genes leading to the aberrant activation of RET, are able to transform hematopoietic cells and skew the hematopoietic differentiation program towards the monocytic/macrophage lineage. The RET fusion genes seem to constitutively mimic the same signaling pathway as RAS mutations frequently involved in CMML. One patient was treated with Sorafenib, a specific inhibitor of the RET TK function, and demonstrated cytological and clinical remissions.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Leucemia Mielomonocítica Crónica/patología , Monocitos/citología , Proteínas Proto-Oncogénicas c-ret/genética , Secuencia de Bases , Cartilla de ADN , Humanos , Hibridación Fluorescente in Situ , Leucemia Mielomonocítica Crónica/genética , Mutación Puntual , Reacción en Cadena de la Polimerasa/métodos , Translocación GenéticaAsunto(s)
Fusión Artificial Génica , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 9 , Proteínas de Homeodominio/genética , Leucemia Mieloide/genética , Proteínas de Complejo Poro Nuclear/genética , Translocación Genética , Enfermedad Aguda , Secuencia de Aminoácidos , Secuencia de Bases , ADN de Neoplasias , Humanos , Cariotipificación , Leucemia Mieloide/etiología , Datos de Secuencia MolecularRESUMEN
B-cell chronic lymphocytic leukemia (B-CLL) therapy remains unsatisfactory due to repeated resurgences of the chemoresistant disease. In this study, we investigated the basis of this chemoresistance by applying the 'side population' (SP) analysis to blood samples from B-CLL patients. We report the existence of few natural SP cells, which harbors phenotypic and cytogenetic hallmarks of B-CLL in most patients with this disease (n=22). SP cells appeared resistant to conventional B-CLL treatments, such as Fludarabine, Bendamustin or Rituximab. Indeed, treatment with Fludarabine (16/18 cases) or Bendamustin (5/7 cases) resulted in complete elimination of non-SP, whereas cells displaying the SP phenotype were the only surviving. Although some B-CLL SP cells were innately chemoresistant, chemotherapy by Fludarabine selected not only innate SP cells but also induced some acquired SP cells, which arose from non-SP by drug-driven evolution. This SP selection by chemotherapeutic treatments is further supported by the overall increase of the SP percentage in patients who experienced chemotherapy in the preceding year. Functionally, proliferative stimulation of SP cells was able to partially replenish in vitro the non-SP cell compartment of the B-CLL disease. The chemoresistance of B-CLL relies, in our model, on the cellular heterogeneity of B-CLL SP cells and on their regenerating dynamics.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , ADP-Ribosil Ciclasa 1/análisis , ADP-Ribosil Ciclasa 1/deficiencia , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Clorhidrato de Bendamustina , Separación Celular/métodos , Colorantes , Resistencia a Antineoplásicos , Citometría de Flujo/métodos , Humanos , Interleucina-2/administración & dosificación , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Compuestos de Mostaza Nitrogenada/administración & dosificación , Fenotipo , Proteínas Recombinantes/uso terapéutico , Rituximab , Vidarabina/administración & dosificación , Vidarabina/análogos & derivadosRESUMEN
Adult and child B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) differ in terms of incidence and prognosis. These disparities are mainly due to the molecular abnormalities associated with these two clinical entities. A genome-wide analysis using oligo SNP arrays recently demonstrated that PAX5 (paired-box domain 5) is the main target of somatic mutations in childhood BCP-ALL being altered in 38.9% of the cases. We report here the most extensive analysis of alterations of PAX5 coding sequence in 117 adult BCP-ALL patients in the unique clinical protocol GRAALL-2003/GRAAPH-2003. Our study demonstrates that PAX5 is mutated in 34% of adult BCP-ALL, mutations being partial or complete deletion, partial or complete amplification, point mutation or fusion gene. PAX5 alterations are heterogeneous consisting in complete loss in 17%, focal deletions in 10%, point mutations in 7% and translocations in 1% of the cases. PAX5 complete loss and PAX5 point mutations differ. PAX5 complete loss seems to be a secondary event and is significantly associated with BCR-ABL1 or TCF3-PBX1 fusion genes and a lower white blood cell count.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteínas de Unión al ADN/genética , Proteínas de Fusión bcr-abl/genética , Factor de Transcripción PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas Proto-Oncogénicas/genética , Adolescente , Adulto , Antineoplásicos/uso terapéutico , Benzamidas , Ensayos Clínicos Fase II como Asunto , Dosificación de Gen , Reordenamiento Génico de Linfocito T/genética , Genómica , Haplotipos , Humanos , Mesilato de Imatinib , Cadenas Pesadas de Inmunoglobulina/genética , Inmunofenotipificación , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Piperazinas/uso terapéutico , Mutación Puntual , Factor de Transcripción 1 de la Leucemia de Células Pre-B , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Pronóstico , Estudios Prospectivos , Pirimidinas/uso terapéutico , Adulto JovenRESUMEN
The t(8;16)(p11;p13) is a rare translocation involved in de novo and therapy-related myelomonocytic and monocytic acute leukemia. It fuses two genes encoding histone acetyltransferases (HATs), MYST3 located at 8p11 to CREBBP located at 16p13. Variant translocations involve other HAT-encoding genes such as EP300, MYST4, NCOA2 or NCOA3. MYST3-linked acute myeloid leukemias (AMLs) share specific clinical and biological features and a poor prognosis. Because of its rarity, the molecular biology of MYST3-linked AMLs remains poorly understood. We have established the genome and gene expression profiles of a multicentric series of 61 M4/M5 AMLs including 18 MYST3-linked AMLs by using array comparative genome hybridization (aCGH) (n=52) and DNA microarrays (n=44), respectively. We show that M4/5 AMLs have a variety of rare genomic alterations. One alteration, a gain of the MYB locus, was found recurrently and only in the MYST3-linked AMLs (7/18 vs 0/34). MYST3-AMLs have also a specific a gene expression profile, which includes overexpression of MYB, CD4 and HOXA genes. These features, reminiscent of T-cell acute lymphoid leukemia (ALL), suggest the targeting of a common T-myeloid progenitor.
Asunto(s)
Perfilación de la Expresión Génica/métodos , Genes myb/genética , Histona Acetiltransferasas/genética , Leucemia Mielomonocítica Aguda/genética , Antígenos CD4/genética , Hibridación Genómica Comparativa , Regulación Neoplásica de la Expresión Génica , Genoma Humano , Proteínas de Homeodominio/genética , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Proto-Oncogénicas c-myb/genéticaRESUMEN
Episomes with the NUP214-ABL1 fusion gene have been observed in 6% of T-ALL. In this multicentric study we collected 27 cases of NUP214-ABL1-positive T-ALL. Median age was 15 years with male predominance. Outcome was poor in 12 patients. An associated abnormality involving TLX1 or TLX3 was found in all investigated cases. Fluorescent in situ hybridization revealed a heterogeneous pattern of NUP214-ABL1 amplification. Multiple episomes carrying the fusion were detected in 24 patients. Episomes were observed in a significant number of nuclei in 18 cases, but in only 1-5% of nuclei in 6. In addition, intrachromosomal amplification (small hsr) was identified either as the only change or in association with episomes in four cases and two T-ALL cell lines (PEER and ALL-SIL). One case showed insertion of apparently non-amplified NUP214-ABL1 sequences at 14q12. The amplified sequences were analyzed using array-based CGH.These findings confirm that the NUP214-ABL1 gene requires amplification for oncogenicity; it is part of a multistep process of leukemogenesis; and it can be a late event present only in subpopulations. Data also provide in vivo evidence for a model of episome formation, amplification and optional reintegration into the genome. Implications for the use of kinase inhibitors are discussed.
Asunto(s)
Amplificación de Genes , Leucemia-Linfoma de Células T del Adulto/genética , Proteínas de Fusión Oncogénica/genética , Adolescente , Adulto , Línea Celular Tumoral , Niño , Preescolar , Femenino , Proteínas de Homeodominio/genética , Humanos , Leucemia-Linfoma de Células T del Adulto/etiología , Masculino , Persona de Mediana Edad , Plásmidos , Proteínas Proto-Oncogénicas/genética , Factores Sexuales , Resultado del Tratamiento , Adulto JovenRESUMEN
Thirty cases of acute myeloid leukaemia (AML) with MYST histone acetyltransferase 3 (MYST3) rearrangement were collected in a retrospective study from 14 centres in France and Belgium. The mean age at diagnosis was 59.4 years and 67% of the patients were females. Most cases (77%) were secondary to solid cancer (57%), haematological malignancy (35%) or both (8%), and appeared 25 months after the primary disease. Clinically, cutaneous localization and disseminated intravascular coagulation were present in 30 and 40% of the cases, respectively. AMLs were myelomonocytic (7%) or monocytic (93%), with erythrophagocytosis (75%) and cytoplasmic vacuoles (75%). Immunophenotype showed no particularity compared with monocytic leukaemia without MYST3 abnormality. Twenty-eight cases carried t(8;16)(p11;p13) with MYST3-CREBBP fusion, one case carried a variant t(8;22)(p11;q13) and one case carried a t(8;19)(p11;q13). Type I (MYST3 exon 16-CREBBP exon 3) was the most frequent MYST3-CREBBP fusion transcript (65%). MYST3 rearrangement was associated with a poor prognosis, as 50% of patients deceased during the first 10 months. All those particular clinical, cytologic, cytogenetic, molecular and prognostic characteristics of AML with MYST3 rearrangement may have allowed an individualization into the World Health Organization classification.
Asunto(s)
Cromosomas Humanos Par 8 , Reordenamiento Génico , Histona Acetiltransferasas/genética , Leucemia Mieloide Aguda/genética , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Cartilla de ADN , Femenino , Humanos , Inmunofenotipificación , Hibridación Fluorescente in Situ , Cariotipificación , Leucemia Mieloide Aguda/inmunología , Masculino , Persona de Mediana Edad , Pronóstico , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
A cytological, immunophenotypical and cytogenetical study of 136 chronic B-cell proliferations (93 CLL, 43 B-cell lymphomas) was led in order to precise diagnosis and to characterize and appreciate chromosomal rearrangements. In this series, mainly selected on blood lymphocytosis criteria, B-CLL were twice more frequent than small B-cell lymphomas. Probes used revealed cryptic abnormalities, which remained unknown by conventional cytogenetics (CC). The frequency of clonal abnormalities (CC and FISH) was 74.8% for this series, with 74.4% for lymphomas and 75.3% for CLL, mainly of Binet stage A (69 A, 13 B, 1 C, 10 unspecified). Proportion was 88.4% in A stages and 84.6% in B stages. In CLL, 13q14 cryptic deletions and translocations were widely majority, 14q32 translocations and trisomy 12 being predominant in lymphoma series. Interphase FISH study of non-clonal metaphasic abnormalities with locus-specific probes often revealed unrecognised clones.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos/genética , Leucemia Linfocítica Crónica de Células B/genética , Linfoma de Células B/genética , Aneuploidia , Cromosomas Humanos/ultraestructura , Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 13/ultraestructura , Células Clonales/patología , Estudios de Cohortes , Femenino , Humanos , Inmunofenotipificación , Hibridación Fluorescente in Situ , Cariotipificación , Leucemia Linfocítica Crónica de Células B/patología , Linfoma de Células B/patología , Trastornos Linfoproliferativos/genética , Masculino , Estadificación de Neoplasias , Eliminación de SecuenciaAsunto(s)
Biomarcadores de Tumor/genética , Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 9/genética , Proteínas de Fusión Oncogénica/genética , Factor de Transcripción PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/clasificación , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas/genética , Translocación Genética/genética , Biomarcadores de Tumor/sangre , Recuento de Células Sanguíneas , Preescolar , Proteínas del Citoesqueleto , Femenino , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Factores de TranscripciónAsunto(s)
Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 14/genética , Cadenas Pesadas de Inmunoglobulina/genética , MicroARNs/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Translocación Genética/genética , Adulto , Secuencia de Bases , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Homología de Secuencia de Ácido NucleicoRESUMEN
Secondary leukemias group essentially together myelodysplastic syndromes and acute leukemias, therapy-related (chemo- or radio-), or consecutive to environmental factors. It's now proven that some recurrent abnormalities are associated with effects of therapeutic agents, as -5/del(5q), -7/del(7q) linked to alkylating agents, or 11q23 and 21q22 abnormalities linked to inhibitors of Topoisomerase II. Even if important differences between secondary and "de novo" forms exist, the discrimination between these 2 categories is not always obvious: many common chromosomal abnormalities, "de novo" leukemias in older patients having characteristics close to those of postalkylating leukemias, neonatal forms possibly secondary to maternal affect. Recent studies identified some others chromosomal abnormalities in the secondary leukemias and confirmed the poor prognosis of these hemopathies. This review sums up criterions, circumstances and cytogenetic abnormalities.
Asunto(s)
Aberraciones Cromosómicas , Leucemia/etiología , Leucemia/genética , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/genética , Antineoplásicos Alquilantes/efectos adversos , Inhibidores Enzimáticos/efectos adversos , Eliminación de Gen , Humanos , Pronóstico , Radiación Ionizante , Inhibidores de Topoisomerasa II , Translocación GenéticaAsunto(s)
Linfocitos B/patología , Interleucina-2/farmacología , Cariotipificación/métodos , Activación de Linfocitos/efectos de los fármacos , Trastornos Linfoproliferativos/patología , Mitógenos/farmacología , Oligonucleótidos/farmacología , División Celular/efectos de los fármacos , Células Cultivadas/efectos de los fármacos , Células Cultivadas/ultraestructura , Aberraciones Cromosómicas , Bandeo Cromosómico/métodos , Estudios de Cohortes , Femenino , Humanos , Hibridación Fluorescente in Situ , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Linfoma de Células B/genética , Linfoma de Células B/patología , Trastornos Linfoproliferativos/genética , Masculino , Metafase , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
In order to identify genomic changes associated with an etoposide resistance acquisition, we used comparative genomic hybridization (CGH) to compare a human lung adenocarcinoma cell line, A549 wild type, and three sublines, A549-VP1-3, exposed to increasing concentrations of the topoisomerase II inhibitor, VP16. R-banding karyotype, fluorescence in situ hybridization (FISH), and Southern blot for the MLL gene were also performed. The CGH analysis showed that the A549-VP3 cell line shared chemoresistance-specific abnormalities (amplification of 11q23-qter, loss of chromosome 17, and deletions of 2p14-pter and 2q23-q24). FISH analysis confirmed the loss of one chromosome 17 in the three resistant sublines and revealed an increased fragmentation of chromosome 2 in more than two segments, depending on the etoposide concentration. FISH with an MLL gene probe showed additional signals of MLL (from three in the A549-WT to seven in the A549-VP3 cell line) translocated onto several other chromosomes. Southern blot indicated an amplification of the MLL gene, dependent on the etoposide concentration, without gene rearrangement. The CGH results are suggestive of loci that could be associated with the acquisition of an etoposide-chemoresistant phenotype. Deletion of the 2p region has already been reported, without any candidate gene being identified. The role of MLL in leukemogenesis has previously been demonstrated, but its role in the development of other tumors or its significance in the chemoresistance process remains to be elucidated.