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1.
Blood ; 134(21): 1821-1831, 2019 11 21.
Artículo en Inglés | MEDLINE | ID: mdl-31527074

RESUMEN

B-cell prolymphocytic leukemia (B-PLL) is a rare hematological disorder whose underlying oncogenic mechanisms are poorly understood. Our cytogenetic and molecular assessments of 34 patients with B-PLL revealed several disease-specific features and potential therapeutic targets. The karyotype was complex (≥3 abnormalities) in 73% of the patients and highly complex (≥5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving MYC [t(MYC)] (62%), deletion (del)17p (38%), trisomy (tri)18 (30%), del13q (29%), tri3 (24%), tri12 (24%), and del8p (23%). Twenty-six (76%) of the 34 patients exhibited an MYC aberration, resulting from mutually exclusive translocations or gains. Whole-exome sequencing revealed frequent mutations in TP53, MYD88, BCOR, MYC, SF3B1, SETD2, CHD2, CXCR4, and BCLAF1. The majority of B-PLL used the IGHV3 or IGHV4 subgroups (89%) and displayed significantly mutated IGHV genes (79%). We identified 3 distinct cytogenetic risk groups: low risk (no MYC aberration), intermediate risk (MYC aberration but no del17p), and high risk (MYC aberration and del17p) (P = .0006). In vitro drug response profiling revealed that the combination of a B-cell receptor or BCL2 inhibitor with OTX015 (a bromodomain and extra-terminal motif inhibitor targeting MYC) was associated with significantly lower viability of B-PLL cells harboring a t(MYC). We concluded that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting MYC may be a useful treatment option in this disease.


Asunto(s)
Leucemia Prolinfocítica Tipo Células B/genética , Proteínas Proto-Oncogénicas c-myc/genética , Proteína p53 Supresora de Tumor/genética , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Análisis Citogenético , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico
2.
Ann Hematol ; 98(12): 2749-2760, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31745601

RESUMEN

After analyzing treatment patterns in chronic lymphocytic leukemia (CLL) (objective 1), we investigated the relative effectiveness of ibrutinib versus other commonly used treatments (objective 2) in patients with treatment-naïve and relapsed/refractory CLL, comparing patient-level data from two randomized registration trials with two real-world databases. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated using a multivariate Cox proportional hazards model, adjusted for differences in baseline characteristics. Rituximab-containing regimens were often prescribed in clinical practice. The most frequently prescribed regimens were fludarabine + cyclophosphamide + rituximab (FCR, 29.3%), bendamustine + rituximab (BR, 17.7%), and other rituximab-containing regimens (22.0%) in the treatment-naïve setting (n = 604), other non-FCR/BR rituximab-containing regimens (38.7%) and non-rituximab-containing regimens (28.5%) in the relapsed/refractory setting (n = 945). Adjusted HRs (95% CI) for progression-free survival (PFS) and overall survival (OS), respectively, with ibrutinib versus real-world regimens were 0.23 (0.14-0.37; p < 0.0001) and 0.40 (0.22-0.76; p = 0.0048) in the treatment-naïve setting, and 0.21 (0.16-0.27; p < 0.0001) and 0.29 (0.21-0.41; p < 0.0001) in the relapsed/refractory setting. When comparing real-world use of ibrutinib (n = 53) versus other real-world regimens in relapsed/refractory CLL (objective 3), adjusted HRs (95% CI) were 0.37 (0.22-0.63; p = 0.0003) for PFS and 0.53 (0.27-1.03; p < 0.0624) for OS. This adjusted analysis, based on nonrandomized patient data, suggests ibrutinib to be more effective than other commonly used regimens for CLL.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bases de Datos Factuales , Leucemia Linfocítica Crónica de Células B , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Adenina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Clorhidrato de Bendamustina/administración & dosificación , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Piperidinas , Rituximab/administración & dosificación , Tasa de Supervivencia , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados
3.
Haematologica ; 102(10): 1758-1766, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28751561

RESUMEN

Splenic diffuse red pulp lymphoma is an indolent small B-cell lymphoma recognized as a provisional entity in the World Health Organization 2008 classification. Its precise relationship to other related splenic B-cell lymphomas with frequent leukemic involvement or other lymphoproliferative disorders remains undetermined. We performed whole-exome sequencing to explore the genetic landscape of ten cases of splenic diffuse red pulp lymphoma using paired tumor and normal samples. A selection of 109 somatic mutations was then evaluated in a cohort including 42 samples of splenic diffuse red pulp lymphoma and compared to those identified in 46 samples of splenic marginal zone lymphoma and eight samples of hairy-cell leukemia. Recurrent mutations or losses in BCOR (the gene encoding the BCL6 corepressor) - frameshift (n=3), nonsense (n=2), splicing site (n=1), and copy number loss (n=4) - were identified in 10/42 samples of splenic diffuse red pulp lymphoma (24%), whereas only one frameshift mutation was identified in 46 cases of splenic marginal zone lymphoma (2%). Inversely, KLF2, TNFAIP3 and MYD88, common mutations in splenic marginal zone lymphoma, were rare (one KLF2 mutant in 42 samples; 2%) or absent (TNFAIP3 and MYD88) in splenic diffuse red pulp lymphoma. These findings define an original genetic profile of splenic diffuse red pulp lymphoma and suggest that the mechanisms of pathogenesis of this lymphoma are distinct from those of splenic marginal zone lymphoma and hairy-cell leukemia.


Asunto(s)
Biomarcadores de Tumor , Variación Genética , Linfoma de Células B/diagnóstico , Linfoma de Células B/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Neoplasias del Bazo/diagnóstico , Neoplasias del Bazo/genética , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Leucemia de Células Pilosas/diagnóstico , Leucemia de Células Pilosas/genética , Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma de Células B de la Zona Marginal/genética , Persona de Mediana Edad , Mutación , Factor 88 de Diferenciación Mieloide/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Secuenciación del Exoma
4.
Br J Haematol ; 173(1): 137-44, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26887776

RESUMEN

Dysregulation of MYC is the genetic hallmark of Burkitt lymphoma (BL) but it is encountered in other aggressive mature B-cell lymphomas. MYC dysregulation needs other cooperating events for BL development. We aimed to characterize these events and assess the differences between adult and paediatric BLs that may explain the different outcomes in these two populations. We analysed patterns of genetic aberrations in a series of 24 BLs: 11 adults and 13 children. We looked for genomic imbalances (copy number variations), copy-neutral loss of heterozygosity (CN-LOH) and mutations in TP53, CDKN2A, ID3 (exon 1), TCF3 (exon17) and CCND3 (exon 6). Young patients displayed more frequent 13q31.3q32.1 amplification, 7q32q36 gain and 5q23.3 CN-LOH, while 17p13 and 18q21.3 CN-LOH were only detected in adult BLs. ID3 mutations were present in all adult samples, but only in 42% of childhood cases. CCND3 and ID3 double-hit mutations, as well as 18q21 CN-LOH, seemed to be associated with poorer outcome. For the first time, we report different genetic anomalies between adult and paediatric BLs, suggesting age-related heterogeneity in Burkitt lymphomagenesis. This may explain the poorer prognosis of adult BLs. Additional studies are needed to confirm these results in the setting of clinical trials.


Asunto(s)
Linfoma de Burkitt/genética , Aberraciones Cromosómicas , Cromosomas Humanos/genética , Pérdida de Heterocigocidad , Proteínas de Neoplasias/genética , Adolescente , Adulto , Factores de Edad , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino
5.
Cytogenet Genome Res ; 147(2-3): 111-7, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26669311

RESUMEN

Supernumerary ring chromosomes (SRC) are usually derived from regions adjacent to the centromere. Their identification may be challenging, particularly in case of low mosaicism. Here, we report on a patient who was referred for major in utero growth retardation, severe developmental delay, facial dysmorphism, cleft palate, and hypospadias. The karyotype showed a small SRC in mosaic. The combination of FISH, M-FISH and array-CGH was necessary for a complete characterization of this SRC. M-FISH revealed that the SRC originated from chromosome 7. Array-CGH performed with a 400K oligonucleotide array showed a gain in region 7q22.1q31.1 present in low mosaic. This result was confirmed by FISH using BAC probes specific for chromosome 7. The SRC was a neocentric ring derived from 7q22.1q31.1 and was found in only 8% of the cells. This is the first patient carrying a mosaic neocentric SRC derived from the long arm of chromosome 7. Our study emphasizes the need to combine different techniques and to use adapted bioinformatic tools for low-mosaicism marker identification. It also contributes to the delineation of the partial trisomy 7q phenotype.


Asunto(s)
Anomalías Múltiples/genética , Cromosomas Humanos Par 7/genética , Mosaicismo , Cromosomas en Anillo , Centrómero/genética , Niño , Preescolar , Bandeo Cromosómico , Hibridación Genómica Comparativa , Discapacidades del Desarrollo , Cara/anomalías , Retardo del Crecimiento Fetal , Estudios de Seguimiento , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Cariotipificación , Masculino
6.
Br J Haematol ; 164(5): 659-67, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24274024

RESUMEN

Follicular Lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) subtype and its course is heterogeneous. At diagnosis, some patients with FL manifest a detectable leukaemic phase (FL-LP), but this feature has been seldom described and is poorly characterized. Among 499 patients diagnosed with FL in Lyon-Sud hospital, 37 (7·4%) had characteristic FL-LP (by cytological blood smears and flow cytometric analysis). In addition, 91/1135 FL patients from the PRIMA study presented FL-LP at study entry. In order to evaluate the outcome of this Lyon-Sud cohort, FL-LP patients were matched with 111 newly diagnosed FL without LP according to the Follicular Lymphoma International Prognostic Index (FLIPI) score, age and treatment. Presence of FL-LP was associated with shorter progression-free survival (PFS) and overall survival (OS) (P = 0·004 and P = 0·031, respectively). Presence of FL-LP and high FLIPI score remained independent prognostic factors in a Cox model for time to progression (TTP). A number of circulating lymphoma cells (CLC) >4 × 10(9) /l was the most significant predictor for a shorter TTP in this Cox model. The prognostic impact of FL-LP on TTP was validated in the PRIMA cohort (P = 0·0004). In conclusion, FL-LP is a rare event associated with shorter PFS and patients with CLC >4 × 10(9) /l have a poorer outcome. These patients should be monitored carefully to consider alternative therapeutic options.


Asunto(s)
Leucocitosis/etiología , Linfoma Folicular/complicaciones , Anciano , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Progresión de la Enfermedad , Femenino , Humanos , Linfoma Folicular/diagnóstico , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/patología , Masculino , Persona de Mediana Edad , Células Neoplásicas Circulantes/patología , Pronóstico , Enfermedades Raras/etiología , Estudios Retrospectivos , Rituximab , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Resultado del Tratamiento
10.
Genes Chromosomes Cancer ; 52(1): 81-92, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23012230

RESUMEN

We previously showed that complex karyotypes (CK) and chromosome 13q abnormalities have an adverse prognostic impact in childhood Burkitt lymphomas/leukemias (BL) and diffuse large B-cell lymphomas (DLBCL). The aim of our study was to identify recurrent alterations associated with MYC rearrangements in aggressive B-cell lymphomas with CK. Multicolor fluorescence in situ hybridization (M-FISH) was performed in 84 patient samples (59 adults and 25 children), including 37 BL (13 lymphomas and 24 acute leukemias), 12 DLBCL, 28 B-cell lymphomas with intermediate features (DLBCL/BL), 4 B-cell precursor acute lymphoblastic leukemias (BCP-ALL), and 3 unclassifiable B-cell lymphomas. New (cytogenetically undetected) abnormalities were identified in 80% of patients. We also refined one-third of the chromosomal aberrations detected by karyotyping. M-FISH proved to be more useful in identifying chromosomal partners involved in unbalanced translocations and in revealing greater complexity of 13q rearrangements. Most of the newly identified or refined recurrent alterations involved 1q, 13q and 3q (gains/losses), 7q and 18q (gains), or 6q (losses), suggesting that these secondary aberrations may play a role in lymphomagenesis. Several patterns of genomic aberrations were identified: 1q gains in BL, trisomies 7 in DLBCL, and 18q-translocations in adult non-BL. BCP-ALL usually displayed an 18q21 rearrangement. BL karyotypes were less complex and aneuploid than those of other MYC-rearranged lymphomas. BCP-ALL and DLBCL/BL were associated with a higher rate of early death than BL and DLBCL. These findings support the categorization of DLBCL/BL as a distinct entity and suggest that BL with CK are indeed different from other aggressive MYC-rearranged lymphomas, which usually show greater genetic complexity. © 2012 Wiley Periodicals, Inc.


Asunto(s)
Linfoma de Burkitt/genética , Aberraciones Cromosómicas , Cromosomas Humanos , Reordenamiento Génico , Genes myc , Linfoma de Células B/genética , Cariotipo Anormal , Adolescente , Niño , Preescolar , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino
11.
EMBO J ; 28(16): 2428-36, 2009 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-19644448

RESUMEN

The localization of genes within the nuclear space is of paramount importance for proper genome functions. However, very little is known on the cis-acting elements determining subnuclear positioning of chromosome segments. We show here that the D4Z4 human subtelomeric repeat localizes a telomere at the nuclear periphery. This perinuclear activity lies within an 80 bp sequence included within a region known to interact with CTCF and A-type Lamins. We further show that a reduced level of either CTCF or A-type Lamins suppresses the perinuclear activities of D4Z4 and that an array of multimerized D4Z4 sequence, which has lost its ability to bind CTCF and A-type Lamins, is not localized at the periphery. Overall, these findings reveal the existence of an 80 bp D4Z4 sequence that is sufficient to position an adjacent telomere to the nuclear periphery in a CTCF and A-type lamins-dependent manner. Strikingly, this sequence includes a 30 bp GA-rich motif, which binds CTCF and is present at several locations in the human genome.


Asunto(s)
Lamina Tipo A/metabolismo , Proteínas Represoras/metabolismo , Telómero/química , Telómero/metabolismo , Animales , Secuencia de Bases , Transporte Biológico , Factor de Unión a CCCTC , Carcinoma/genética , Carcinoma/metabolismo , Línea Celular Tumoral , Nucléolo Celular/química , Nucléolo Celular/metabolismo , Regulación hacia Abajo , Células Epiteliales/citología , Células Epiteliales/metabolismo , Femenino , Humanos , Elementos Aisladores , Región de Control de Posición , Unión Proteica , Proteínas Represoras/genética , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/metabolismo
12.
Histopathology ; 62(6): 876-93, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23611359

RESUMEN

AIMS: To describe 76 cases of splenic marginal zone lymphoma (SMZL), including correlations with clinical and other characteristics. METHODS AND RESULTS: Patients were predominantly female, with a median age of 62 years. The main clinical presentation was splenomegaly, except for eight cases presenting with evolution of autoimmune disorders or spontaneous splenic rupture. White pulp infiltration was nodular, with a monophasic (42%) or biphasic (53%) pattern, and associated diffuse or nodular infiltration of the red pulp, except for four cases which had atrophic white pulp. Plasmacytic differentiation and the MYD88 L265P mutation were observed in 18% and 5% of the cases, respectively. Histological progression was considered in cases with a significant association of large cells with Ki67 > 30% and macronodular architecture (P = 0.001). Other significant correlations were found between del7q (44%) and del6q (17%) (P = 0.018), IGHV1-2*04 segment usage (35%) (P = 0.001) and unmutated IGHV (39%) (P = 0.019), and between CD5 expression (27%) and higher lymphocytosis (P = 0.002). Patients requiring intensive chemotherapy after splenectomy because of clinical and/or histological progression had significantly shorter overall survival (P = 0.012). CONCLUSIONS: We report the histological spectrum of SMZL, and discuss the differential diagnosis and requirement for molecular and cytogenetic analysis in atypical cases.


Asunto(s)
Aberraciones Cromosómicas , Genes de las Cadenas Pesadas de las Inmunoglobulinas , Linfoma de Células B de la Zona Marginal/genética , Linfoma de Células B de la Zona Marginal/inmunología , Mutación , Neoplasias del Bazo/genética , Neoplasias del Bazo/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Linfoma de Células B de la Zona Marginal/patología , Masculino , Persona de Mediana Edad , Factor 88 de Diferenciación Mieloide/genética , Pronóstico , Neoplasias del Bazo/patología
13.
Haematologica ; 98(4): 649-54, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23065509

RESUMEN

Waldenström's macroglobulinemia is a disease of mature B cells, the genetic basis of which is poorly understood. Few recurrent chromosomal abnormalities have been reported, and their prognostic value is not known. We conducted a prospective cytogenetic study of Waldenström's macroglobulinemia and examined the prognostic value of chromosomal aberrations in an international randomized trial. The main aberrations were 6q deletions (30%), trisomy 18 (15%), 13q deletions (13%), 17p (TP53) deletions (8%), trisomy 4 (8%), and 11q (ATM) deletions (7%). There was a significant association between trisomy of chromosome 4 and trisomy of chromosome 18. Translocations involving the IGH genes were rare (<5%). Deletion of 6q and 11q, and trisomy 4, were significantly associated with adverse clinical and biological parameters. Patients with TP53 deletion had short progression-free survival and short disease-free survival. Although rare (<5%), trisomy 12 was associated with short progression-free survival. In conclusion, the cytogenetic profile of Waldenström's macroglobulinemia appears to differ from that of other B-cell lymphomas. Chromosomal abnormalities may help with diagnosis and prognostication, in conjunction with other clinical and biological characteristics.


Asunto(s)
Aberraciones Cromosómicas , Macroglobulinemia de Waldenström/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Clorambucilo/uso terapéutico , Deleción Cromosómica , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 18/genética , Cromosomas Humanos Par 4/genética , Cromosomas Humanos Par 6/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Cariotipo , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Trisomía , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Macroglobulinemia de Waldenström/tratamiento farmacológico , Macroglobulinemia de Waldenström/patología
14.
Br J Haematol ; 158(4): 489-98, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22686190

RESUMEN

The translocation t(14;18) and its t(2;18) and t(18,22) variants, which involve the BCL2 genetic hallmark for follicular lymphoma (FL), have been reported in several cases of chronic B-cell lymphoproliferative disease (CLPD) and frequently in chronic lymphocytic leukaemia (CLL). We describe here the clinical, morphological, immunological, cytogenetic and molecular findings from 37 cases of t(14;18)-positive CLPD, identified from our series of non-FL B-cell neoplasms (n=993) that were routinely analysed in peripheral blood by conventional cytogenetics analyses. The FL diagnosis was excluded by morphology and immunology (the samples were CD10 negative in all cases). The BCL2 translocations were observed in 22 CLL cases, including 7 monoclonal B-cell lymphocytosis (MBL) cases re-classified according to the new International Workshop on CLL criteria, six small lymphocytic lymphoma (SLL) cases, 1 splenic marginal zone lymphoma (SMZL) case and eight cases of unclassifiable CLPD with overlapping CLL/MZL features. In the CLL cases, the IGH/BCL2 fusion was remarkably associated with trisomy 12 (13/22) and mutated IGHV status (20/21) and did not affect the outcome. Moreover, most of these CLLs harboured a low mutation load of BCL6 gene and unmutated FAS (CD95) loci, which points to a post-germinal-centre cellular origin.


Asunto(s)
Genes bcl-2/genética , Cadenas Pesadas de Inmunoglobulina/genética , Trastornos Linfoproliferativos/genética , Fusión de Oncogenes , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 18/genética , Humanos , Inmunofenotipificación , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Leucemia Linfocítica Crónica de Células B/terapia , Linfocitosis/genética , Linfocitosis/patología , Linfocitosis/terapia , Trastornos Linfoproliferativos/patología , Trastornos Linfoproliferativos/terapia , Masculino , Persona de Mediana Edad , Translocación Genética , Resultado del Tratamiento , Trisomía
15.
Blood ; 115(11): 2214-9, 2010 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-19965626

RESUMEN

The t(14;18)(q32;q21) involving the immunoglobulin heavy chain locus (IGH) and the MALT1 gene is a recurrent abnormality in mucosa-associated lymphoid tissue (MALT) lymphomas. However, the nucleotide sequence of only one t(14;18)-positive MALT lymphoma has been reported so far. We here report the molecular characterization of the IGH-MALT1 fusion products in 5 new cases of t(14;18)-positive MALT lymphomas. Similar to the IGH-associated translocations in follicular and mantle cell lymphomas, the IGH-MALT1 junctions in MALT lymphoma showed all features of a recombination signal sequence-guided V(D)J-mediated translocation at the IGH locus. Furthermore, analogous to follicular and mantle cell lymphoma, templated nucleotides (T-nucleotides) were identified at the t(14;18)/IGH-MALT1 breakpoint junctions. On chromosome 18, we identified a novel major breakpoint region in MALT1 upstream of its coding region. Moreover, the presence of duplications of MALT1 nucleotides in one case suggests an underlying staggered DNA-break process not consistent with V(D)J-mediated recombination. The molecular characteristics of the t(14;18)/IGH-MALT1 resemble those found in the t(14;18)/IGH-BCL2 in follicular lymphoma and t(11;14)/CCND1-IGH in mantle cell lymphoma, suggesting that these translocations could be generated by common pathomechanisms involving illegitimate V(D)J-mediated recombination on IGH as well as new synthesis of T-nucleotides and nonhomologous end joining (NHEJ) or alternative NHEJ repair pathways on the IGH-translocation partner.


Asunto(s)
Caspasas/genética , Puntos de Rotura del Cromosoma , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 18/genética , Linfoma de Células B de la Zona Marginal/genética , Mutagénesis Insercional/genética , Proteínas de Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Translocación Genética , Anciano , Secuencia de Bases , Femenino , Sitios Genéticos/genética , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Linfoma Folicular/genética , Linfoma de Células del Manto/genética , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Mutación/genética , Nucleótidos/genética , Moldes Genéticos
16.
Blood ; 116(8): 1317-20, 2010 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-20460502

RESUMEN

Sequence variants at the TERT-CLPTM1L locus in chromosome 5p have been recently associated with disposition for various cancers. Here we show that this locus including the gene encoding the telomerase reverse-transcriptase TERT at 5p13.33 is rarely but recurrently targeted by somatic chromosomal translocations to IGH and non-IG loci in B-cell neoplasms, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, mantle cell lymphoma and splenic marginal zone lymphoma. In addition, cases with genomic amplification of TERT locus were identified. Tumors bearing chromosomal aberrations involving TERT showed higher TERT transcriptional expression and increased telomerase activity. These data suggest that deregulation of TERT gene by chromosomal abnormalities leading to increased telomerase activity might contribute to B-cell lymphomagenesis.


Asunto(s)
Leucemia de Células B/genética , Linfoma de Células B/genética , Telomerasa/genética , Translocación Genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Niño , Femenino , Perfilación de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Leucemia de Células B/patología , Linfoma de Células B/patología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Telomerasa/metabolismo
17.
Blood ; 115(16): 3215-23, 2010 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-20032498

RESUMEN

The prognostic impact of minimal residual disease (MRD) was analyzed in 259 patients with mantle cell lymphoma (MCL) treated within 2 randomized trials of the European MCL Network (MCL Younger and MCL Elderly trial). After rituximab-based induction treatment, 106 of 190 evaluable patients (56%) achieved a molecular remission (MR) based on blood and/or bone marrow (BM) analysis. MR resulted in a significantly improved response duration (RD; 87% vs 61% patients in remission at 2 years, P = .004) and emerged to be an independent prognostic factor for RD (hazard ratio = 0.4, 95% confidence interval, 0.1-0.9, P = .028). MR was highly predictive for prolonged RD independent of clinical response (complete response [CR], complete response unconfirmed [CRu], partial response [PR]; RD at 2 years: 94% in BM MRD-negative CR/CRu and 100% in BM MRD-negative PR, compared with 71% in BM MRD-positive CR/CRu and 51% in BM MRD-positive PR, P = .002). Sustained MR during the postinduction period was predictive for outcome in MCL Younger after autologous stem cell transplantation (ASCT; RD at 2 years 100% vs 65%, P = .001) and during maintenance in MCL Elderly (RD at 2 years: 76% vs 36%, P = .015). ASCT increased the proportion of patients in MR from 55% before high-dose therapy to 72% thereafter. Sequential MRD monitoring is a powerful predictor for treatment outcome in MCL. These trials are registered at www.clinicaltrials.gov as #NCT00209222 and #NCT00209209.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Inmunoterapia , Linfoma de Células del Manto/patología , Linfoma de Células del Manto/terapia , Radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Separación Celular , Terapia Combinada , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Inmunoterapia/métodos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasia Residual , Reacción en Cadena de la Polimerasa , Pronóstico , Resultado del Tratamiento
20.
Nucleosides Nucleotides Nucleic Acids ; 41(11): 1099-1108, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35199627

RESUMEN

Extracellular adenosine is produced from ATP by CD39 and CD73, and can modulate tumor development by acting on cancer cells or immune cells. Adenosine metabolism has been poorly studied in uveal melanoma. We studied the protein levels of CD39 and CD73 in a small, well described cohort of patients with uveal melanoma. Our results show a high variability in the levels of the two proteins, both in positivity and in intensity. Our results suggest that similar studies on larger cohorts could determine the clinical value and the druggability of these enzymes in the given clinical setting.Supplemental data for this article is available online at http://dx.doi.org/10.1080/15257770.2022.2032738.


Asunto(s)
Apirasa , Melanoma , Humanos , 5'-Nucleotidasa/metabolismo , Adenosina/metabolismo , Adenosina Trifosfato/metabolismo , Antígenos CD/metabolismo , Apirasa/metabolismo
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