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1.
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
2.
Genes Chromosomes Cancer ; 54(10): 595-605, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26252834

RESUMEN

We report five chronic myeloid leukaemia (CML) patients in whom we identified and characterized undescribed BCR-ABL1 fusion transcripts. We investigated the precise features of the molecular rearrangements and the minimal residual disease follow-up for these five patients. Three resulted from new rearrangements between the BCR and ABL1 sequences (the breakpoints being located within BCR exon 13 in two cases and within BCR exon 18 in one case). The other two cases revealed a complex e8-[ins]-a2 fusion transcript involving a third partner gene, PRDM12 and SPECC1L, respectively. Moreover, single nucleotide polymorphism-array analysis performed in the latter two cases showed copy number alterations shared by the two patients, thus identifying genes that were deleted during rearrangement and suggesting their potential role in CML pathogenesis. Interestingly, we highlight that the prognosis of alterations, such as the presence of an e8a2 transcript or the deletion of various genes, which have been controversial, may be definitively erased by the introduction of tyrosine kinase inhibitors (TKIs).


Asunto(s)
Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Adulto , Anciano , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad
3.
J Clin Lab Anal ; 29(2): 153-61, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24652675

RESUMEN

BACKGROUND: The rigorous cytological review by manual or automatic microscopic analysis is critical in the detection of circulating neoplastic cells, since their morphology as well as their count contributes to the diagnosis and prognosis of many diseases. However, the cytological analysis is not always obvious and requires trained and competent cytologist. In this context, the alarms and/or parameters generated by hematology analyzer could be particularly informative to alert the operators. METHODS: Blood samples from patients with Sezary syndrome (n = 9) were studied with Sysmex XN-1000 analyzer, and compared to patients with benign or tumoral skin lesions (n = 47) and patients with chronic lymphoproliferative B-cell diseases (n = 51) used as control. RESULTS: In present series, the value of structural lymphoid parameters (LyX and LyZ) and the alarm Blast/Abn Lympho were statistically higher in Sezary cases than in control cases. In addition, the value of LyX was associated to the count of circulating Sezary cells and value of LyZ to the presence of large Sezary cells, both parameters described as prognostic factors. CONCLUSION: The combination of alarm Blast/Abn Lympho and structural parameters (Ly-X/Ly-Z/Ly-Y) may allow to define rule of blood slide review to screen circulating Sezary cells, and give promising results in B-cell diseases.


Asunto(s)
Pruebas Hematológicas/instrumentación , Síndrome de Sézary/sangre , Linfocitos T/patología , Autoanálisis , Linfocitos B/patología , Recuento de Células Sanguíneas , Núcleo Celular/patología , Citoplasma/patología , Diagnóstico Diferencial , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Masculino , Persona de Mediana Edad
5.
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
6.
Mod Pathol ; 24(7): 993-1003, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21499231

RESUMEN

Angioimmunoblastic T-cell lymphoma is immunologically defined by the expression of CD10 and the follicular helper T cell (T(FH)) markers such as CXCL13, programmed death-1 (PD-1) and inducible T-cell costimulator (ICOS). This T(FH) profile has been mainly reported by immunohistochemistry. Here, using multiparametric flow cytometry, the relevance of ICOS and PD-1 to angioimmunoblastic T-cell lymphoma diagnosis was evaluated in lymph node (n=15) as well as in peripheral blood (n=13) among a series of 28 angioimmunoblastic T-cell lymphoma cases, in addition to the CD10 expression (available in 26 lymph node and 15 peripheral blood specimens). In this series, CD10 expression was present in 23/26 (88%) lymph node and in 12/15 (80%) peripheral blood cases and ICOS in 13/15 (87%) lymph node and in 6/13 (47%) peripheral blood cases, whereas neither significant CD10 nor ICOS T cells were identified in the control group (lymph nodes with reactive hyperplasia=10, peripheral blood of healthy donors=15). PD-1 expression was less informative as observed in both angioimmunoblastic T-cell lymphoma and control cases. The multiparametric approach allowed us to confirm the frequent blood dissemination in angioimmunoblastic T-cell lymphoma and to show that circulating neoplastic T cells correspond more often to a CD10-positive subset than to an ICOS-positive subset. Consequently, if ICOS constitutes an additional feature for the diagnosis of angioimmunoblastic T-cell lymphoma, it appears less sensitive than CD10 expression for the detection of circulating neoplastic T cells.


Asunto(s)
Antígenos de Diferenciación de Linfocitos T/biosíntesis , Linfadenopatía Inmunoblástica/metabolismo , Linfoma de Células T/metabolismo , Células Neoplásicas Circulantes/metabolismo , Neprilisina/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/análisis , Antígenos CD/biosíntesis , Antígenos de Diferenciación de Linfocitos T/análisis , Proteínas Reguladoras de la Apoptosis/análisis , Proteínas Reguladoras de la Apoptosis/biosíntesis , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/sangre , Separación Celular , Femenino , Citometría de Flujo , Humanos , Proteína Coestimuladora de Linfocitos T Inducibles , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Linfoma de Células T/patología , Masculino , Persona de Mediana Edad , Neprilisina/análisis , Receptor de Muerte Celular Programada 1
7.
Biol Cell ; 101(9): 511-24, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19250063

RESUMEN

BACKGROUND INFORMATION: miRNAs (microRNAs) are a class of non-coding RNAs that inhibit gene expression by binding to recognition elements, mainly in the 3' UTR (untranslated region) of mRNA. A single miRNA can target several hundred mRNAs, leading to a complex metabolic network. miR-16 (miRNA-16), located on chromosome 13q14, is involved in cell proliferation and apoptosis regulation; it may interfere with either oncogenic or tumour suppressor pathways, and is implicated in leukaemogenesis. These data prompted us to search for and validate novel targets of miR-16. RESULTS: In the present study, by using a combined bioinformatics and molecular approach, we identified two novel putative targets of miR-16, caprin-1 (cytoplasmic activation/proliferation-associated protein-1) and HMGA1 (high-mobility group A1), and we also studied cyclin E which had been previously recognized as an miR-16 target by bioinformatics database. Using luciferase activity assays, we demonstrated that miR-16 interacts with the 3' UTR of the three target mRNAs. We showed that miR-16, in MCF-7 and HeLa cell lines, down-regulates the expression of caprin-1, HMGA1a, HMGA1b and cyclin E at the protein level, and of cyclin E, HMGA1a and HMGA1b at the mRNA levels. CONCLUSIONS: Taken together, our data demonstrated that miR-16 can negatively regulate two new targets, HMGA1 and caprin-1, which are involved in cell proliferation. In addition, we also showed that the inhibition of cyclin E expression was due, at least in part, to a decrease in its mRNA stability.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Proliferación Celular , Proteína HMGA1a/metabolismo , MicroARNs/metabolismo , Secuencia de Aminoácidos , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Proteína HMGA1a/química , Proteína HMGA1a/genética , Proteína HMGA1b/química , Proteína HMGA1b/genética , Proteína HMGA1b/metabolismo , Humanos , MicroARNs/química , MicroARNs/genética , Datos de Secuencia Molecular , Unión Proteica , Alineación de Secuencia
8.
Leuk Res ; 32(10): 1608-10, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18448166

RESUMEN

We report the emergence of a chronic myeloid leukaemia (CML) during the course of a JAK2V617F-positive chronic idiopathic myelofibrosis (CIMF) in the absence of any myelosuppressive treatment. Although a response to imatinib was observed, the underlying myelofibrosis persisted after treatment and hydroxyurea was finally added to control the persistent thrombocytosis. Such rare patients with co-existing BCR-ABL translocation and JAK2V617F mutation must be identified in view of the possibility of targeted therapies. Moreover, the detection of BCR-ABL translocation appears to be crucial especially in the case of treated CIMF with an atypical course to identify CML before acute transformation.


Asunto(s)
Janus Quinasa 2/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Mielofibrosis Primaria/complicaciones , Sustitución de Aminoácidos , Enfermedad Crónica , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/complicaciones , Masculino , Persona de Mediana Edad , Mutación Puntual , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/tratamiento farmacológico , ARN Mensajero/análisis
9.
Oncotarget ; 9(34): 23589-23598, 2018 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-29805758

RESUMEN

In splenic marginal zone lymphoma (SMZL), specific and functional Toll-like Receptor (TLR) patterns have been recently described, suggesting their involvement in tumoral proliferation. Splenic diffuse red pulp lymphoma with villous lymphocytes (SDRPL) is close to but distinct from SMZL, justifying here the comparison of TLR patterns and functionality in both entities. Distinct TLR profiles were observed in both lymphoma subtypes. SDRPL B cells showed higher expression of TLR7 and to a lesser degree TLR9, in comparison to SMZL B cells. In both entities, TLR7 and TLR9 pathways appeared functional, as shown by IL-6 production upon TLR7 and TLR9 agonists stimulations. Interestingly, circulating SDRPL, but not SMZL B cells, constitutively expressed CD86. In addition, stimulation with both TLR7 and TLR9 agonists significantly increased CD80 expression in circulating SDRPL but not SMZL B cells. Finally, TLR7 and TLR9 stimulations had no impact on proliferation and apoptosis of SMZL or SDRPL B cells. In conclusion, SMZL and SDRPL may derive from different splenic memory B cells with specific immunological features that can be used as diagnosis markers in the peripheral blood.

11.
Leuk Res ; 31(6): 865-8, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17208297

RESUMEN

Dasatinib is efficient in vitro against most of CML cells harboring ABL kinase domain mutations and induces high rates of response in imatinib-resistant CML patients. Here, we monitored the mutated BCR-ABL transcripts during the follow-up of 12 CML patients treated with dasatinib. We identified four groups of patients based on their sensitivity to dasatinib. Clinical responses were correlated to the in vitro sensitivity of BCR-ABL mutants to dasatinib, however, some discrepancies were observed in a subfraction of CML patients, suggesting subtle differences between in vitro observations and clinical entities and/or the onset of other mechanisms responsible for dasatinib resistance.


Asunto(s)
Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Mutación , Polimorfismo de Longitud del Fragmento de Restricción , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Tiazoles/administración & dosificación , Adulto , Anciano , Benzamidas , Dasatinib , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Estudios de Seguimiento , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Piperazinas/administración & dosificación
12.
Cancer Genet Cytogenet ; 175(2): 159-65, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17556073

RESUMEN

High-resolution multicolor banding (mBAND) analysis was applied to precisely fine-map the genomic extent of 7q deletions in a series of 26 marginal zone lymphoma patients displaying the abnormality on conventional karyotypes. Using this approach, the breakpoints and the extent of deletions revealed by conventional banding techniques had to be re-defined in 70% of cases. Although no common minimal region of deletion was delineated, mBAND demonstrated the involvement of the 7q32 region in more than 90% of cases. In addition, unsuspected translocations and intrachromosomal changes could be identified in four cases. Taken together, these data demonstrate that mBAND represents an alternative cytogenetic tool in the comprehensive analysis of chromosome aberrations in hematologic malignancies, allowing rapid screening and precise delineation of structural rearrangements of a defined chromosome. This also confirms the localization in the vicinity of band 7q32 of putative candidate gene(s) involved in the pathogenic development of the disease.


Asunto(s)
Bandeo Cromosómico , Deleción Cromosómica , Cromosomas Humanos Par 7/genética , Linfoma de Células B/genética , Femenino , Humanos , Masculino
13.
Mol Cell Biol ; 24(13): 5808-20, 2004 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15199137

RESUMEN

The CCR4-associated protein CAF1 has been demonstrated to play several roles in the control of transcription and of mRNA decay. To gain further insight into its physiological function, we generated CAF1-deficient mice. They are viable, healthy, and normal in appearance; however, mCAF1(-/-) male mice are sterile. The crossing of mCAF1(+/-) mice gave a Mendelian ratio of mCAF1(+/+), mCAF1(+/-), and mCAF1(-/-) pups, indicating that haploid mCAF1-deficient germ cells differentiate normally. The onset of the defect occurs during the first wave of spermatogenesis at 19 to 20 days after birth, during progression of pachytene spermatocytes to haploid spermatids and spermatozoa. Early disruption of spermatogenesis was evidenced by Sertoli cell vacuolization and tubular disorganization. The most mature germ cells were the most severely depleted, but progressively all germ cells were affected, giving Sertoli cell-only tubes, large interstitial spaces, and small testes. This phenotype could be linked to a defect(s) in germ cells and/or to inadequate Sertoli cell function, leading to seminiferous tubule disorganization and finally to a total disappearance of germ cells. The mCAF1-deficient mouse provides a new model of failed spermatogenesis in the adult that may be relevant to some cases of human male sterility.


Asunto(s)
Proteínas/fisiología , Espermatogénesis , Animales , Exorribonucleasas , Células Germinativas/patología , Haploidia , Inmunohistoquímica , Infertilidad Masculina , Masculino , Ratones , Ratones Noqueados , Microscopía Electrónica , Fenotipo , Proteínas/genética , Proteínas Represoras , Ribonucleasas , Túbulos Seminíferos/patología , Células de Sertoli/patología , Factores de Transcripción
14.
Cancer Res ; 65(15): 6521-5, 2005 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-16061630

RESUMEN

More than 35 different partner genes with the mixed lineage leukemia (MLL) gene have been cloned from leukemia cells with translocations involving chromosome 11 band q23. In this study, we report on a novel fusion partner of the MLL gene, AF4p12, which we have identified as the human homologue to the furry gene of Drosophila. AF4p12, highly conserved in evolution, encodes a large protein of 3,105 amino acids. The expression of AF4p12 has been preferentially detected in colon, placenta, and brain tissues and in tumor cells of lymphoid origin. We show that the t(4;11)(p12;q23) translocation results in the creation of a chimeric RNA encoding a putative fusion protein containing 1,362 amino acids from the NH2-terminal part of MLL and 712 amino acids from the COOH-terminal part of AF4p12. FLT3 and HOXA9 genes are overexpressed in this leukemia. We found that the COOH-terminal part of AF4p12 fused to MLL contains a leucine zipper motif and exhibits transcriptional activation properties when fused to Gal4 DNA-binding domains in transient transfection assays. The AF4p12 fragment fused to MLL may contribute to the oncogenic activation of MLL, possibly through specific recruitment of the transcriptional machinery.


Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proto-Oncogenes/genética , Factores de Transcripción/genética , Anciano , Secuencia de Aminoácidos , Animales , Fusión Artificial Génica , Secuencia de Bases , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 4/genética , Proteínas de Unión al ADN/biosíntesis , Drosophila/genética , Femenino , N-Metiltransferasa de Histona-Lisina , Humanos , Datos de Secuencia Molecular , Proteína de la Leucemia Mieloide-Linfoide , Neoplasias Primarias Secundarias/genética , Proteínas de Fusión Oncogénica/biosíntesis , Estructura Terciaria de Proteína , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/genética , Factores de Transcripción/biosíntesis , Activación Transcripcional , Translocación Genética
15.
Haematologica ; 91(12): 1717-9, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17145615

RESUMEN

We describe that the neoplastic gammadelta T-cells from patients with hepatosplenic gammadelta T-cell lymphoma have a lower expression of TCR-gammadelta/CD3 complex compared to their normal or reactive counterparts. Interestingly, with the use of an appropriate antibody association, this feature is easily and rapidly observed on flow cytometry graphics.


Asunto(s)
Complejo CD3/biosíntesis , Regulación Neoplásica de la Expresión Génica/inmunología , Linfoma de Células T/sangre , Receptores de Antígenos de Linfocitos T gamma-delta/biosíntesis , Complejo CD3/sangre , Humanos , Linfoma de Células T/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/sangre
16.
Leuk Res ; 47: 1-7, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27235717

RESUMEN

New B-cell receptor-targeted therapies such as ibrutinib, a Bruton tyrosine kinase inhibitor, are now proposed for lymphoid pathologies. The putative benefits of its combination with glucocorticoids were evaluated here. We compared the effects of dexamethasone (DXM), ibrutinib and their in vitro combination on proliferation and metabolic stress markers in stimulated normal B-lymphocytes and in malignant lymphocytes from chronic lymphocytic leukemia (CLL) patients. In both cellular models, cell cycle progression was globally inhibited by DXM and/or ibrutinib. This inhibition was significantly amplified by DXM addition to ibrutinib and was related to a significant decrease in the expression of the cell cycle regulatory proteins CDK4 and cyclin E. Apoptosis increased especially with DXM/ibrutinib combination and was associated with a significant decrease in Mcl-1 expression. Treatment effects on metabolic stress were evaluated by DNA damage recognition after 53BP1 foci labeling. The percentage of cells with more than five 53BP1 foci decreased significantly with ibrutinib in normal and CLL lymphocytes. This decrease was strongly reinforced, in CLL, by DXM addition. Our data indicated that, in vitro, DXM potentiated antiproliferative effects of ibrutinib and decreased DNA damage in lymphoid B-cells. Thus their combination may be proposed for CLL treatment.


Asunto(s)
Linfocitos B/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Dexametasona/farmacología , Leucemia Linfocítica Crónica de Células B/patología , Pirazoles/farmacología , Pirimidinas/farmacología , Adenina/análogos & derivados , Anciano , Anciano de 80 o más Años , Antineoplásicos Hormonales/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Piperidinas , Estrés Fisiológico/efectos de los fármacos , Células Tumorales Cultivadas
17.
Cytometry B Clin Cytom ; 90(5): 433-9, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-26482097

RESUMEN

BACKGROUND: Altered Toll-like receptor (TLR) expression levels and/or mutations in its signaling pathway (such as MyD88 mutation) contribute to the pathogenesis of lymphoproliferative disorders (LPD). CD180 is an orphan member of the TLR family that modulates the signaling of several TLRs, but only limited studies have evaluated its expression by flow cytometry (FCM) in LPD. METHODS: Using a multiparameter FCM approach, we have assessed CD180 mean fluorescence intensity (MFI) in lymph nodes (LNs) and peripheral blood (PB) samples obtained from patients with follicular lymphoma (FL; LN/PB, n = 44/n = 15), chronic lymphocytic leukemia (CLL, n = 26/n = 21), mantle cell lymphoma (MCL, n = 13/n = 17), and marginal zone lymphoma (MZL, n = 16/n = 12). Specimens from non-tumoral PB and LN (n = 8/n = 12) were used as controls. RESULTS: In the LN specimens, FL and control B-cells showed similar CD180 expression (MFI = 1,049 vs. 1,381, P > 0.05; Mann-Whitney U-test). This level was markedly lower in the other LPDs, MCL (MFI = 396, P < 0.05), or CLL (MFI = 502 P < 0.05), and similar to MZL (MFI = 858, P > 0.05). However, the CD180 expression of FL B-cells assessed in PB was dim and/or negative, in the same range as MCL and CLL (FL MFI = 453, MCL MFI = 305, CLL MFI = 420, P > 0.05) but lower than in MZL (MFI = 895, P < 0.05). Therefore, these results suggest a modulation of CD180 expression by neoplastic FL B-cells based on the anatomical compartment. CONCLUSION: These FCM data confirm the usefulness of CD180 in the accurate diagnosis of LPDs and emphasize the need to interpret this marker according to the origin of the sample. © 2015 Clinical Cytometry Society.


Asunto(s)
Antígenos CD/análisis , Linfocitos B/inmunología , Linfoma Folicular/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/inmunología , Linfocitos B/patología , Femenino , Citometría de Flujo/métodos , Humanos , Inmunofenotipificación/métodos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/patología , Ganglios Linfáticos/patología , Linfoma Folicular/diagnóstico , Linfoma de Células del Manto/diagnóstico , Linfoma de Células del Manto/inmunología , Linfoma de Células del Manto/patología , Masculino , Persona de Mediana Edad
18.
Oncogene ; 21(14): 2227-35, 2002 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-11948405

RESUMEN

Signaling of TGFbeta family members such as activin is tightly regulated by soluble binding proteins. Follistatin binds to activin A with high affinity, and prevents activin binding to its own receptors, thereby blocking its signaling. We previously identified FLRG gene from a B-cell leukemia carrying a t(11;19)(q13;p13) translocation. We and others have already shown that FLRG, which is highly homologous to follistatin, may be involved in the regulation of the activin function through its binding to activin. In this study, we found that, like follistatin, FLRG protein inhibited activin A signaling as demonstrated by the use of a transcriptional reporter assay, and blocked the activin A-induced growth inhibition of HepG2 cells. We have recently shown that the TGFbeta-induced expression of FLRG occurs at a transcriptional level through the action of Smad proteins. Here we show that activin A increases FLRG and follistatin at both the mRNA and protein levels. We found that Smad proteins are involved in the activin A-induced transcription activation of FLRG and follistatin. Finally we demonstrate that FLRG protein regulates its own activin-induced expression. In conclusion, activin A induces FLRG and follistatin expression. This observation, in conjunction with the antagonistic effect of FLRG and follistatin on activin signaling, indicates that these two proteins participate in a negative feedback loop which regulates the activin function.


Asunto(s)
Activinas/genética , Activinas/metabolismo , Activinas/farmacología , Proteínas de Unión al ADN/metabolismo , Glicoproteínas/genética , Glicoproteínas/metabolismo , Subunidades beta de Inhibinas/metabolismo , Subunidades beta de Inhibinas/farmacología , Transactivadores/metabolismo , Transcripción Genética/efectos de los fármacos , Activinas/antagonistas & inhibidores , Western Blotting , División Celular , Regulación hacia Abajo/efectos de los fármacos , Retroalimentación Fisiológica/efectos de los fármacos , Folistatina , Proteínas Relacionadas con la Folistatina , Humanos , Subunidades beta de Inhibinas/antagonistas & inhibidores , Regiones Promotoras Genéticas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Smad , Células Tumorales Cultivadas
19.
Leuk Res ; 29(9): 1073-7, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16038734

RESUMEN

Quantitative monitoring of imatinib mesylate (IM)-resistant, mutated BCR-ABL(+) cells during the follow-up of CML could be useful for optimizing therapeutic management. We retrospectively analyzed T315I mutated BCR-ABL clones throughout the CML history of two patients by nested-PCR-RFLP. At the time of progression, the T315I mutation represented 100% of the BCR-ABL transcripts. During follow-up, we showed that (i) despite a molecular response to IM, a high proportion of T315I transcripts were present (>85%) and predictive of relapse, (ii) interruption of IM and switching to other therapies resulted in a significant reduction in mutant transcript level while total BCR-ABL(+) transcripts remained stable.


Asunto(s)
Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , ARN Mensajero/genética , Secuencia de Bases , Benzamidas , Cartilla de ADN , Monitoreo de Drogas , Estudios de Seguimiento , Humanos , Mesilato de Imatinib , Mutación , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Estudios Retrospectivos
20.
Haematologica ; 90(12): 1708-9, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16330452

RESUMEN

Eighteen cases of mantle cell lymphomas (MCL) with an atypical t(11;14) were studied using fluorescence in situ hybridization experiments (FISH). The atypical presentation was confirmed and unsuspected duplicated cases were identified in six patients. These data underline that FISH analysis must be be systematically performed in cases with an aberrant presentation to prevent a misdiagnosis.


Asunto(s)
Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 14/genética , Linfoma de Células del Manto/genética , Translocación Genética , Aneuploidia , Cromosomas Humanos Par 11/ultraestructura , Cromosomas Humanos Par 14/ultraestructura , Duplicación de Gen , Humanos , Hibridación Fluorescente in Situ , Cariotipificación
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