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1.
Blood ; 138(17): 1583-1589, 2021 10 28.
Artículo en Inglés | MEDLINE | ID: mdl-34133718

RESUMEN

Although light-chain amyloidosis (AL) and multiple myeloma (MM) are characterized by tumor plasma cell (PC) expansion in bone marrow (BM), their clinical presentation differs. Previous attempts to identify unique pathogenic mechanisms behind such differences were unsuccessful, and no studies have investigated the differentiation stage of tumor PCs in patients with AL and MM. We sought to define a transcriptional atlas of normal PC development in secondary lymphoid organs (SLOs), peripheral blood (PB), and BM for comparison with the transcriptional programs (TPs) of tumor PCs in AL, MM, and monoclonal gammopathy of undetermined significance (MGUS). Based on bulk and single-cell RNA sequencing, we observed 13 TPs during transition of normal PCs throughout SLOs, PB, and BM. We further noted the following: CD39 outperforms CD19 to discriminate newborn from long-lived BM-PCs; tumor PCs expressed the most advantageous TPs of normal PC differentiation; AL shares greater similarity to SLO-PCs whereas MM is transcriptionally closer to PB-PCs and newborn BM-PCs; patients with AL and MM enriched in immature TPs had inferior survival; and protein N-linked glycosylation-related TPs are upregulated in AL. Collectively, we provide a novel resource to understand normal PC development and the transcriptional reorganization of AL and other monoclonal gammopathies.


Asunto(s)
Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/patología , Mieloma Múltiple/patología , Células Plasmáticas/patología , Transcriptoma , Adulto , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/genética , Mieloma Múltiple/genética , Células Plasmáticas/metabolismo , Células Tumorales Cultivadas
2.
Am J Hematol ; 97(7): 903-914, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35472012

RESUMEN

Interstitial 14q32 deletions involving IGH gene are infrequent events in chronic lymphocytic leukemia (CLL), affecting less than 5% of patients. To date, little is known about their clinical impact and molecular underpinnings, and its mutational landscape is currently unknown. In this work, a total of 871 CLLs were tested for the IGH break-apart probe, and 54 (6.2%) had a 300 kb deletion of 3'IGH (del-3'IGH CLLs), which contributed to a shorter time to first treatment (TFT). The mutational analysis by next-generation sequencing of 317 untreated CLLs (54 del-3'IGH and 263 as the control group) showed high mutational frequencies of NOTCH1 (30%), ATM (20%), genes involved in the RAS signaling pathway (BRAF, KRAS, NRAS, and MAP2K1) (15%), and TRAF3 (13%) within del-3'IGH CLLs. Notably, the incidence of TRAF3 mutations was significantly higher in del-3'IGH CLLs than in the control group (p < .001). Copy number analysis also revealed that TRAF3 loss was highly enriched in CLLs with 14q deletion (p < .001), indicating a complete biallelic inactivation of this gene through deletion and mutation. Interestingly, the presence of mutations in the aforementioned genes negatively refined the prognosis of del-3'IGH CLLs in terms of overall survival (NOTCH1, ATM, and RAS signaling pathway genes) and TFT (TRAF3). Furthermore, TRAF3 biallelic inactivation constituted an independent risk factor for TFT in the entire CLL cohort. Altogether, our work demonstrates the distinct genetic landscape of del-3'IGH CLL with multiple molecular pathways affected, characterized by a TRAF3 biallelic inactivation that contributes to a marked poor outcome in this subgroup of patients.


Asunto(s)
Leucemia Linfocítica Crónica de Células B , Genes de las Cadenas Pesadas de las Inmunoglobulinas , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Mutación , Pronóstico , Factor 3 Asociado a Receptor de TNF/genética
3.
Br J Haematol ; 192(5): 843-852, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32780894

RESUMEN

Deletion of the long arm of chromosome 6 (del6q) is the most frequent cytogenetic abnormality in Waldenström macroglobulinaemia (WM), occurring in approximately 50% of patients. Its effect on patient outcome has not been completely established. We used fluorescence in situ hybridisation to analyse the prevalence of del6q in selected CD19+ bone marrow cells of 225 patients with newly diagnosed immunoglobulin M (IgM) monoclonal gammopathies. Del6q was identified in one of 27 (4%) cases of IgM-monoclonal gammopathy of undetermined significance, nine of 105 (9%) of asymptomatic WM (aWM), and 28/93 (30%) of symptomatic WM (sWM), and was associated with adverse prognostic features and higher International Prognostic Scoring System for WM (IPSSWM) score. Asymptomatic patients with del6q ultimately required therapy more often and had a shorter time to transformation (TT) to symptomatic disease (median TT, 30 months vs. 199 months, respectively, P < 0·001). When treatment was required, 6q-deleted patients had shorter progression-free survival (median 20 vs. 47 months, P < 0·001). The presence of del6q translated into shorter overall survival (OS), irrespective of the initial diagnosis, with a median OS of 90 compared with 131 months in non-del6q patients (P = 0·01). In summary, our study shows that del6q in IgM gammopathy is associated with symptomatic disease, need for treatment and poorer clinical outcomes.


Asunto(s)
Transformación Celular Neoplásica/genética , Macroglobulinemia de Waldenström/genética , Anciano , Enfermedades Asintomáticas , Células de la Médula Ósea/química , Células de la Médula Ósea/ultraestructura , Deleción Cromosómica , Cromosomas Humanos Par 6/genética , Femenino , Humanos , Inmunoglobulina M/sangre , Inmunofenotipificación , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Gammopatía Monoclonal de Relevancia Indeterminada/genética , Paraproteínas/análisis , Pronóstico , Supervivencia sin Progresión , Medición de Riesgo , Análisis de Supervivencia , Factores de Tiempo , Resultado del Tratamiento , Macroglobulinemia de Waldenström/patología
4.
Blood ; 127(24): 3035-9, 2016 06 16.
Artículo en Inglés | MEDLINE | ID: mdl-27069257

RESUMEN

Immunoglobulin light-chain amyloidosis (AL) and multiple myeloma (MM) are 2 distinct monoclonal gammopathies that involve the same cellular compartment: clonal plasma cells (PCs). Despite the fact that knowledge about MM PC biology has significantly increased in the last decade, the same does not apply for AL. Here, we used an integrative phenotypic, molecular, and genomic approach to study clonal PCs from 24 newly diagnosed patients with AL. Through principal-component-analysis, we demonstrated highly overlapping phenotypic profiles between AL and both monoclonal gammopathy of undetermined significance and MM PCs. However, in contrast to MM, highly purified fluorescence-activated cell-sorted clonal PCs from AL (n = 9) showed almost normal transcriptome, with only 38 deregulated genes vs normal PCs; these included a few tumor-suppressor (CDH1, RCAN) and proapoptotic (GLIPR1, FAS) genes. Notwithstanding, clonal PCs in AL (n = 11) were genomically unstable, with a median of 9 copy number alterations (CNAs) per case, many of such CNAs being similar to those found in MM. Whole-exome sequencing (WES) performed in 5 AL patients revealed a median of 15 nonrecurrent mutations per case. Altogether, our results show that in the absence of a unifying mutation by WES, clonal PCs in AL display phenotypic and CNA profiles similar to MM, but their transcriptome is remarkably similar to that of normal PCs.


Asunto(s)
Amiloidosis/genética , Cadenas Ligeras de Inmunoglobulina/genética , Paraproteinemias/genética , Células Plasmáticas/metabolismo , Transcriptoma , Amiloidosis/metabolismo , Amiloidosis/patología , Células Clonales/metabolismo , Células Clonales/patología , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunofenotipificación , Análisis por Micromatrices , Paraproteinemias/metabolismo , Paraproteinemias/patología , Fenotipo , Células Plasmáticas/patología
5.
Ann Hematol ; 97(3): 475-484, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-29353304

RESUMEN

Immunoglobulin M (IgM) monoclonal gammopathies show considerable variability, involving three different stages of presentation: IgM monoclonal gammopathy of undetermined significance (IgM-MGUS), asymptomatic Waldenström's macroglobulinemia (AWM), and symptomatic WM (SWM). Despite recent findings about the genomic and transcriptomic characteristics of such disorders, we know little about the causes of this clinical heterogeneity or the mechanisms involved in the progression from indolent to symptomatic forms. To clarify these matters, we have performed a gene expression and mutational study in a well-characterized cohort of 69 patients, distinguishing between the three disease presentations in an attempt to establish the relationship with the clinical and biological features of the patients. Results showed that the frequency of genetic alterations progressively increased from IgM-MGUS to AWM and SWM. This means that, in contrast to MYD88 p.L265P and CXCR4 WHIM mutations, present from the beginning of the pathogenesis, most of them would be acquired during the course of the disease. Moreover, the expression study revealed a higher level of expression of genes belonging to the Toll-like receptor (TLR) signaling pathway in symptomatic versus indolent forms, which was also reflected in the disease presentation and prognosis. In conclusion, our findings showed that IgM monoclonal gammopathies present higher mutational burden as the disease progresses, in parallel to the upregulation of relevant pathogenic pathways. This study provides a translational view of the genomic basis of WM pathogenesis.


Asunto(s)
Heterogeneidad Genética , Inmunoglobulina M/genética , Gammopatía Monoclonal de Relevancia Indeterminada/genética , Macroglobulinemia de Waldenström/genética , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Gammopatía Monoclonal de Relevancia Indeterminada/patología , Pronóstico , Macroglobulinemia de Waldenström/patología
6.
Blood ; 125(15): 2370-80, 2015 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-25655603

RESUMEN

Although information about the molecular pathogenesis of Waldenström macroglobulinemia (WM) has significantly advanced, the precise cell of origin and the mechanisms behind WM transformation from immunoglobulin-M (IgM) monoclonal gammopathy of undetermined significance (MGUS) remain undetermined. Here, we undertook an integrative phenotypic, molecular, and genomic approach to study clonal B cells from newly diagnosed patients with IgM MGUS (n = 22), smoldering (n = 16), and symptomatic WM (n = 11). Through principal component analysis of multidimensional flow cytometry data, we demonstrated highly overlapping phenotypic profiles for clonal B cells from IgM MGUS, smoldering, and symptomatic WM patients. Similarly, virtually no genes were significantly deregulated between fluorescence-activated cell sorter-sorted clonal B cells from the 3 disease groups. Interestingly, the transcriptome of the Waldenström B-cell clone was highly different than that of normal CD25(-)CD22(+) B cells, whereas significantly less genes were differentially expressed and specific WM pathways normalized once the transcriptome of the Waldenström B-cell clone was compared with its normal phenotypic (CD25(+)CD22(+low)) B-cell counterpart. The frequency of specific copy number abnormalities [+4, del(6q23.3-6q25.3), +12, and +18q11-18q23] progressively increased from IgM MGUS and smoldering WM vs symptomatic WM (18% vs 20% and 73%, respectively; P = .008), suggesting a multistep transformation of clonal B cells that, albeit benign (ie, IgM MGUS and smoldering WM), already harbor the phenotypic and molecular signatures of the malignant Waldenström clone.


Asunto(s)
Linfocitos B/patología , Transformación Celular Neoplásica/genética , Gammopatía Monoclonal de Relevancia Indeterminada/genética , Macroglobulinemia de Waldenström/genética , Linfocitos B/metabolismo , Transformación Celular Neoplásica/patología , Células Clonales , Citometría de Flujo , Dosificación de Gen , Regulación Neoplásica de la Expresión Génica , Genómica , Humanos , Inmunoglobulina M/análisis , Gammopatía Monoclonal de Relevancia Indeterminada/patología , Mutación , Factor 88 de Diferenciación Mieloide/genética , Fenotipo , Macroglobulinemia de Waldenström/patología
7.
Br J Haematol ; 172(3): 428-38, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26567765

RESUMEN

The introduction of Rituximab has improved the outcome and survival rates of Burkitt lymphoma (BL). However, early relapse and refractoriness are current limitations of BL treatment and new biological factors affecting the outcome of these patients have not been explored. This study aimed to identify the presence of genomic changes that could predict the response to new therapies in BL. Forty adolescent and adult BL patients treated with the Dose-Intensive Chemotherapy Including Rituximab (Burkimab) protocol (Spanish Programme for the Study and Treatment of Haematological Malignancies; PETHEMA) were analysed using array-based comparative genomic hybridization (CGH). In addition, the presence of TP53, TCF3 (E2A), ID3 and GNA13 mutations was assessed by next-generation sequencing (NGS). Ninety-seven per cent of the patients harboured genomic imbalances. Losses on 11q, 13q, 15q or 17p were associated with a poor response to Burkimab therapy (P = 0·038), shorter progression-free survival (PFS; P = 0·007) and overall survival (OS; P = 0·009). The integrative analysis of array-CGH and NGS showed that 26·3% (5/19) and 36·8% (7/19) of patients carried alterations in the TP53 and TCF3 genes, respectively. TP53 alterations were associated with shorter PFS (P = 0·011) while TCF3 alterations were associated with shorter OS (P = 0·032). Genetic studies could be used for risk stratification of BL patients treated with the Burkimab protocol.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/genética , Aberraciones Cromosómicas , Adolescente , Adulto , Anciano , Hibridación Genómica Comparativa/métodos , Femenino , Genoma , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Rituximab/administración & dosificación , Resultado del Tratamiento , Adulto Joven
8.
Blood ; 124(8): 1300-3, 2014 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-24876564

RESUMEN

Solitary plasmacytoma represents a heterogeneous group of patients; approximately half develop multiple myeloma (MM) in 2 or 3 years, whereas others remain disease-free at 10 years. By definition, these patients do not have morphologic bone marrow (BM) plasma cell (PC) infiltration. Here, we investigated whether sensitive BM evaluation of patients with solitary bone plasmacytoma (SBP; n = 35) and extramedullary plasmacytoma (EMP; n = 29) through multiparameter flow cytometry (MFC) would unravel the presence of clonal PCs in otherwise disease-free BM, and whether BM clonality predicted higher risk of progression. BM clonal PCs were detected in 17 of 35 SBP (49%) and 11 of 29 EMP (38%) patients. Seventy-one percent of flow-positive vs only 8% of flow-negative SBP patients evolved to MM (median time to progression of 26 months vs not reached; hazard ratio, 17.4; P < .001). No significant differences were observed among EMP cases. Our results highlight the importance of MFC for sensitive BM evaluation of SBP patients, to predict risk of developing treatment-requiring MM and to plan disease monitoring.


Asunto(s)
Neoplasias Óseas , Citometría de Flujo , Mieloma Múltiple , Plasmacitoma , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/metabolismo , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Neoplasias Óseas/terapia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/metabolismo , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , Estadificación de Neoplasias/métodos , Plasmacitoma/metabolismo , Plasmacitoma/mortalidad , Plasmacitoma/patología , Plasmacitoma/terapia , Estudios Retrospectivos , Factores de Riesgo
9.
Transfusion ; 55(7): 1745-51, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25702711

RESUMEN

BACKGROUND: Mirasol pathogen reduction technology (PRT) treatment inactivates bacteria, viruses, and parasites in plasma products and platelets (PLTs) suspended in plasma and PLT additive solutions (PAS). Few clinical studies exist documenting transfusions with PAS. This study objective was to evaluate the count increments of PRT-treated PAS-C and PAS-E buffy coat (BC) PLTs in routine use observational settings. STUDY DESIGN AND METHODS: PLT pools of five or six BCs were collected, processed, and suspended in PAS-C or PAS-E, respectively. Products were exposed to ultraviolet light in the presence of riboflavin and then transfused into 19 patients with hematologic diseases. Patients were monitored for PLT corrected count increment (CCI) at 1 and 24 hours and for any adverse events in the 72 hours after transfusion. Sterility monitoring was performed with a microbial detection system (BacT/ALERT, bioMérieux). RESULTS: The PAS-E products had significantly higher PLT concentrations and counts than the PAS-C products. The mean CCIs of per-protocol (PP) units at 1 and 24 hours were 11,900 (n=27) and 5500 (n=30), respectively. Seventy-eight percent of PP transfusions classify as successful with CCIs at 1 hour of higher than 7500, and 63% higher than 4500 at 24 hours. One patient was excluded from all analyses as she was refractory to Mirasol-treated PLT transfusions and follow-up untreated transfusion products. No adverse events were observed and no contaminated products were detected by BacT/ALERT. CONCLUSION: PRT-treated BC PLTs in PAS-C or PAS-E demonstrate PLT transfusion success rates in hematology patients with thrombocytopenia that are comparable to previous studies examining PLTs stored in plasma.


Asunto(s)
Conservación de la Sangre , Desinfección/métodos , Enfermedades Hematológicas , Fármacos Fotosensibilizantes/farmacología , Transfusión de Plaquetas , Riboflavina/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Enfermedades Hematológicas/sangre , Enfermedades Hematológicas/terapia , Humanos , Soluciones Isotónicas , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Factores de Tiempo
10.
Eur J Haematol ; 93(5): 422-8, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24813417

RESUMEN

To assess the presence of genetic imbalances in patients with myeloproliferative neoplasms (MPNs), 38 patients with chronic eosinophilia were studied by array comparative genomic hybridization (aCGH): seven had chronic myelogenous leukaemia (CML), BCR-ABL1 positive, nine patients had myeloproliferative neoplasia Ph- (MPN-Ph-), three had a myeloid neoplasm associated with a PDGFRA rearrangement, and the remaining two cases were Lymphoproliferative T neoplasms associated with eosinophilia. In addition, 17 patients had a secondary eosinophilia and were used as controls. Eosinophilic enrichment was carried out in all cases. Genomic imbalances were found in 76% of all MPN patients. Losses on 20q were the most frequent genetic abnormality in MPNs (32%), affected the three types of MPN studied. This study also found losses at 11q13.3 in 26% of patients with MPN-Ph- and in 19p13.11 in two of the three patients with an MPN associated with a PDGFRA rearrangement. In addition, 29% of patients with CML had losses on 8q24. In summary, aCGH revealed clonality in eosinophils in most MPNs, suggesting that it could be a useful technique for defining clonality in these diseases. The presence of genetic losses in new regions could provide new insights into the knowledge of these MPN associated with eosinophilia.


Asunto(s)
Aberraciones Cromosómicas , Eosinofilia/genética , Eosinófilos/metabolismo , Genoma , Neoplasias Hematológicas/genética , Trastornos Mieloproliferativos/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Cromosomas Humanos Par 11/química , Cromosomas Humanos Par 19/química , Cromosomas Humanos Par 20/química , Cromosomas Humanos Par 8/química , Enfermedad Crónica , Células Clonales , Hibridación Genómica Comparativa , Eosinofilia/diagnóstico , Eosinofilia/patología , Eosinófilos/patología , Femenino , Proteínas de Fusión bcr-abl/genética , Inestabilidad Genómica , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/patología , Humanos , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/patología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética
11.
Blood ; 117(13): 3613-6, 2011 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-21266717

RESUMEN

The clinical value of multiparameter flow cytometry (MFC) immunophenotyping in primary or light chain amyloidosis (AL) remains unknown. We studied 44 consecutive bone marrow samples from newly diagnosed patients with amyloidosis; 35 patients with AL and 9 with other forms of amyloidosis. Monoclonal plasma cells (PCs) were identifiable by MFC immunophenotyping in 34 of 35 (97%) patients with AL, whereas it was absent from all but 1 of the 9 (11%) patients with other forms of amyloidosis. Quantification of bone marrow plasma cells (BMPCs) by MFC immunophenotyping was a significant prognostic factor for overall survival (OS) (≤ 1% vs > 1% BMPC cutoff; 2-year OS rates of 90% vs 44%, P = .02). Moreover, detecting persistent normal PCs at diagnosis identifies a subgroup of patients with AL with prolonged OS (> 5% vs ≤ 5% normal PC within all BMPC cutoff, 2-year rates of 88% vs 37%, P = .01). MFC immunophenotyping could be clinically useful for the demonstration of PC clonality in AL and for the prognostication of patients with AL.


Asunto(s)
Amiloidosis/diagnóstico , Citometría de Flujo/métodos , Cadenas Ligeras de Inmunoglobulina/metabolismo , Inmunofenotipificación/métodos , Adulto , Anciano , Anciano de 80 o más Años , Amiloidosis/metabolismo , Femenino , Cardiopatías/diagnóstico , Cardiopatías/metabolismo , Humanos , Enfermedades Renales/diagnóstico , Enfermedades Renales/metabolismo , Hepatopatías/diagnóstico , Hepatopatías/metabolismo , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico
12.
Cancers (Basel) ; 15(5)2023 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-36900349

RESUMEN

(1) Background: New therapeutic strategies have improved the prognosis of multiple myeloma (MM), changing the accepted view of this disease from being incurable to treatable. (2) Methods: We studied 1001 patients with MM between 1980 and 2020, grouping patients into ten-year periods by diagnosis 1980-1990, 1991-2000, 2001-2010 and 2011-2020. (3) Results: After 65.1 months of follow-up, the median OS of the cohort was 60.3 months, and OS increased significantly over time: 22.4 months in 1980-1990, 37.4 months in 1991-2000, 61.8 months in 2001-2010 and 103.6 months in 2011-2020 (p < 0.001). Using novel agents in the front-line setting for myeloma patients yielded a significantly better OS than in those treated with conventional therapies, especially when combinations of at least two novel agents were used. The median OS of patients treated with the combination of at least two novel agents in induction was significantly prolonged compared to those treated with a single novel agent or conventional therapy in induction: 143.3 vs. 61.0 vs. 42.2 months (p < 0.001). The improvement was apparent in all patients regardless of age at diagnosis. In addition, 132 (13.2%) patients were long-term survivors (median OS ≥ 10 years). Some independent clinical predictors of long-term survival were identified: ECOG < 1, age at diagnosis ≤ 65 years, non-IgA subtype, ISS-1 and standard-risk cytogenetic. Achieving CR and undergoing ASCT were positively associated with >10 years of survival. (4) Conclusions: The combination of novel agents appears to be the main factor for the improvement in survival in MM, which is becoming a chronic and even curable disease in a subtype of patients without high-risk features.

13.
Blood ; 114(20): 4369-72, 2009 Nov 12.
Artículo en Inglés | MEDLINE | ID: mdl-19755674

RESUMEN

Multiparameter flow cytometry immunophenotyping allows discrimination between normal (N-) and myelomatous (MM-) plasma cells (PCs) within the bone marrow plasma cell compartment (BMPCs). Here we report on the prognostic relevance of detecting more than 5% residual normal plasma cells from all bone marrow plasma cells (N-PCs/BMPCs) by multiparameter flow cytometry in a series of 594 newly diagnosed symptomatic MM patients, uniformly treated according to the Grupo Español de MM 2000 (GEM2000) protocol. Our results show that symptomatic MM patients with more than 5% N-PCs/BMPCs (n = 80 of 594; 14%) have a favorable baseline clinical prospect, together with a significantly lower frequency of high-risk cytogenetic abnormalities and higher response rates. Moreover, this group of patients had a significantly longer progression-free survival (median, 54 vs 42 months, P = .001) and overall survival (median, not reached vs 89 months, P = .04) than patients with less than or equal to 5% N-PCs/BMPCs. Our findings support the clinical value of detecting residual normal PCs in MM patients at diagnosis because this reveals a good prognostic category that could benefit from specific therapeutic approaches. This trial was registered at www.clinicaltrials.gov as NCT00560053.


Asunto(s)
Células de la Médula Ósea/patología , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Células Plasmáticas/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica , Supervivencia sin Enfermedad , Femenino , Citometría de Flujo , Trasplante de Células Madre Hematopoyéticas , Humanos , Inmunofenotipificación , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/terapia , Pronóstico
14.
Clin Transl Med ; 11(2): e304, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33634999

RESUMEN

BACKGROUND: Several genetic alterations have been identified as driver events in chronic lymphocytic leukemia (CLL) pathogenesis and oncogenic evolution. Concurrent driver alterations usually coexist within the same tumoral clone, but how the cooperation of multiple genomic abnormalities contributes to disease progression remains poorly understood. Specifically, the biological and clinical consequences of concurrent high-risk alterations such as del(11q)/ATM-mutations and del(17p)/TP53-mutations have not been established. METHODS: We integrated next-generation sequencing (NGS) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 techniques to characterize the in vitro and in vivo effects of concurrent monoallelic or biallelic ATM and/or TP53 alterations in CLL prognosis, clonal evolution, and therapy response. RESULTS: Targeted sequencing analysis of the co-occurrence of high-risk alterations in 271 CLLs revealed that biallelic inactivation of both ATM and TP53 was mutually exclusive, whereas monoallelic del(11q) and TP53 alterations significantly co-occurred in a subset of CLL patients with a highly adverse clinical outcome. We determined the biological effects of combined del(11q), ATM and/or TP53 mutations in CRISPR/Cas9-edited CLL cell lines. Our results showed that the combination of monoallelic del(11q) and TP53 mutations in CLL cells led to a clonal advantage in vitro and in in vivo clonal competition experiments, whereas CLL cells harboring biallelic ATM and TP53 loss failed to compete in in vivo xenotransplants. Furthermore, we demonstrated that CLL cell lines harboring del(11q) and TP53 mutations show only partial responses to B cell receptor signaling inhibitors, but may potentially benefit from ATR inhibition. CONCLUSIONS: Our work highlights that combined monoallelic del(11q) and TP53 alterations coordinately contribute to clonal advantage and shorter overall survival in CLL.


Asunto(s)
Leucemia Linfocítica Crónica de Células B/genética , Proteína p53 Supresora de Tumor/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Deleción Cromosómica , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Ratones , Persona de Mediana Edad , Mutación/genética , Pronóstico
15.
Blood ; 112(10): 4017-23, 2008 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-18669875

RESUMEN

Minimal residual disease (MRD) assessment is standard in many hematologic malignancies but is considered investigational in multiple myeloma (MM). We report a prospective analysis of the prognostic importance of MRD detection by multiparameter flow cytometry (MFC) in 295 newly diagnosed MM patients uniformly treated in the GEM2000 protocol VBMCP/VBAD induction plus autologous stem cell transplantation [ASCT]). MRD status by MFC was determined at day 100 after ASCT. Progression-free survival (PFS; median 71 vs 37 months, P < .001) and overall survival (OS; median not reached vs 89 months, P = .002) were longer in patients who were MRD negative versus MRD positive at day 100 after ASCT. Similar prognostic differentiation was seen in 147 patients who achieved immunofixation-negative complete response after ASCT. Moreover, MRD(-) immunofixation-negative (IFx(-)) patients and MRD(-) IFx(+) patients had significantly longer PFS than MRD(+) IFx(-) patients. Multivariate analysis identified MRD status by MFC at day 100 after ASCT as the most important independent prognostic factor for PFS (HR = 3.64, P = .002) and OS (HR = 2.02, P = .02). Our findings demonstrate the clinical importance of MRD evaluation by MFC, and illustrate the need for further refinement of MM re-sponse criteria. This trial is registered at http://clinicaltrials.gov under identifier NCT00560053.


Asunto(s)
Mieloma Múltiple/sangre , Mieloma Múltiple/terapia , Trasplante de Células Madre , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bleomicina/administración & dosificación , Carmustina/administración & dosificación , Cisplatino/administración & dosificación , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Citometría de Flujo/métodos , Humanos , Masculino , Persona de Mediana Edad , Mitomicina/administración & dosificación , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/mortalidad , Neoplasia Residual , Valor Predictivo de las Pruebas , Trasplante de Células Madre/métodos , Tasa de Supervivencia , Trasplante Autólogo , Vincristina/administración & dosificación
16.
Haematologica ; 95(5): 745-51, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20133893

RESUMEN

BACKGROUND: Internal tandem duplications of the FLT3 gene (FLT3-ITDs) are frequent in patients with acute promyelocytic leukemia (APL), however its clinical impact remains controversial. DESIGN AND METHODS: We analyzed the prognostic significance of FLT3-ITD mutant level and size, as well as FLT3-D835 point mutations, PML-RARalpha expression and other predictive factors in 129 APL patients at diagnosis enrolled on the Spanish LPA96 (n=43) or LPA99 (n=86) PETHEMA trials. RESULTS: FLT3-ITDs and D835 mutations were detected in 21% and 9% of patients, respectively. Patients with increased ITD mutant/wild-type ratio or longer ITD size displayed shorter 5-year relapse-free survival (RFS) (P=0.048 and P<0.0001, respectively). However, patients with D835 mutations did not show differences in RFS or overall survival (OS). Moreover, patients with initial normalized copy number (NCN) of PML-RARalpha transcripts less than the 25(th) percentile had adverse clinical features and shorter 5-year RFS (P<0.0001) and OS (P=0.004) compared to patients with higher NCN. Patients with low NCN showed increased incidence of ITDs (P=0.001), with higher ratios (P<0.0001) and/or longer sizes (P=0.007). Multivariate analysis showed that long FLT3-ITD (P=0.001), low PML-RARalpha levels (P=0.004) and elevated WBC counts (>10x10(9)/L) (P=0.018) were independent predictors for shorter RFS. We identified a subgroup of patients with high WBC, long FLT3-ITD and low NCN of transcripts that showed an extremely bad prognosis (5-year RFS 23.4%, P<0.0001). CONCLUSIONS: In conclusion, FLT3-ITD size and PML-RARalpha transcript levels at diagnosis could contribute to improve the risk stratification in APL.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Proteínas de Fusión Oncogénica/genética , Secuencias Repetidas en Tándem/genética , Tirosina Quinasa 3 Similar a fms/genética , Adulto , Biomarcadores de Tumor/genética , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Leucemia Promielocítica Aguda/metabolismo , Masculino , Persona de Mediana Edad , Mutación Puntual/genética , Factores de Riesgo , Adulto Joven
17.
Diagnostics (Basel) ; 10(7)2020 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-32635531

RESUMEN

The clonal basis of relapse in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is complex and not fully understood. Next-generation sequencing (NGS), array comparative genomic hybridization (aCGH), and multiplex ligation-dependent probe amplification (MLPA) were carried out in matched diagnosis-relapse samples from 13 BCP-ALL patients to identify patterns of genetic evolution that could account for the phenotypic changes associated with disease relapse. The integrative genomic analysis of aCGH, MLPA and NGS revealed that 100% of the BCP-ALL patients showed at least one genetic alteration at diagnosis and relapse. In addition, there was a significant increase in the frequency of chromosomal lesions at the time of relapse (p = 0.019). MLPA and aCGH techniques showed that IKZF1 was the most frequently deleted gene. TP53 was the most frequently mutated gene at relapse. Two TP53 mutations were detected only at relapse, whereas the three others showed an increase in their mutational burden at relapse. Clonal evolution patterns were heterogeneous, involving the acquisition, loss and maintenance of lesions at relapse. Therefore, this study provides additional evidence that BCP-ALL is a genetically dynamic disease with distinct genetic profiles at diagnosis and relapse. Integrative NGS, aCGH and MLPA analysis enables better molecular characterization of the genetic profile in BCP-ALL patients during the evolution from diagnosis to relapse.

18.
J Pers Med ; 10(3)2020 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-32967112

RESUMEN

BACKGROUND: B-acute lymphoblastic leukemia (B-ALL) is a hematological neoplasm of the stem lymphoid cell of the B lineage, characterized by the presence of genetic alterations closely related to the course of the disease. The number of alterations identified in these patients grows as studies of the disease progress, but in clinical practice, the conventional techniques frequently used are only capable of detecting the most common alterations. However, techniques, such as next-generation sequencing (NGS), are being implemented to detect a wide spectrum of new alterations that also include point mutations. METHODS: In this study, we designed and validated a comprehensive custom NGS panel to detect the main genetic alterations present in the disease in a single step. For this purpose, 75 B-ALL diagnosis samples from patients previously characterized by standard-of-care diagnostic techniques were sequenced. RESULTS: The use of the custom NGS panel allowed the correct detection of the main genetic alterations present in B-ALL patients, including the presence of an aneuploid clone in 14 of the samples and some of the recurrent fusion genes in 35 of the samples. The panel was also able to successfully detect a number of secondary alterations, such as single nucleotide variants (SNVs) and copy number variations (CNVs) in 66 and 46 of the samples analyzed, respectively, allowing for further refinement of the stratification of patients. The custom NGS panel could also detect alterations with a high level of sensitivity and reproducibility when the findings obtained by NGS were compared with those obtained from other conventional techniques. CONCLUSIONS: The use of this custom NGS panel allows us to quickly and efficiently detect the main genetic alterations present in B-ALL patients in a single assay (SNVs and insertions/deletions (INDELs), recurrent fusion genes, CNVs, aneuploidies, and single nucleotide polymorphisms (SNPs) associated with pharmacogenetics). The application of this panel would thus allow us to speed up and simplify the molecular diagnosis of patients, helping patient stratification and management.

19.
Leukemia ; 33(5): 1256-1267, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30542145

RESUMEN

Early diagnosis and risk stratification are key to improve outcomes in light-chain (AL) amyloidosis. Here we used multidimensional-flow-cytometry (MFC) to characterize bone marrow (BM) plasma cells (PCs) from a series of 166 patients including newly-diagnosed AL amyloidosis (N = 94), MGUS (N = 20) and multiple myeloma (MM, N = 52) vs. healthy adults (N = 30). MFC detected clonality in virtually all AL amyloidosis (99%) patients. Furthermore, we developed an automated risk-stratification system based on BMPCs features, with independent prognostic impact on progression-free and overall survival of AL amyloidosis patients (hazard ratio: ≥ 2.9;P ≤ .03). Simultaneous assessment of the clonal PCs immunophenotypic protein expression profile and the BM cellular composition, mapped AL amyloidosis in the crossroad between MGUS and MM; however, lack of homogenously-positive CD56 expression, reduction of B-cell precursors and a predominantly-clonal PC compartment in the absence of an MM-like tumor PC expansion, emerged as hallmarks of AL amyloidosis (ROC-AUC = 0.74;P < .001), and might potentially be used as biomarkers for the identification of MGUS and MM patients, who are candidates for monitoring pre-symptomatic organ damage related to AL amyloidosis. Altogether, this study addressed the need for consensus on how to use flow cytometry in AL amyloidosis, and proposes a standardized MFC-based automated risk classification ready for implementation in clinical practice.


Asunto(s)
Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Médula Ósea/metabolismo , Evolución Clonal , Femenino , Citometría de Flujo , Humanos , Isotipos de Inmunoglobulinas/sangre , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/mortalidad , Inmunofenotipificación , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Estadificación de Neoplasias , Medición de Riesgo
20.
J Hematol Oncol ; 10(1): 83, 2017 04 11.
Artículo en Inglés | MEDLINE | ID: mdl-28399885

RESUMEN

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a highly genetically heterogeneous disease. Although CLL has been traditionally considered as a mature B cell leukemia, few independent studies have shown that the genetic alterations may appear in CD34+ hematopoietic progenitors. However, the presence of both chromosomal aberrations and gene mutations in CD34+ cells from the same patients has not been explored. METHODS: Amplicon-based deep next-generation sequencing (NGS) studies were carried out in magnetically activated-cell-sorting separated CD19+ mature B lymphocytes and CD34+ hematopoietic progenitors (n = 56) to study the mutational status of TP53, NOTCH1, SF3B1, FBXW7, MYD88, and XPO1 genes. In addition, ultra-deep NGS was performed in a subset of seven patients to determine the presence of mutations in flow-sorted CD34+CD19- early hematopoietic progenitors. Fluorescence in situ hybridization (FISH) studies were performed in the CD34+ cells from nine patients of the cohort to examine the presence of cytogenetic abnormalities. RESULTS: NGS studies revealed a total of 28 mutations in 24 CLL patients. Interestingly, 15 of them also showed the same mutations in their corresponding whole population of CD34+ progenitors. The majority of NOTCH1 (7/9) and XPO1 (4/4) mutations presented a similar mutational burden in both cell fractions; by contrast, mutations of TP53 (2/2), FBXW7 (2/2), and SF3B1 (3/4) showed lower mutational allele frequencies, or even none, in the CD34+ cells compared with the CD19+ population. Ultra-deep NGS confirmed the presence of FBXW7, MYD88, NOTCH1, and XPO1 mutations in the subpopulation of CD34+CD19- early hematopoietic progenitors (6/7). Furthermore, FISH studies showed the presence of 11q and 13q deletions (2/2 and 3/5, respectively) in CD34+ progenitors but the absence of IGH cytogenetic alterations (0/2) in the CD34+ cells. Combining all the results from NGS and FISH, a model of the appearance and expansion of genetic alterations in CLL was derived, suggesting that most of the genetic events appear on the hematopoietic progenitors, although these mutations could induce the beginning of tumoral cell expansion at different stage of B cell differentiation. CONCLUSIONS: Our study showed the presence of both gene mutations and chromosomal abnormalities in early hematopoietic progenitor cells from CLL patients.


Asunto(s)
Aberraciones Cromosómicas , Células Madre Hematopoyéticas/patología , Leucemia Linfocítica Crónica de Células B/patología , Mutación , Antígenos CD19 , Antígenos CD34 , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Hibridación Fluorescente in Situ/métodos , Leucemia Linfocítica Crónica de Células B/genética
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