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C Jiménez,
E Sebastián,
M Del Carmen Chillón,
P Giraldo,
J Mariano Hernández,
F Escalante,
T J González-López,
C Aguilera,
A García de Coca,
I Murillo, [......],
A Balanzategui,
M Eugenia Sarasquete,
R Corral,
L A Marín,
B Paiva,
E M Ocio, N C Gutiérrez,
M González,
J F San Miguel,
R García-Sanz
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ABSTRACT: We evaluated the MYD88 L265P mutation in Waldenström's Macroglobulinemia (WM) and B-cell Lymphoproliferative Disorders by specific PCR (sensitivity ~10-3). No mutation was seen in normal donors, while it was present in 101/117 (86%) WM patients, 27/31 (87%) IgM monoclonal gammapathies of uncertain significance (MGUS), 3/14 (21%) splenic marginal zone lymphomas, and 9/48 (19%) non-germinal center (GC) Diffuse Large B-Cell Lymphomas (DLBCL). The mutation was absent in all 28 GC-DLBCL, 13 DLBCL not subclassified, 35 hairy cell leukemias, 39 chronic lymphocytic leukemias (16 with M-component), 25 IgA or IgG-MGUS, 24 multiple myeloma (3 with an IgM isotype), 6 amyloidosis, 9 lymphoplasmacytic lymphomas, and 1 IgM-related neuropathy. Among WM and IgM-MGUS, MYD88 L265P mutation associated with some differences in clinical & biological characteristics, although usually minor; wild-type MYD88 cases had smaller M-component (1.77 vs 2.72 g/dl, P = 0.022), more lymphocytosis (24% vs 5%, P=0.006), higher LDH level (371 vs 265 UI/l, P=0.002), atypical immunophenotype (CD23-CD27++FMC7++), less IGHV somatic hypermutation (57% vs 97%, P=0.012) and less IGHV3-23 gene selection (9% vs 27%, P=0.014). These small differences did not lead to different time to first therapy, response to treatment, or progression-free or overall survival.Leukemia accepted article preview online, 28 February 2013; doi:10.1038/leu.2013.62.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2013; · 8.30 Impact Factor
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M Del Rey,
K O'Hagan,
M Dellett,
S Aibar,
H A A Colyer,
M E Alonso,
M Díez-Campelo,
R N Armstrong,
D J Sharpe, N C Gutiérrez,
J L García,
J De Las Rivas,
K I Mills,
J M Hernández-Rivas
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ABSTRACT: Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases.Leukemia advance online publication, 14 September 2012; doi:10.1038/leu.2012.253.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 08/2012; · 8.30 Impact Factor
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L López-Corral,
M E Sarasquete,
S Beà,
R García-Sanz,
M V Mateos,
L A Corchete,
J M Sayagués,
E M García,
J Bladé,
A Oriol,
M T Hernández-García,
P Giraldo,
J Hernández,
M González,
J M Hernández-Rivas,
J F San Miguel, N C Gutiérrez
[show abstract]
[hide abstract]
ABSTRACT: Genetic events mediating transformation from premalignant monoclonal gammopathies (MG) to multiple myeloma (MM) are unknown. To obtain a comprehensive genomic profile of MG from the early to late stages, we performed high-resolution analysis of purified plasma cells from 20 MGUS, 20 smoldering MM (SMM) and 34 MM by high-density 6.0 SNP array. A progressive increase in the incidence of copy number abnormalities (CNA) from MGUS to SMM and to MM (median 5, 7.5 and 12 per case, respectively) was observed (P=0.006). Gains on 1q, 3p, 6p, 9p, 11q, 19p, 19q and 21q along with 1p, 16q and 22q deletions were significantly less frequent in MGUS than in MM. Although 11q and 21q gains together with 16q and 22q deletions were apparently exclusive of MM status, we observed that these abnormalities were also present in minor subclones in MGUS. Overall, a total of 65 copy number-neutral LOH (CNN-LOH) were detected. Their frequency was higher in active MM than in the asymptomatic entities (P=0.047). A strong association between genetic lesions and fragile sites was also detected. In summary, our study shows an increasing genomic complexity from MGUS to MM and identifies new chromosomal regions involved in CNA and CNN-LOH.Leukemia advance online publication, 19 June 2012; doi:10.1038/leu.2012.128.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2012; · 8.30 Impact Factor
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B Paiva, N-C Gutiérrez,
X Chen,
M-B Vídriales,
M-Á Montalbán,
L Rosiñol,
A Oriol,
J Martínez-López,
M-V Mateos,
L López-Corral, [......],
E Bengoechea,
M-J Terol,
R de Paz,
A Martin,
J Hernández,
A Orfao,
J-J Lahuerta,
J Bladé,
A Pandiella,
J-F San Miguel
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ABSTRACT: The presence of CD19 in myelomatous plasma cells (MM-PCs) correlates with adverse prognosis in multiple myeloma (MM). Although CD19 expression is upregulated by CD81, this marker has been poorly investigated and its prognostic value in MM remains unknown. We have analyzed CD81 expression by multiparameter flow cytometry in MM-PCs from 230 MM patients at diagnosis included in the Grupo Español de Mieloma (GEM)05>65 years trial as well as 56 high-risk smoldering MM (SMM). CD81 expression was detected in 45% (103/230) MM patients, and the detection of CD81(+) MM-PC was an independent prognostic factor for progression-free (hazard ratio=1.9; P=0.003) and overall survival (hazard ratio=2.0; P=0.02); this adverse impact was validated in an additional series of 325 transplant-candidate MM patients included in the GEM05 <65 years trial. Moreover, CD81(+) SMM (n=34/56, 57%) patients had a shorter time to progression to MM (P=0.02). Overall, our results show that CD81 may have a relevant role in MM pathogenesis and represent a novel adverse prognostic marker in myeloma.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2012; 26(8):1862-9. · 8.30 Impact Factor
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A E Rodríguez,
C Robledo,
J L García,
M González, N C Gutiérrez,
J A Hernández,
V Sandoval,
A García de Coca,
I Recio,
A Risueño,
G Martín-Núñez,
E García,
R Fisac,
J Conde,
J de las Rivas,
J M Hernández
[show abstract]
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ABSTRACT: The presence of genetic changes is a hallmark of chronic lymphocytic leukemia (CLL). The most common cytogenetic abnormalities with independent prognostic significance in CLL are 13q14, ATM and TP53 deletions and trisomy 12. However, CLL displays a great genetic and biological heterogeneity. The aim of this study was to analyze the genomic imbalances in CLL cytogenetic subsets from both genomic and gene expression perspectives to identify new recurrent alterations.
The genomic imbalances and expression levels of 67 patients were analyzed. The novel recurrent abnormalities detected with bacterial artificial chromosome array were confirmed by FISH and oligonucleotide microarrays. In all cases, gene expression profiling was assessed.
Copy number alterations were identified in 75% of cases. Overall, the results confirmed FISH studies for the regions frequently involved in CLL and also defined a new recurrent gain on chromosome 20q13.12, in 19% (13/67) of the CLL patients. Oligonucleotide expression correlated with the regions of loss or gain of genomic material, suggesting that the changes in gene expression are related to alterations in copy number.
Our study demonstrates the presence of a recurrent gain in 20q13.12 associated with overexpression of the genes located in this region, in CLL cytogenetic subgroups.
Annals of Oncology 01/2012; 23(8):2138-46. · 6.43 Impact Factor
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B Paiva,
M Pérez-Andrés,
M-B Vídriales,
J Almeida,
N de las Heras,
M-V Mateos,
L López-Corral, N C Gutiérrez,
J Blanco,
A Oriol, [......],
Y González,
A Martín,
A Sureda,
M Schmidt-Hieber,
A Schmitz,
H E Johnsen,
J-J Lahuerta,
J Bladé,
J F San-Miguel,
A Orfao
[show abstract]
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ABSTRACT: Disappearance of normal bone marrow (BM) plasma cells (PC) predicts malignant transformation of monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) into symptomatic multiple myeloma (MM). The homing, behavior and survival of normal PC, but also CD34(+) hematopoietic stem cells (HSC), B-cell precursors, and clonal PC largely depends on their interaction with stromal cell-derived factor-1 (SDF-1) expressing, potentially overlapping BM stromal cell niches. Here, we investigate the distribution, phenotypic characteristics and competitive migration capacity of these cell populations in patients with MGUS, SMM and MM vs healthy adults (HA) aged >60 years. Our results show that BM and peripheral blood (PB) clonal PC progressively increase from MGUS to MM, the latter showing a slightly more immature immunophenotype. Of note, such increased number of clonal PC is associated with progressive depletion of normal PC, B-cell precursors and CD34(+) HSC in the BM, also with a parallel increase in PB. In an ex vivo model, normal PC, B-cell precursors and CD34(+) HSC from MGUS and SMM, but not MM patients, were able to abrogate the migration of clonal PC into serial concentrations of SDF-1. Overall, our results show that progressive competition and replacement of normal BM cells by clonal PC is associated with more advanced disease in patients with MGUS, SMM and MM.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2011; 25(4):697-706. · 8.30 Impact Factor
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ABSTRACT: Heavy chain diseases (HCDs) are rare B-cell lymphoproliferative neoplasias characterized by the production of a monoclonal component consisting of a truncated monoclonal Ig heavy chain without the associated light chain. Among them, patients with gamma-HCD are so rare that no more than 150 cases can be found in the literature. In this paper, we report one additional case: an 83-year-old man with a gamma-HCD, in whom a kappa light chain component was detected in the serum by using the serum free light-chain assessment and in addition monoclonal kappa cytoplasmic expression was detected in bone marrow plasma cells by flow cytometric analysis. In the work-up of the patient, the underlying anatomopathological lymphoproliferative disease corresponded to a lymphoplasmacytic lymphoma, as it is stated in the current World Health Organization classification (2008), with both lymphadenopathic and bone marrow infiltration. As in other cases, several autoimmune manifestations (antiphospholipidic syndrome and immune thrombocytopenia) were present during the course of the disease in this patient. This case report illustrates a new case of gamma-HCD, in which serum free light-chain analysis and flow cytometry represented a valuable tool for diagnosis, a finding that could be very important for the future management of these patients.
Annals of Clinical Biochemistry 10/2010; 47(Pt 6):570-2. · 2.17 Impact Factor
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N C Gutiérrez,
M E Sarasquete,
I Misiewicz-Krzeminska,
M Delgado,
J De Las Rivas,
F V Ticona,
E Fermiñán,
P Martín-Jiménez,
C Chillón,
A Risueño,
J M Hernández,
R García-Sanz,
M González,
J F San Miguel
[show abstract]
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ABSTRACT: Specific microRNA (miRNA) signatures have been associated with different cytogenetic subtypes in acute leukemias. This finding prompted us to investigate potential associations between genetic abnormalities in multiple myeloma (MM) and singular miRNA expression profiles. Moreover, global gene expression profiling was also analyzed to find correlated miRNA gene expression and select miRNA target genes that show such correlation. For this purpose, we analyzed the expression level of 365 miRNAs and the gene expression profiling in 60 newly diagnosed MM patients, selected to represent the most relevant recurrent genetic abnormalities. Supervised analysis showed significantly deregulated miRNAs in the different cytogenetic subtypes as compared with normal PC. It is interesting to note that miR-1 and miR-133a clustered on the same chromosomal loci, were specifically overexpressed in the cases with t(14;16). The analysis of the relationship between miRNA expression and their respective target genes showed a conserved inverse correlation between several miRNAs deregulated in MM cells and CCND2 expression level. These results illustrate, for the first time, that miRNA expression pattern in MM is associated with genetic abnormalities, and that the correlation of the expression profile of miRNA and their putative mRNA targets is useful to find statistically significant protein-coding genes in MM pathogenesis associated with changes in specific miRNAs.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 03/2010; 24(3):629-37. · 8.30 Impact Factor
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M Garayoa,
J L Garcia,
C Santamaria,
A Garcia-Gomez,
J F Blanco,
A Pandiella,
J M Hernández,
F M Sanchez-Guijo,
M-C del Cañizo, N C Gutiérrez,
J F San Miguel
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ABSTRACT: It is an open question whether in multiple myeloma (MM) bone marrow stromal cells contain genomic alterations, which may contribute to the pathogenesis of the disease. We conducted an array-based comparative genomic hybridization (array-CGH) analysis to compare the extent of unbalanced genomic alterations in mesenchymal stem cells from 21 myeloma patients (MM-MSCs) and 12 normal donors (ND-MSCs) after in vitro culture expansion. Whereas ND-MSCs were devoid of genomic imbalances, several non-recurrent chromosomal gains and losses (>1 Mb size) were detected in MM-MSCs. Using real-time reverse transcription PCR, we found correlative deregulated expression for five genes encoded in regions for which genomic imbalances were detected using array-CGH. In addition, only MM-MSCs showed a specific pattern of 'hot-spot' regions with discrete (<1 Mb) genomic alterations, some of which were confirmed using fluorescence in situ hybridization (FISH). Within MM-MSC samples, unsupervised cluster analysis did not correlate with particular clinicobiological features of MM patients. We also explored whether cytogenetic abnormalities present in myelomatous plasma cells (PCs) were shared by matching MSCs from the same patients using FISH. All MM-MSCs were cytogenetically normal for the tested genomic alterations. Therefore we cannot support a common progenitor for myeloma PCs and MSCs.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2009; 23(8):1515-27. · 8.30 Impact Factor
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A Armellini,
M E Sarasquete,
R García-Sanz,
M C Chillón,
A Balanzategui,
M Alcoceba,
M Fuertes,
R López,
J M Hernández,
J Fernández-Calvo,
M Sierra,
M Megido,
A Orfão, N C Gutiérrez,
M González,
J F San Miguel
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ABSTRACT: RAN, ZHX2 and RCBTB2 (CHC1L) expression was evaluated by quantitative real time reverse transcription polymerase chain reaction in plasma cells from 85 monoclonal gammopathies: 58 symptomatic multiple myeloma (MM) (52 untreated, six relapsed), eight smouldering MM, five monoclonal gammopathy of undetermined significance, four plasma cell leukaemias and 10 myeloid cell lines. ZHX2 was weakly expressed in high-risk/proliferative disease compared to low-risk or indolent disease. High ZHX2 expression was associated with better response and longer survival after high-dose therapy. RCBTB2 expression was weaker in hyperdiploid versus non-hyperdiploid cases while RAN was more expressed in symptomatic MM and cell lines.
British Journal of Haematology 05/2008; 141(2):212-5. · 4.94 Impact Factor
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ABSTRACT: Multiple myeloma (MM) is a B-cell malignancy characterised by the accumulation of clonal plasma cells (PC) in the bone marrow (BM). The molecular bases for this incurable disease have been widely investigated in the last years, and the development of modern genomic technologies has contributed to the understanding of the pathogenesis of MM. The molecular mechanisms that explain the cellular origin of myeloma cells, the cytogenetic abnormalities and their clinical implications, and the biological information provided by gene expression profiling analysis are reviewed in this paper. In addition, a molecular classification of MM in seven groups based on the relationship between gene expression profiling, chromosomal translocations and prognostic outcome is also presented. And finally, the recent hypothesis of a potential unifying event in the pathogenesis of MM, supported by cyclin D deregulation in virtually all MM tumours, will be summarised.
Clinical and Translational Oncology 11/2007; 9(10):618-24. · 1.33 Impact Factor
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ABSTRACT: The tumoral clone of Waldenström's macroglobulinemia (WM) shows a wide morphological heterogeneity, which ranges from B lymphocytes (BL) to plasma cells (PC). By means of genome-wide expression profiling we have been able to identify genes exclusively deregulated in BL and PC from WM, but with a similar expression pattern in their corresponding cell counterparts from chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), as well as normal individuals. The differentially expressed genes have important functions in B-cell differentiation and oncogenesis. Thus, two of the genes downregulated in WM-BL were IL4R, which plays a relevant role in CLL B-cell survival, and BACH2, which participates in the development of class-switched PC. Interestingly, one of the upregulated genes in WM-BL was IL6. A set of four genes was able to discriminate clonal BL from WM and CLL: LEF1 (WNT/beta-catenin pathway), MARCKS, ATXN1 and FMOD. We also found deregulation of genes involved in plasma cell differentiation such as PAX5, which was overexpressed in WM-PC, and IRF4 and BLIMP1, which were underexpressed. In addition, three of the target genes activated by PAX5 - CD79, BLNK and SYK - were upregulated in WM-PC. In summary, these results indicate that both PC and BL from WM are genetically different from the MM and CLL cell counterpart.
Leukemia 04/2007; 21(3):541-9. · 9.56 Impact Factor
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N C Gutiérrez,
M V Castellanos,
M L Martín,
M V Mateos,
J M Hernández,
M Fernández,
D Carrera,
L Rosiñol,
J M Ribera,
J M Ojanguren,
L Palomera,
S Gardella,
L Escoda,
J C Hernández-Boluda,
J L Bello,
J de la Rubia,
J J Lahuerta,
J F San Miguel
[show abstract]
[hide abstract]
ABSTRACT: Fluorescence in situ hybridization (FISH) has become a powerful technique for prognostic assessment in multiple myeloma (MM). However, the existence of associations between cytogenetic abnormalities compels us to re-assess the value of each abnormality. A total of 260 patients with MM at the time of diagnosis, enrolled in the GEM-2000 Spanish transplant protocol, have been analyzed by FISH in order to ascertain the independent influence on myeloma prognosis of IGH translocations, as well as RB and P53 deletions. Survival analyses showed that patients with t(4;14), RB or P53 deletions had a significantly shorter survival than patients without these abnormalities. However, patients with RB deletions without other abnormalities in FISH analysis, displayed a similar outcome to those patients without genetic changes by FISH (46 vs 54 months, P=0.3). In the multivariate analysis the presence of t(4;14), RB deletion associated with other abnormalities, age >60 years, high proportion of S-phase cells and advanced stage of the disease according to the International Staging System retained their independent prognostic influence. In summary, RB deletion as a sole abnormality does not lead to a shortening in the survival of MM patients, whereas t(4;14) confers the worst prognosis in MM patients treated with high-dose chemotherapy.
Leukemia 01/2007; 21(1):143-50. · 9.56 Impact Factor
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J M Hernández,
C Castilla, N C Gutiérrez,
I M Isidro,
M Delgado,
J de las Rivas,
E Fermiñán,
J L García,
E M Ocio,
M C del Cañizo,
J F San Miguel
Leukemia 07/2005; 19(6):1088-91. · 9.56 Impact Factor
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N C Gutiérrez,
R López-Pérez,
J M Hernández,
I Isidro,
B González,
M Delgado,
E Fermiñán,
J L García,
L Vázquez,
M González,
J F San Miguel
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ABSTRACT: Bone marrow samples from 43 adult patients with de novo diagnosed acute myeloid leukemia (AML)--10 acute promyelocytic leukemias (APL) with t(15;17), four AML with inv(16), seven monocytic leukemias and 22 nonmonocytic leukemias--were analyzed using high-density oligonucleotide microarrays. Hierarchical clustering analysis segregated APL, AML with inv(16), monocytic leukemias and the remaining AML into separate groups. A set of only 21 genes was able to assign AML to one of these three classes: APL, inv(16) and other AML subtype without a specific translocation. Quantitative RT-PCR performed for 18 out of these predictor genes confirmed microarray results. APL expressed high levels of FGF13 and FGFR1 as well as two potent angiogenic factors, HGF and VEGF. AML with inv(16) showed an upregulation of MYH11 and a downregulation of a gene encoding a core-binding factor protein, RUNX3. Genes involved in cell adhesion represented the most altered functional category in monocytic leukemias. Two major groups emerged from the remaining 22 AML: cluster A with 10 samples and cluster B with 12. All the eight leukemias that were either refractory to treatment or that relapsed afterwards were assigned to cluster B. In the latter cluster, CD34 upregulation and serine proteases downregulation is consistent with a maturation arrest and lack of granulocytic differentiation.
Leukemia 04/2005; 19(3):402-9. · 9.56 Impact Factor
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J L García,
J M Hernandez, N C Gutiérrez,
T Flores,
D González,
M J Calasanz,
J A Martínez-Climent,
M A Piris,
C Lopéz-Capitán,
M B González,
M D Odero,
J F San Miguel
[show abstract]
[hide abstract]
ABSTRACT: Comparative genomic hybridization (CGH) studies have demonstrated a high incidence of chromosomal imbalances in non-Hodgkin's lymphoma. However, the information on the genomic imbalances in Burkitt's Lymphoma (BL) is scanty. Conventional cytogenetics was performed in 34 cases, and long-distance PCR for t(8;14) was performed in 18 cases. A total of 170 changes were present with a median of four changes per case (range 1-22). Gains of chromosomal material (143) were more frequent than amplifications (5) or losses (22). The most frequent aberrations were gains on chromosomes 12q (26%), Xq (22%), 22q (20%), 20q (17%) and 9q (15%). Losses predominantly involved chromosomes 13q (17%) and 4q (9%). High-level amplifications were present in the regions 1q23-31 (three cases), 6p12-p25 and 8p22-p23. Upon comparing BL vs Burkitt's cell leukemia (BCL), the latter had more changes (mean 4.3 +/- 2.2) than BL (mean 2.7 +/- 3.2). In addition, BCL cases showed more frequently gains on 8q, 9q, 14q, 20q, and 20q, 9q, 8q and 14q, as well as losses on 13q and 4q. Concerning outcome, the presence of abnormalities on 1q (ascertained either by cytogenetics or by CGH), and imbalances on 7q (P=0.01) were associated with a short survival.
Leukemia 11/2003; 17(10):2016-24. · 9.56 Impact Factor
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J M Hernández,
G Martín, N C Gutiérrez,
J Cervera,
M T Ferro,
M J Calasanz,
J A Martínez-Climent,
E Luño,
M Tormo,
C Rayón,
J Díaz-Mediavilla,
M González,
J D González-San Miguel,
K Pérez-Equiza,
C Rivas,
J Esteve,
M del C Alvarez,
J Odriozola,
J M Ribera,
M A Sanz
[show abstract]
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ABSTRACT: To analyze in patients with de novo acute promyelocytic leukemia (APL) treated with an ATRA plus anthracyclin-based protocol if the presence of additional cytogenetic aberrations to the t(15;17) influences: 1. clinical and biological presenting features; 2. disease outcome.
One hundred and thirteen patients with newly diagnosed APL enrolled in the APL-96 protocol of the Spanish PETHEMA group were studied by conventional karyotyping, FISH and RT-PCR for the PML-RARa fusion. Treatment was homogeneous in all cases and consisted of anthracyclines and ATRA.
Additional chromosome aberrations were observed in 30% of cases. The most frequent secondary changes were +8 (14 cases), and abnormalities of chromosomes 9 or 3 (4 patients each), and of chromosomes 1 and 8 (3 cases each). No clinical, biological, morphological, immunophenotypic or molecular differences were observed between the group of APLs with t(15;17) alone and the group of patients with additional changes. Patients with additional changes had a higher rates of complete remission (CR) and 4-year disease-free survival (DFS) (97%, and 97%, respectively) than patients with t(15;17) alone (CR, 70% and DFS, 84%) but these differences were not statistically significant.
Patients with APL and additional cytogenetic abnormalities do not show different clinical, biological, morphological or molecular features as compared to patients with t(15;17) alone. The prognosis of patients with APL and t(15;17) alone and those with additional changes is similar in both groups. This study indicates that there is no rationale for administering more intensive treatment in APL patients with additional cytogenetic abnormalities receiving ATRA plus anthracycline-based chemotherapy.
Haematologica 09/2001; 86(8):807-13. · 6.42 Impact Factor
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ABSTRACT: To analyze the genomic differences between multiple myeloma (MM) and plasma cell leukemia (PCL), a total of 30 cases were studied by comparative genomic hybridization (CGH). In five cases with a low proportion of plasma cells (PC) in bone marrow, an enrichment of PC was performed by using immunomagnetic beads conjugated with the monoclonal antibody B-B4. In 24 out of the 25 MM (96%) and in all five PCL (100%) patients DNA copy number changes were identified by CGH analysis; in the MM case without chromosomal imbalances, the immunomagnetic enrichment of PC had failed. The most recurrent changes in MM patients were gains at chromosomes 15q (48%), 11q (44%), 3q (40%), 9q (40%) and 1q (36%). By contrast, all PCL patients showed gains in 1q. Losses of chromosomal material were significantly more frequent in PCL than in MM patients (P = 0.03): losses on 13q in 80% of PCL vs 28% of MM; and on chromosome 16 in 80% vs 12%, respectively. In addition, PCL patients showed losses of 2q and 6p that were not present in MM. The CGH data show differences in chromosomal imbalances between MM and PCL.
Leukemia 06/2001; 15(5):840-5. · 9.56 Impact Factor
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ABSTRACT: Cytogenetic studies in multiple myleoma (MM) are limited by the difficulties in obtaining metaphases that can be investigated and few studies have analyzed the relationship between cytogenetics and clinical disease characteristics. The aim of our study was to analyze the recurrent cytogenetic changes in MM and to correlate them with clinical and biological characteristics including the percentage of S-phase plasma cells (PCs).
Chromosomal abnormalities were analyzed in 86 patients with MM. In all patients, two types of cultures (5 d culture with interleukin-4 and unstimulated 72 h culture) were used for cytogenetic analysis. DNA content analysis (ploidy and cell cycle analysis) together with the most relevant clinical and biological disease features were studied.
Cytogenetic analysis was successful in 72 of the 86 patients (84%). Forty-seven patients (65%) had an abnormal karyotype. The most frequent trisomies involved chromosomes 3, 5, 9, 11, 15, 19, 22, 1, 7, 17, 18, and 21, and monosomies affected chromosomes 13 and 8, while structural changes involved chromosomes 1, 11, 14q32, 4p16 and 16q22-23. Patients with abnormal karyotype displayed a poor performance status, advanced stage, anemia and a high percentage of bone marrow plasma cells. In addition, MM patients with -13/13q- and 11q abnormalities showed a significantly higher proportion of S-phase PCs (p=0.02).
In summary, our study shows a relationship between unfavorable cytogenetics (-13/13q-/11q abnormalities) and a high percentage of S-phase PCs, a well-known adverse prognostic factor.
Haematologica 12/2000; 85(11):1146-52. · 6.42 Impact Factor
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ABSTRACT: Atypical chronic myeloid leukemia (aCML) is an infrequent chronic myeloproliferative disorder characterized by leukocytosis, absence of Philadelphia chromosome or BCR-ABL rearrangement, and marked myeloid dysplasia. Some cases have an absolute monocytosis but can be distinguished from chronic myelomonocytic leukemia (CMML) by the presence of a higher percentage (> 15%) of circulating immature granulocytes.
In a series of 11 patients with a diagnosis of aCML according to the FAB proposals we have analyzed the most relevant clinical, hematological and cytogenetic characteristics.
The median age was 65 years (16-84). All but one case showed, at time of diagnosis, leukocytosis (median WBC was 36 x 10(9)/l), 55% had moderate anemia and 36% had thrombocytopenia. Most cases had marked dysplasia, particularly in the granulocytic lineage (82% of the cases), and all cases showed bone marrow red hypoplasia. Cytogenetic abnormalities were present in 9 out of the 11 patients. Trisomy 8 was observed in three cases and other clonal chromosomal abnormalities included deletions of 5q, 13q, 17p, 12q, and 11q as well as a t(6;8)(p23;q22) translocation. Fluorescence in situ hybridization (FISH) studies failed to demonstrate ETV-6 gene involvement. The median survival time from diagnosis was only 14 months (range 3-56 months).
These data suggest that aCML is a rare disease which is characterized by leukocytosis, with dysgranulopoiesis, BM erythroid hypoplasia, chromosomal, though not recurrent, abnormalities and poor prognosis.
Annals of Oncology 05/2000; 11(4):441-4. · 6.43 Impact Factor
