125 results on '"Rossi, Davide"'
Search Results
2. Common nonmutational NOTCH1 activation in chronic lymphocytic leukemia
- Author
-
Fabbri, Giulia, Holmes, Antony B., Viganotti, Mara, Scuoppo, Claudio, Belver, Laura, Herranz, Daniel, Yan, Xiao-Jie, Kieso, Yasmine, Rossi, Davide, Gaidano, Gianluca, Chiorazzi, Nicholas, Ferrando, Adolfo A., and Dalla-Favera, Riccardo
- Published
- 2017
3. Richter Syndrome
- Author
-
Rossi, Davide, Gaidano, Gianluca, and Malek, Sami, editor
- Published
- 2013
- Full Text
- View/download PDF
4. Comparative analysis of targeted next-generation sequencing panels for the detection of gene mutations in chronic lymphocytic leukemia: an ERIC multi-center study
- Author
-
Sutton, Lesley-Ann, Ljungström, Viktor, Enjuanes, Anna, Cortese, Diego, Skaftason, Aron, Tausch, Eugen, Kozubik, Katerina Stano, Nadeu, Ferran, Armand, Marine, Malcikova, Jikta, Djureinovic, Tatjana, Forster, Jade, Davis, Zadie, Oscier, David, Rossi, Davide, Ghia, Paolo, Strefford, Jonathan C., Pospisilova, Sarka, Stilgenbauer, Stephan, Davi, Frederic, Campo, Elias, Stamatopoulos, Kostas, Rosenquist, Richard, Karolinska Institutet [Stockholm], Uppsala University, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), University of Ulm (UUlm), Central European Institute of Technology [Brno] (CEITEC MU), Brno University of Technology [Brno] (BUT), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), University of Southampton, Oncology Institute of Southern Switzerland (IOSI), Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), IRCCS Ospedale San Raffaele [Milan, Italy], Karolinska University Hospital [Stockholm], Sutton, Lesley-Ann, Ljungström, Viktor, Enjuanes, Anna, Cortese, Diego, Skaftason, Aron, Tausch, Eugen, Stano Kozubik, Katerina, Nadeu, Ferran, Armand, Marine, Malcikova, Jikta, Pandzic, Tatjana, Forster, Jade, Davis, Zadie, Oscier, David, Rossi, Davide, Ghia, Paolo, Strefford, Jonathan C, Pospisilova, Sarka, Stilgenbauer, Stephan, Davi, Frederic, Campo, Elia, Stamatopoulos, Kosta, and Rosenquist, Richard
- Subjects
Cytogenetics and Molecular Genetics ,[SDV]Life Sciences [q-bio] ,Mutation ,Next-generation sequencing ,High-Throughput Nucleotide Sequencing ,Humans ,Chronic Lymphocytic Leukemia ,Hematology ,Hematologi ,Genomics ,Precision Medicine ,Leukemia, Lymphocytic, Chronic, B-Cell ,Article - Abstract
International audience; Next-generation sequencing (NGS) has transitioned from research to clinical routine, yet the comparability of different technologies for mutation profiling remains an open question. We performed a European multicenter (n=6) evaluation of three amplicon-based NGS assays targeting 11 genes recurrently mutated in chronic lymphocytic leukemia. Each assay was assessed by two centers using 48 pre-characterized chronic lymphocytic leukemia samples; libraries were sequenced on the Illumina MiSeq instrument and bioinformatics analyses were centralized. Across all centers the median percentage of target reads ≥100x ranged from 94.2- 99.8%. In order to rule out assay-specific technical variability, we first assessed variant calling at the individual assay level i.e., pairwise analysis of variants detected amongst partner centers. After filtering for variants present in the paired normal sample and removal of PCR/sequencing artefacts, the panels achieved 96.2% (Multiplicom), 97.7% (TruSeq) and 90% (HaloPlex) concordance at a variant allele frequency (VAF) >0.5%. Reproducibility was assessed by looking at the inter-laboratory variation in detecting mutations and 107 of 115 (93% concordance) mutations were detected by all six centers, while the remaining eight variants (7%) were undetected by a single center. Notably, 6 of 8 of these variants concerned minor subclonal mutations (VAF 5%, after rigorous validation, the use of unique molecular identifiers may be necessary to reach a higher sensitivity and ensure consistent and accurate detection of low-frequency variants.
- Published
- 2020
5. Genetics and epigenetics of CLL.
- Author
-
Paul, Pamella, Stüssi, Georg, Bruscaggin, Alessio, and Rossi, Davide
- Subjects
CHRONIC lymphocytic leukemia ,GENETICS ,IMMUNOGLOBULIN heavy chains ,EPIGENETICS ,SOMATIC mutation - Abstract
Chronic lymphocytic leukemia (CLL) has a heterogeneous biological behavior, which is highly influenced by its immunogenetic, epigenetic, and genomic properties. The remarkably variable clinical course of the disease has been associated with genetic features such as chromosomal abnormalities, the presence of either high or low numbers of somatic hypermutations (SHM) in the variable region of the immunoglobulin heavy chain locus (IGHV), and somatic mutations of several specific driver genes. Next-generation sequencing (NGS) technologies have provided a comprehensive characterization of the genomic and epigenomic landscape in CLL, elucidating important underlying mechanisms of the disease's biology. The scope of this review is to summarize the most recent discoveries about novel genetic and epigenetic alterations, discussing their impact on clinical outcomes and response to currently available therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
6. NOTCH1 mutations identify a chronic lymphocytic leukemia patient subset with worse prognosis in the setting of a rituximab-based induction and consolidation treatment
- Author
-
Bo, Michele Dal, Del Principe, Maria Ilaria, Pozzo, Federico, Ragusa, Dario, Bulian, Pietro, Rossi, Davide, Capelli, Giovanni, Rossi, Francesca Maria, Niscola, Pasquale, Buccisano, Francesco, Bomben, Riccardo, Zucchetto, Antonella, Maurillo, Luca, de Fabritiis, Paolo, Amadori, Sergio, Gaidano, Gianluca, Gattei, Valter, and Del Poeta, Giovanni
- Published
- 2014
- Full Text
- View/download PDF
7. Anatomical heterogeneity of residual disease in chronic lymphocytic leukemia treated with ibrutinib.
- Author
-
Condoluci, Adalgisa, Milan, Lisa, Forestieri, Gabriela, Terzi di Bergamo, Lodovico, Spina, Valeria, Bruscaggin, Alessio, Deambrogi, Clara, Moia, Riccardo, Deodato, Marina, Fahrni, Gaby, Mattarucchi, Roberta, Merli, Michele, Gerber, Bernhard, Stussi, Georg, Passamonti, Francesco, Gregor, Michael, Tedeschi, Alessandra, Gaidano, Gianluca, Rossi, Davide, and Ceriani, Luca
- Subjects
CHRONIC lymphocytic leukemia ,CHRONIC leukemia ,CHRONIC diseases ,BRUTON tyrosine kinase - Abstract
Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase III study. (C), The line plots show the tumor volume (ml, yellow), MRD (ml, gray) and ctDNA (hGE/ml, blue) of patients achieving partial response until 96 weeks post treatment. Circulating tumor DNA (ctDNA) [the tumor-derived portion of total cell-free DNA (cfDNA) circulating in blood] allows minimally invasive lymphoma diagnostics. [Extracted from the article]
- Published
- 2022
- Full Text
- View/download PDF
8. A leukemia-protective germline variant mediates chromatin module formation via transcription factor nucleation.
- Author
-
Llimos, Gerard, Gardeux, Vincent, Koch, Ute, Kribelbauer, Judith F., Hafner, Antonina, Alpern, Daniel, Pezoldt, Joern, Litovchenko, Maria, Russeil, Julie, Dainese, Riccardo, Moia, Riccardo, Mahmoud, Abdurraouf Mokhtar, Rossi, Davide, Gaidano, Gianluca, Plass, Christoph, Lutsik, Pavlo, Gerhauser, Clarissa, Waszak, Sebastian M., Boettiger, Alistair, and Radtke, Freddy
- Subjects
TRANSCRIPTION factors ,CHROMATIN ,CHRONIC lymphocytic leukemia ,GERM cells ,LYMPHOCYTIC leukemia - Abstract
Non-coding variants coordinate transcription factor (TF) binding and chromatin mark enrichment changes over regions spanning >100 kb. These molecularly coordinated regions are named "variable chromatin modules" (VCMs), providing a conceptual framework of how regulatory variation might shape complex traits. To better understand the molecular mechanisms underlying VCM formation, here, we mechanistically dissect a VCM-modulating noncoding variant that is associated with reduced chronic lymphocytic leukemia (CLL) predisposition and disease progression. This common, germline variant constitutes a 5-bp indel that controls the activity of an AXIN2 gene-linked VCM by creating a MEF2 binding site, which, upon binding, activates a super-enhancer-like regulatory element. This triggers a large change in TF binding activity and chromatin state at an enhancer cluster spanning >150 kb, coinciding with subtle, long-range chromatin compaction and robust AXIN2 up-regulation. Our results support a model in which the indel acts as an AXIN2 VCM-activating TF nucleation event, which modulates CLL pathology. Non-coding variants can regulate transcription factor binding and gene expression at variable chromatin modules. Here, the authors show that a germline variant induces transcription factor nucleation through chromatin compaction leading to AXIN2 up-regulation and is associated to better prognosis in chronic lymphocytic leukaemia. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
9. Elastin MIcrofibriL INterfacer1 (EMILIN‐1) is an alternative prosurvival VLA‐4 ligand in chronic lymphocytic leukemia.
- Author
-
Tissino, Erika, Pivetta, Eliana, Capuano, Alessandra, Capasso, Guido, Bomben, Riccardo, Caldana, Chiara, Rossi, Francesca Maria, Pozzo, Federico, Benedetti, Dania, Boldorini, Renzo, Gaidano, Gianluca, Rossi, Davide, Zamò, Alberto, Hartmann, Tanja Nicole, Doliana, Roberto, Colombatti, Alfonso, Gattei, Valter, Spessotto, Paola, and Zucchetto, Antonella
- Subjects
CHRONIC lymphocytic leukemia ,ELASTIN ,LEUCOCYTE elastase ,BONE marrow - Abstract
CD49d, the α4 chain of the VLA‐4 integrin, is a negative prognosticator in chronic lymphocytic leukemia (CLL) with a key role in CLL cell‐microenvironment interactions mainly occurring via its ligands VCAM‐1 and fibronectin. In the present study, we focused on EMILIN‐1 (Elastin‐MIcrofibriL‐INterfacer‐1), an alternative VLA‐4 ligand whose role has been so far reported only in non‐hematological settings, by investigating: i) the distribution of EMILIN‐1 in CLL‐involved tissues; ii) the capability of EMILIN‐1 to operate, via its globular C1q (gC1q) domain, as additional adhesion ligand in CLL; iii) the functional meaning of EMILIN‐1 gC1q/VLA‐4 interactions in CLL. EMILIN‐1 is widely present in the CLL‐involved areas of bone marrow biopsies (BMBs) without difference between CD49d negative and positive cases, displaying at least three different expression patterns: "fibrillar", "dot‐like" and "mixed". The lack in CLL‐BMB of neutrophil elastase, whose proteolytic activity degrades EMILIN‐1 and impairs EMILIN‐1 function, suggests full functional EMILIN‐1 in CLL independently of its expression pattern. Functionally, EMILIN‐1 gC1q domain promotes adhesion of CLL cells through specific interaction with VLA‐4, and releases pro‐survival signals for CLL cells, as demonstrated by enhanced ERK and AKT phosphorylation and impairment of in‐vitro‐induced apoptosis. EMILIN‐1/VLA‐4 interaction can efficiently contribute to the maintenance of the neoplastic clone in CLL. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
10. Biology and Treatment of Richter Transformation.
- Author
-
Condoluci, Adalgisa and Rossi, Davide
- Subjects
RICHTER syndrome ,CHRONIC lymphocytic leukemia ,BIOLOGY ,HODGKIN'S disease ,LYMPHOMAS - Abstract
Richter transformation (RT), defined as the development of an aggressive lymphoma on a background of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), represents a clinical unmet need because of its dismal prognosis. An increasing body of knowledge in the field of RT is arising from the recent development of preclinical models depicting the biology underlying this aggressive disease. Consistently, new therapeutic strategies based on a genetic rationale are exploring actionable pathogenic pathways to improve the outcome of patients in this setting. In this review, we summarize the current understandings on RT biology and the available treatment options. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
11. IRF4 L116R mutation promotes proliferation of chronic lymphocytic leukemia B cells inducing MYC.
- Author
-
Benatti, Stefania, Atene, Claudio Giacinto, Fiorcari, Stefania, Mesini, Nicolò, Martinelli, Silvia, Zucchini, Patrizia, Bacchelli, Francesca, Maccaferri, Monica, Debbia, Giulia, Potenza, Leonardo, Rossi, Davide, Vallisa, Daniele, Trentin, Livio, Gaidano, Gianluca, Luppi, Mario, Marasca, Roberto, and Maffei, Rossana
- Subjects
CHRONIC lymphocytic leukemia ,B cells ,GENETIC mutation ,CHRONIC leukemia ,RICHTER syndrome ,INTERFERON regulatory factors - Abstract
Keywords: chronic lymphocytic leukemia; IRF4 L116R mutation; proliferation; MYC EN chronic lymphocytic leukemia IRF4 L116R mutation proliferation MYC 707 711 5 12/07/21 20211201 NES 211201 DATA AVAIBILITY STATEMENT The data that support the findings of the study are available on requests from the corresponding author. MYC protein level was inspected in IRF4 transfected CLL cells by immunoblotting after 72 h of co-culture, observing increased MYC protein in IRF4-mutant CLL cells as compared to IRF4-WT cells and control samples (Figure 2E). We first screened a multicenter cohort of 460 CLL patients that comprised 365 untreated CLL cases, 51 treated CLL, including 32 pluri-treated CLL, and 44 Richter transformed cases. [Extracted from the article]
- Published
- 2021
- Full Text
- View/download PDF
12. Lymphocyte Doubling Time As A Key Prognostic Factor To Predict Time To First Treatment In Early-Stage Chronic Lymphocytic Leukemia.
- Author
-
Morabito, Fortunato, Tripepi, Giovanni, Moia, Riccardo, Recchia, Anna Grazia, Boggione, Paola, Mauro, Francesca Romana, Bossio, Sabrina, D'Arrigo, Graziella, Martino, Enrica Antonia, Vigna, Ernesto, Storino, Francesca, Fronza, Gilberto, Di Raimondo, Francesco, Rossi, Davide, Condoluci, Adalgisa, Colombo, Monica, Fais, Franco, Fabris, Sonia, Foa, Robin, and Cutrona, Giovanna
- Subjects
CHRONIC lymphocytic leukemia ,PROGNOSIS ,LYMPHOCYTES ,LYMPHOCYTE count ,DIAGNOSIS - Abstract
The prognostic role of lymphocyte doubling time (LDT) in chronic lymphocytic leukemia (CLL) was recognized more than three decades ago when the neoplastic clone's biology was almost unknown. LDT was defined as the time needed for the peripheral blood lymphocyte count to double the of the initial observed value. Herein, the LDT prognostic value for time to first treatment (TTFT) was explored in our prospective O-CLL cohort and validated in in two additional CLL cohorts. Specifically, newly diagnosed Binet stage A CLL patients from 40 Italian Institutions, representative of the whole country, were prospectively enrolled into the O-CLL1-GISL protocol (clinicaltrial.gov identifier: NCT00917540). Two independent cohorts of newly diagnosed CLL patients recruited respectively at the Division of Hematology in Novara, Italy, and at the Hospital Clinic in Barcelona, Spain, were utilized as validation cohorts. In the training cohort, TTFT of patients with LDT >12 months was significantly longer related to those with a shorter LDT. At Cox multivariate regression model, LDT ≤ 12 months maintained a significant independent relationship with shorter TTFT along with IGHV unmutated (IGHV unmut) status, 11q and 17p deletions, elevated β2M, Rai stage I-II, and NOTCH1 mutations. Based on these statistics, two regression models were constructed including the same prognostic factors with or without the LDT. The model with the LTD provided a significantly better data fitting (χ
2 = 8.25, P=0.0041). The risk prediction developed including LDT had better prognostic accuracy than those without LDT. Moreover, the Harrell'C index for the scores including LDT were higher than those without LDT, although the accepted 0.70 threshold exceeded in both cases. These findings were also confirmed when the same analysis was carried out according to TTFT's explained variation. When data were further analyzed based on the combination between LDT and IGHV mutational status in the training and validation cohorts, IGHV unmut and LDT>12months group showed a predominant prognostic role over IGHV mut LTD ≤ 12 months (P=0.006) in the O-CLL validation cohort. However, this predominance was of borden-line significance (P=0.06) in the Barcelona group, while the significant prognostic impact was definitely lost in the Novara group. Overall, in this study, we demonstrated that LDT could be re-utilized together with the more sophisticated prognostic factors to manage the follow-up plans for Binet stage A CLL patients. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
13. Mutations in the 3' untranslated region (3' UTR) of NOTCH1 are associated with low CD20 expression levels in chronic lymphocytic leukemia
- Author
-
Bittolo, Tamara, Pozzo, Federico, Bomben, Riccardo, D'Agaro, Tiziana, Bravin, Vanessa, Bulian, Pietro, Rossi, Francesca Maria, Zucchetto, Antonella, Degan, Massimo, Macor, Paolo, D'Arena, Giovanni, Chiarenza, Annalisa, Zaja, Francesco, Pozzato, Gabriele, Di Raimondo, Francesco, Rossi, Davide, Gaidano, Gianluca, Del Poeta, Giovanni, Gattei, Valter, Dal Bo, Michele, Bittolo, Tamara, Pozzo, Federico, Bomben, Riccardo, D'Agaro, Tiziana, Bravin, Vanessa, Bulian, Pietro, Rossi, Francesca Maria, Zucchetto, Antonella, Degan, Massimo, Macor, Paolo, D'Arena, Giovanni, Chiarenza, Annalisa, Zaja, Francesco, Pozzato, Gabriele, Di Raimondo, Francesco, Rossi, Davide, Gaidano, Gianluca, Del Poeta, Giovanni, Gattei, Valter, and Dal Bo, Michele
- Subjects
CD20 ,Chronic Lymphocytic Leukemia ,NOTCH1 ,anti-CD20 immunotherapy ,hemic and lymphatic diseases ,embryonic structures ,cardiovascular system ,sense organs ,biological phenomena, cell phenomena, and immunity - Abstract
letter
- Published
- 2017
14. Redefining the prognostic likelihood of chronic lymphocytic leukaemia patients with borderline percentage of immunoglobulin variable heavy chain region mutations.
- Author
-
Raponi, Sara, Ilari, Caterina, Della Starza, Irene, Cappelli, Luca V., Cafforio, Luciana, Piciocchi, Alfonso, Arena, Valentina, Mariglia, Paola, Mauro, Francesca R., Gentile, Massimo, Cutrona, Giovanna, Moia, Riccardo, Favini, Chiara, Morabito, Fortunato, Rossi, Davide, Gaidano, Gianluca, Guarini, Anna, Del Giudice, Ilaria, and Foà, Robin
- Subjects
CHRONIC leukemia ,LYMPHOCYTIC leukemia ,IMMUNOGLOBULIN heavy chains ,CHRONIC lymphocytic leukemia ,PERCENTILES - Abstract
Summary: In chronic lymphocytic leukaemia (CLL), caution is warranted regarding the clinical implications of immunoglobulin variable heavy chain region (IGHV) rearrangements with a 'borderline' (BL) percentage of mutations (i.e. 97–97·9% IGHV identity). We analysed the IGHV mutational status in 759 untreated CLL patients (cohort 1). BL‐CLL (n = 36, 5%) showed a time to first treatment (TFT) similar to that of M‐CLL (n = 338) and significantly longer than that of UM‐CLL (n = 385), despite the enrichment in subset #2 cases. In fact, CLLs belonging to subset #2 (n = 15/759, 2%) were significantly more frequent among BL‐CLLs (n = 5/36, 14%), with a brief TFT. TFT of BL‐CLL remained comparable to that of M‐CLL also considering the 327 CLL patients evaluated at diagnosis. These findings were then validated in an independent cohort 2 of 759 newly diagnosed CLL patients (BL‐CLL: n = 11, 1·4%) and in all newly diagnosed patients from cohorts 1 and 2 (n = 1 086, 84% stage A; BL‐CLL: n = 47, 4·3%). BL‐CLL at diagnosis showed a biological profile comparable to that of M‐CLL with a low frequency of unfavourable prognostic markers, except for a significant enrichment in subset #2. Our data suggest that the prognosis of BL‐CLL is good and similar to that of M‐CLL, with the exception of subset #2 cases. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
15. Overview of non‐coding mutations in chronic lymphocytic leukemia.
- Author
-
Spina, Valeria and Rossi, Davide
- Abstract
Chronic lymphocytic leukemia (CLL) is the most frequent leukemia type in which the genetic alterations influencing the clinico‐biological course are not entirely understood. CLL has a heterogeneous course, with some patients showing an indolent course and others experiencing an aggressive course. Whole‐genome sequencing and whole‐exome sequencing studies identified recurrently mutated genes in CLL and profiled its clonal evolution patterns. However, more recent whole‐genome sequencing studies also identified variants in non‐coding sequences of the CLL genome, revealing important lesions outside the protein‐coding regions. Here we describe the most representative non‐coding lesion of the CLL genome, including lesions in the 3′‐UTR region of NOTCH1 which result in the truncation of the NOTCH1 protein PEST domain, and non‐coding mutations in an enhancer region on chromosome 9p13 which result in reduced expression of the PAX5 transcription factor. In addition, we describe the role of microRNA in CLL, in particular the miR15a/miR16‐1 microRNA recurrently affected by deletions of chromosome 13q14. Together, new findings in non‐coding genome genetic lesions provide a more complete portrait of the genomic landscape of CLL with clinical implications. Whole genome/exome sequencing studies in CLL revealed recurrently mutated driver genes, such as NOTCH1, MYD88, TP53, ATM and SF3B1. However, more recent WGS studies also identified variants in non‐coding sequences of the CLL genome, revealing important lesions outside the protein‐coding regions and providing a more complete portrait of the genomic landscape of CLL, with clinical implications. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
16. Predictive value of the CLL‐IPI in CLL patients receiving chemo‐immunotherapy as first‐line treatment.
- Author
-
Gentile, Massimo, Shanafelt, Tait D., Mauro, Francesca Romana, Reda, Gianluigi, Rossi, Davide, Laurenti, Luca, Del Principe, Maria Ilaria, Cutrona, Giovanna, Angeletti, Ilaria, Coscia, Marta, Herishanu, Yair, Chiarenza, Annalisa, Molica, Stefano, Ciolli, Stefania, Goldschmidt, Neta, Angrilli, Francesco, Giordano, Annamaria, Rago, Angela, Bairey, Osnat, and Tripepi, Giovanni
- Subjects
CHRONIC lymphocytic leukemia ,LYMPHOCYTIC leukemia ,PROGRESSION-free survival ,IMMUNOTHERAPY ,LEUKEMIA treatment - Abstract
The article discusses a study on the predictive value of the chronic lymphocytic leukemia-international prognostic index (CLL-IPI), determined at the time of first treatment, for progression-free survival (PFS) in CLL patients who underwent different frontline chemo-immunotherapy treatment regimens. Topics include the treatment regimens undergone by the patients, capability of the CLL-IPI score to predict PFS, and prognostic power of CLL-IPI when evaluated at the time of first-line therapy.
- Published
- 2018
- Full Text
- View/download PDF
17. Frequency and clinical relevance of coding and noncoding NOTCH1 mutations in early stage Binet A chronic lymphocytic leukemia patients.
- Author
-
Lionetti, Marta, Barbieri, Marzia, Favasuli, Vanessa, Taiana, Elisa, Fabris, Sonia, Favoino, Chiara, Ciceri, Gabriella, Matis, Serena, Colombo, Monica, Massara, Rosanna, Reda, Gianluigi, Gentile, Massimo, Spina, Valeria, Rossi, Davide, Baldini, Luca, Gaidano, Gianluca, Fais, Franco, Ferrarini, Manlio, Morabito, Fortunato, and Cutrona, Giovanna
- Subjects
CHRONIC lymphocytic leukemia ,MEDICAL coding ,LYMPHOCYTIC leukemia - Published
- 2020
- Full Text
- View/download PDF
18. NOTCH1 mutational status in chronic lymphocytic leukaemia: clinical relevance of subclonal mutations and mutation types.
- Author
-
D'Agaro, Tiziana, Bittolo, Tamara, Bravin, Vanessa, Dal Bo, Michele, Pozzo, Federico, Bulian, Pietro, Rossi, Francesca M., Zucchetto, Antonella, Degan, Massimo, D'Arena, Giovanni, Chiarenza, Annalisa, Zaja, Francesco, Pozzato, Gabriele, Di Raimondo, Francesco, Rossi, Davide, Gaidano, Gianluca, Del Poeta, Giovanni, Gattei, Valter, and Bomben, Riccardo
- Subjects
GENETIC mutation ,CHRONIC lymphocytic leukemia ,PROTEINS ,GENETIC testing ,LYMPHOCYTIC leukemia - Abstract
The article offers information on clinical relevance of subclonal mutations and mutation types in NOTCH1 mutational status in chronic lymphocytic leukaemia. It mentions the role of NOTCH1 gene mutations in chronic lymphocytic leukaemia (CLL). It discusses the capacity of NOTCH1 mutations to predict both time to first treatment and overall survival.
- Published
- 2018
- Full Text
- View/download PDF
19. Biology and treatment of Richter syndrome.
- Author
-
Rossi, Davide, Spina, Valeria, and Gaidano, Gianluca
- Subjects
- *
RICHTER syndrome , *PROGNOSIS , *RITUXIMAB , *CHRONIC lymphocytic leukemia , *FORECASTING - Abstract
Richter syndrome (RS) is the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL). Two pathologic variants of RS are recognized: namely, the diffuse large B-cell lymphoma (DLBCL) variant and the rare Hodgkin lymphoma (HL) variant. Histologic documentation is mandatory to diagnose RS. The clinical suspicion of RS should be based on clinical signs and symptoms. Differential diagnosis between CLL progression and RS and choice of the biopsy site may takeadvantageofpositronemissiontomography/computed tomography. Molecular lesions of regulators of proliferation (CDKN2A, NOTCH1, MYC) and apoptosis (TP53) overall associatewith~90% of DLBCL-type RS, whereas the biology of the HL-type RS is largely unknown. The prognosis of the DLBCL-type RS is unfavorable; the outcome of HL-type RS appears to be better. The most important RS prognostic factor is the clonal relationship between the CLL and the aggressive lymphoma clones, with clonally unrelated RS having a better prognosis. Rituximab-containing combination chemotherapy for DLBCL is the most widely used treatment in DLBCL-type RS. Fit patients who respond to induction therapy should be offered stem cell transplantation (SCT) to prolong survival. Adriamycin, bleomycin, vinblastine, and dacarbazine is the preferred regimen for the HL-type RS, and SCT consolidation is less used in this condition. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
20. Increased SHISA3 expression characterizes chronic lymphocytic leukemia patients sensitive to lenalidomide.
- Author
-
Maffei, Rossana, Fiorcari, Stefania, Martinelli, Silvia, Benatti, Stefania, Bulgarelli, Jenny, Rizzotto, Lara, Debbia, Giulia, Santachiara, Rita, Rigolin, Gian Matteo, Forconi, Francesco, Rossi, Davide, Laurenti, Luca, Palumbo, Giuseppe A., Vallisa, Daniele, Cuneo, Antonio, Gaidano, Gianluca, Luppi, Mario, and Marasca, Roberto
- Subjects
CHRONIC lymphocytic leukemia ,CLINICAL trials ,CYTOKINES ,GENE expression ,CANCER patients - Abstract
Lenalidomide is a therapeutically effective drug in chronic lymphocytic leukemia (CLL). Twenty-seven CLL patients were treated with lenalidomide in a phase II clinical trial. Ten patients were grouped as responders (R) and 6 as nonresponders (NR). We evaluated T lymphocytes, NK, monocytes and dendritic cells at baseline and after treatment. A gene expression analysis was performed on 16 CLL samples collected before treatment. The levels of immune cells or immune-related cytokines are not different between R and NR patients. However, CLL patients sensitive to lenalidomide clearly show a peculiar gene expression profile in leukemic cells. The most up-regulated gene (fold change = +23 in R vs. NR) is Wnt inhibitor SHISA homolog 3 (SHISA3). SHISA3highCLL are characterized by a restrained activation of Wnt signaling and sensibility to lenalidomide-induced apoptosis. In conclusion, SHISA3 is a candidate gene for the identification of CLL patients who will benefit of lenalidomide treatment as single agent. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
21. Treatment of Richter's Syndrome.
- Author
-
Condoluci, Adalgisa and Rossi, Davide
- Subjects
CHRONIC lymphocytic leukemia diagnosis ,CHRONIC lymphocytic leukemia treatment ,HODGKIN'S disease treatment ,CHRONIC lymphocytic leukemia ,B cell lymphoma ,DIFFERENTIAL diagnosis ,DISEASE progression ,HODGKIN'S disease ,NEOPLASTIC cell transformation ,DIAGNOSIS ,TUMOR treatment - Abstract
Opinion Statement: Based on the available literature, mostly derived from retrospective or non-randomized phase I or II studies, it is difficult to define an optimized treatment approach for patients developing Richter's syndrome (RS). Early recognition of chronic lymphocytic leukemia (CLL) patients presenting clinical features suspected for a transformation is useful to avoid exposing them to multiple lines of therapy that, being targeted to CLL progression, have poor efficacy against RS. Because of the low specificity (~ 50-60%) of clinical signs of RS (such as rapid and discordant bulky localized lymphadenopathies, elevated LDH levels, emergent physical deterioration, and/or fever in the absence of infection), a 18FDG PET/CT and a biopsy are recommended to confirm RS. A 18FDG PET/CT showing low uptake is helpful to rule out RS and avoid unnecessary risks and costs of performing a biopsy. A 18FDG PET/CT showing a high uptake is not diagnostic of RS but may help in the choice of the site where the biopsy is to be performed. In the setting of the diffuse large B-cell lymphoma (DLBCL) variant of RS, the definition of a clonal relationship between RS and the underlying CLL may guide the choice of treatment. If a clonal relationship is confirmed (the most common situation), rituximab-CHOP-like treatment does not guarantee long-lasting remissions, and should be used as induction therapy followed by consolidation with a stem cell transplant in physically fit patients. If the CLL and RS are clonally unrelated (the less common situation), the management should be that of a de novo DLBCL. In the setting of the rare Hodgkin lymphoma variant of RS, which is usually clonally unrelated to the CLL, ABVD with or without radiotherapy may be curative of the aggressive lymphoma. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
22. Predictive and prognostic biomarkers in the era of new targeted therapies for chronic lymphocytic leukemia.
- Author
-
Rossi, Davide, Gerber, Bernhard, and Stüssi, Georg
- Subjects
- *
CHRONIC lymphocytic leukemia , *PROGNOSIS , *FORECASTING , *THERAPEUTICS , *PHYSICIANS - Abstract
Treatment options for chronic lymphocytic leukemia (CLL) have improved with the introduction of the B-cell receptor inhibitors ibrutinib and idelalisib, and of the BCL2 inhibitor venetoclax. While awaiting the results of head to head comparisons between novel agents and chemoimmunotherapy, predictive biomarkers can assist physicians in treatment tailoring. Though novel agents have modified the landscape of predictors at the time of treatment requirement, the usefulness of historical CLL prognostic biomarkers is still up-to-date when considering anticipation of time to first treatment. This review discusses: (i) disease-related (TP53 defects, immunoglobulin gene mutations), therapy-related (duration of remission), and patient-related (age, comorbidities) biomarkers that can be used in the clinical practice to inform CLL treatment decision either at the time of first line therapy and disease relapse; and (ii) the need of new biomarkers to re-define high-risk CLL because of the questioning by novel agents of historical prognostic factors. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
23. The clinical implications of gene mutations in chronic lymphocytic leukaemia.
- Author
-
Rossi, Davide and Gaidano, Gianluca
- Subjects
- *
CHRONIC lymphocytic leukemia , *GENETIC mutation , *PROGNOSIS , *PROTEINS , *PHENOTYPES , *SEQUENCE analysis - Abstract
Chronic lymphocytic leukaemia (CLL) is a molecularly heterogeneous disease as revealed by recent genomic studies. Among genetic lesions that are recurrent in CLL, few clinically validated prognostic markers, such as TP53 mutations and 17p deletion, are available for the use in clinical practice to guide treatment decisions. Recently, several novel molecular markers have been identified in CLL. Though these mutations have not yet gained the qualification of predictive factors for treatment tailoring, they have shown to be promising to refine the prognostic stratification of patients. The introduction of targeted drugs is changing the genetics of CLL, and has disclosed the acquisition of previously unexpected drug resistant mutations in signalling pathway genes. Ultra-deep next generation sequencing has allowed to reach deep levels of resolution of the genetic portrait of CLL providing a precise definition of its subclonal genetic architecture. This approach has shown that small subclones harbouring drug resistant mutations anticipate the development of a chemorefractory phenotype. Here we review the recent advances in the definition of the genomic landscape of CLL and the ongoing research to characterise the clinical implications of old and new molecular lesions in the setting of both conventional chemo-immunotherapy and targeted drugs. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
24. Richter's syndrome: Novel and promising therapeutic alternatives.
- Author
-
Rossi, Davide
- Abstract
Richter's syndrome (RS) is the development of an aggressive lymphoma in patients with a previous or concomitant diagnosis of chronic lymphocytic leukemia (CLL). The incidence rate for RS is ∼0.5% per year of observation. In the presence of clinical suspicious of RS, diagnosis of transformation and choice of the site of biopsy may take advantage of 18 FDG PET/CT. Molecular lesions of tumor suppression regulators ( TP53 ), cell cycle ( CDKN2A ) and cell proliferation ( NOTCH1 , MYC ) overall account for ∼90% of RS and may be responsible for its aggressive clinical phenotype. The prognosis of RS is generally highly unfavorable. However, the pattern of survival is not homogeneous and the clonal relationship between the CLL and the aggressive lymphoma clones is the most important prognostic factor. Rituximab-containing polychemotherapy represents the back-bone for induction treatment in RS. Younger patients who respond to induction therapy should be offered stem cell transplant to prolong survival. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
25. Inter- and intra-patient clonal and subclonal heterogeneity of chronic lymphocytic leukaemia: evidences from circulating and lymph nodal compartments.
- Author
-
Del Giudice, Ilaria, Marinelli, Marilisa, Wang, Jiguang, Bonina, Silvia, Messina, Monica, Chiaretti, Sabina, Ilari, Caterina, Cafforio, Luciana, Raponi, Sara, Mauro, Francesca R., Di Maio, Valeria, De Propris, Maria S., Nanni, Mauro, Ciardullo, Carmela, Rossi, Davide, Gaidano, Gianluca, Guarini, Anna, Rabadan, Raul, and Foà, Robin
- Subjects
CHRONIC lymphocytic leukemia ,LYMPH nodes ,CLONAL selection theory ,DELETION mutation ,CANCER relapse ,SOMATIC mutation - Abstract
Whole exome sequencing and copy number aberration ( CNA) analysis were performed on cells taken from peripheral blood ( PB) and lymph nodes ( LN) of patients with chronic lymphocytic leukaemia ( CLL). Of 64 non-silent somatic mutations, 54 (84·4%) were clonal in both compartments, 3 (4·7%) were PB-specific and 7 (10·9%) were LN-specific. Most of the LN- or PB-specific mutations were subclonal in the other corresponding compartment (variant frequency 0·5-5·3%). Of 41 CNAs, 27 (65·8%) were shared by both compartments and 7 (17·1%) were LN- or PB-specific. Overall, 6 of 9 cases (66·7%) showed genomic differences between the compartments. At subsequent relapse, Case 10, with 6 LN-specific lesions, and Case 100, with 6 LN-specific and 8 PB-specific lesions, showed, in the PB, the clonal expansion of LN-derived lesions with an adverse impact: SF3B1 mutation, BIRC3 deletion , del8(p23·3-p11·1), del9(p24·3-p13·1) and gain 2(p25·3-p14). CLL shows an intra-patient clonal heterogeneity according to the disease compartment, with both LN and PB-specific mutations/ CNAs. The LN microenvironment might contribute to the clonal selection of unfavourable lesions, as LN-derived mutations/ CNAs can appear in the PB at relapse. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
26. Association between gene and miRNA expression profiles and stereotyped subset #4 B-cell receptor in chronic lymphocytic leukemia.
- Author
-
Maura, Francesco, Cutrona, Giovanna, Mosca, Laura, Matis, Serena, Lionetti, Marta, Fabris, Sonia, Agnelli, Luca, Colombo, Monica, Massucco, Carlotta, Ferracin, Manuela, Zagatti, Barbara, Reverberi, Daniele, Gentile, Massimo, Recchia, Anna Grazia, Bossio, Sabrina, Rossi, Davide, Gaidano, Gianluca, Molica, Stefano, Cortelezzi, Agostino, and Di Raimondo, Francesco
- Subjects
GENE expression ,MICRORNA ,B cell receptors ,CHRONIC lymphocytic leukemia ,CYTOGENETICS ,DOWNREGULATION ,GENETICS - Abstract
In this study we investigated specific biological and clinical features associated with chronic lymphocytic leukemia (CLL) patients carrying stereotyped BCR subset #4 (IGHV4–34) among a prospective cohort of 462 CLL/MBL patients in early stage (Binet A). All subset #4 patients (n= 16) were characterized by the IGHV mutated gene configuration, and absence of unfavorable cytogenetic lesions,NOTCH1orSF3B1mutations. Gene and miRNA expression profiling evidenced that the leukemic cells of subset #4 cases showed significant downregulation ofWDFY4, MF2Aand upregulation ofPDGFA, FGFR1andTFECgene transcripts, as well as the upregulation of miR-497 and miR-29c. The transfection of miR-497 mimic in primary leukemic CLL cells induced a downregulation ofBCL2, a known validated target of this miRNA. Our data identify biological characteristics associated with subset #4 patients, providing further evidence for the putative role of BCR in shaping the features of the tumor cells in CLL. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
27. Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia.
- Author
-
Rossi, Davide, Terzi-di-Bergamo, Lodovico, De Paoli, Lorenzo, Cerri, Michaela, Ghilardi, Guido, Chiarenza, Annalisa, Bulian, Pietro, Visco, Carlo, Mauro, Francesca R., Morabito, Fortunato, Cortelezzi, Agostino, Zaja, Francesco, Forconi, Francesco, Laurenti, Luca, Del Giudice, Ilaria, Gentile, Massimo, Vincelli, Iolanda, Motta, Marina, Coscia, Marta, and Rigolin, Gian Matteo
- Subjects
- *
CHRONIC lymphocytic leukemia treatment , *DISEASE remission , *CYCLOPHOSPHAMIDE , *RITUXIMAB , *FLUDARABINE , *CHRONIC lymphocytic leukemia , *GENETICS - Abstract
Fludarabine, cyclophosphamide, and rituximab (FCR) has represented a significant treatment advancement in chronic lymphocytic leukemia (CLL). In the new scenario of targeted agents, there is an increasing interest in identifying patients who gain the maximum benefit from FCR. In this observational multicenter retrospective analysis of 404 CLL patients receiving frontline FCR, the combination of three biomarkers that are widely tested before treatment (IGHV mutation status, 11q deletion and 17p deletion; available in 80% of the study cohort) allowed to identify a very low-risk category of patients carrying mutated IGHV genes but neither 11q or 17p deletion that accounted for 28% of all cases. The majority of very low-risk patients (71%) remained free of progression after treatment and their hazard of relapse decreased after 4 years from FCR. The life expectancy of very low-risk patients (91% at 5 years) was superimposable to that observed in the matched normal general population, indicating that neither the disease nor complications of its treatment affected survival in this favorable CLL group. These findings need a prospective validation and may be helpful for the design of clinical trials aimed at comparing FCR to new targeted treatments of CLL, and, possibly, for optimized disease management. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
28. Molecular deregulation of signaling in lymphoid tumors.
- Author
-
Spina, Valeria, Martuscelli, Lavinia, and Rossi, Davide
- Subjects
CELL communication ,LYMPHOID tissue ,CHRONIC lymphocytic leukemia ,GENETIC mutation ,T cell receptors ,CANCER - Abstract
Genomic studies have led to a significant impact both on the pace and the nature of understanding the molecular and biological bases of a variety of lymphoid tumors. An increasingly emerging aspect from genomic studies is that malignant lymphoid cells manipulate signaling pathways that are central to the homeostasis of their normal counterpart, including B- and T-cell receptor signaling, NF- κB signaling, Toll-like receptor signaling, cytokine signaling, MAP kinase signaling, and NOTCH signaling. This review aims at covering the signaling pathways that are affected by mutations in lymphoid tumors, and how genetic alteration of these pathways may contribute to disease pathogenesis and management. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
29. XIII. Molecular pathogenesis of transformed lymphomas.
- Author
-
Rossi, Davide
- Published
- 2015
- Full Text
- View/download PDF
30. NOTCH1, SF3B1, BIRC3 and TP53 mutations in patients with chronic lymphocytic leukemia undergoing first-line treatment: correlation with biological parameters and response to treatment.
- Author
-
Chiaretti, Sabina, Marinelli, Marilisa, Del Giudice, Ilaria, Bonina, Silvia, Piciocchi, Alfonso, Messina, Monica, Vignetti, Marco, Rossi, Davide, Di Maio, Valeria, Mauro, Francesca Romana, Guarini, Anna, Gaidano, Gianluca, and Foà, Robin
- Subjects
LYMPHOCYTIC leukemia ,RITUXIMAB ,IMMUNOGLOBULINS ,CYCLOPHOSPHAMIDE ,LEUKEMIA treatment - Abstract
In chronic lymphocytic leukemia, NOTCH1, SF3B1, BIRC3 and TP53 disruptions are recurrent and affect survival. To define their incidence and clinical impact in patients undergoing first-line treatment, we evaluated 163 cases enrolled in the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) LLC0405 protocol (fludarabine plus alemtuzumab or fludarabine plus cyclophosphamide), for young patients, or in the ML21445 protocol (chlorambucil plus rituximab), for elderly patients. NOTCH1, SF3B1, BIRC3 and TP53 disruptions were detected in 15.9%, 12.2%, 8.6% and 10.4% of cases. NOTCH1 mutations correlated with a shorter treatment-free interval ( p = 0.058), an unmutated immunoglobulin heavy variable gene ( IGHV) status ( p < 0.0001), CD38 and ZAP-70 expression ( p = 0.0025 and 0.026, respectively) and trisomy 12 ( p = 0.0028), SF3B1 mutations with an unmutated IGHV status ( p = 0.02), and BIRC3 disruptions with an unmutated IGHV configuration ( p = 0.01) and 11q deletion ( p < 0.0001). NOTCH1 and SF3B1 did not appear to impact on overall response, while an inferior response was observed for BIRC3- and TP53-disrupted cases in the LLC0405 and ML21445 protocols, respectively. Progression-free survival, evaluable in the LLC0405 protocol - not affected by NOTCH1, SF3B1 and TP53 - appeared inferior for BIRC3 disruption. NOTCH1 and SF3B1 mutations may be overcome by aggressive regimens, while BIRC3 might impact on outcome also in intensive regimens. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
31. Italian external and multicentric validation of the MD Anderson Cancer Center nomogram and prognostic index for chronic lymphocytic leukaemia patients: analysis of 1502 cases.
- Author
-
Gentile, Massimo, Mauro, Francesca R., Rossi, Davide, Vincelli, Iolanda, Tripepi, Giovanni, Recchia, Anna G., De Stefano, Laura, Campanelli, Melissa, Giannarelli, Diana, Bossio, Sabrina, Morabito, Lucio, Vigna, Ernesto, Gaidano, Gianluca, Foà, Robin, and Morabito, Fortunato
- Subjects
CHRONIC lymphocytic leukemia ,LYMPHOCYTE count ,NOMOGRAPHY (Mathematics) ,LYMPHOCYTOSIS ,LYMPH nodes ,PROGNOSIS - Abstract
We performed an external and multicentric validation of the nomogram and prognostic index ( PI) proposed by the MD Anderson Cancer Center to prognostically stratify chronic lymphocytic leukaemia ( CLL) patients in 1502 CLL cases. All six parameters involved in the nomogram and PI (age, sex, absolute lymphocyte count, number of lymph node groups, Rai stage and β2-microglobulin) were independently associated with survival. The nomogram was accurate in predicting survival (c-index = 0·82). According to the PI, 38·7% of patients were at low-risk, 58·3% at intermediate-risk and 3% at high-risk. The estimated median survival times were: not reached for low-risk, 13·4 years for intermediate-risk and 3·4 years for high-risk. The estimated median and 5-year survival by PI were similar to those originally reported. The PI remained a predictor of survival when analysis was limited to 847 Rai stage 0 ( P < 0·0001) and 151 clinical monoclonal B-cell lymphocytosis ( cMBL) cases ( P = 0·033). Finally, the PI allowed prediction of time to therapy in all patients ( P < 0·0001), in Rai 0 ( P < 0·0001) and in cMBL cases ( P = 0·044). Our results confirm the ability of the PI to predict prognosis, even in early stage disease cases. The study also extended the utility of the PI to cMBL cases. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
32. High-throughput sequencing for the identification of NOTCH1 mutations in early stage chronic lymphocytic leukaemia: biological and clinical implications.
- Author
-
Lionetti, Marta, Fabris, Sonia, Cutrona, Giovanna, Agnelli, Luca, Ciardullo, Carmela, Matis, Serena, Ciceri, Gabriella, Colombo, Monica, Maura, Francesco, Mosca, Laura, Gentile, Massimo, Recchia, Anna G., Ilariucci, Fiorella, Musolino, Caterina, Molica, Stefano, Di Raimondo, Francesco, Cortelezzi, Agostino, Rossi, Davide, Gaidano, Gianluca, and Morabito, Fortunato
- Subjects
CHRONIC lymphocytic leukemia ,GENETIC mutation ,B cells ,LYMPHOCYTOSIS ,NUCLEOTIDE sequence - Abstract
NOTCH1 mutations have recently emerged as new genetic lesions significantly correlated with survival in chronic lymphocytic leukaemia ( CLL). We performed deep next generation sequencing of the NOTCH1 mutation hotspot in 384 cases at diagnosis, including 100 monoclonal B cell lymphocytosis ( MBL) and 284 Binet stage A CLL cases, enrolled in the Gruppo Italiano Studio Linfomi O- CLL1 multicentre trial. The NOTCH1 c.7541_7542del CT dinucleotide deletion was detected and confirmed by an extremely sensitive polymerase chain reaction-based approach in 11% of MBL and 13·4% of CLL patients. Remarkably, the NOTCH1 mutation was often observed at low clonal level, mainly in MBL patients. Sequential analyses in a fraction of cases showed that the NOTCH1 mutation generally does not occur during the disease course and that the mutational load in positive cases tends to be stable over time. NOTCH1-mutated cases, even at low clonal level, displayed a significant reduction in median progression-free survival, although NOTCH1 mutation lost its prognostic impact in a multivariate analysis including 11q and/or 17p deletion, IGHV mutational status, and MBL or CLL status. Our data highlight the importance of using highly sensitive methods to measure NOTCH1 mutations, in order to improve prognostic stratification and obtain useful information for potential therapeutic approaches. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
33. Endothelin-1 Promotes Survival and Chemoresistance in Chronic Lymphocytic Leukemia B Cells through ETA Receptor.
- Author
-
Maffei, Rossana, Bulgarelli, Jenny, Fiorcari, Stefania, Martinelli, Silvia, Castelli, Ilaria, Valenti, Vanessa, Rossi, Davide, Bonacorsi, Goretta, Zucchini, Patrizia, Potenza, Leonardo, Vallisa, Daniele, Gattei, Valter, Poeta, Giovanni Del, Forconi, Francesco, Gaidano, Gianluca, Narni, Franco, Luppi, Mario, and Marasca, Roberto
- Subjects
ENDOTHELIN receptors ,PROMOTERS (Genetics) ,METASTASIS ,CHRONIC lymphocytic leukemia ,B cells ,CELLULAR signal transduction ,MITOGEN-activated protein kinases - Abstract
The endothelin axis, comprising endothelins (ET-1, ET-2 and ET-3) and their receptors (ET
A R and ETB R), has emerged as relevant player in tumor growth and metastasis. Here, we investigated the involvement of ET-1/ETA R axis in chronic lymphocytic leukemia (CLL). CLL cells expressed higher levels of ET-1 and ETA receptor as compared to normal B cells. ET-1 peptide stimulated phosphoinositide-3-kinase and mitogen-activated protein kinase signaling pathways, improved survival and promoted proliferation of leukemic cells throughout ETA R triggering. Moreover, the blockade of ETA R by the selective antagonist BQ-123 inhibited the survival advantage acquired by CLL cells in contact with endothelial layers. We also found that blocking ETA R via BQ-123 interferes with ERK phosphorylation and CLL pro-survival effect mediated by B-cell receptor (BCR) activation. The pro-apoptotic effect of phosphoinositide-3-kinase δ inhibitor idelalisib and mitogen-activated protein kinase inhibitor PD98059 was decreased by the addition of ET-1 peptide. Then, ET-1 also reduced the cytotoxic effect of fludarabine on CLL cells cultured alone or co-cultured on endothelial layers. ETA R blockade by BQ-123 inhibited the ET-1-mediated protection against drug-induced apoptosis. Lastly, higher plasma levels of big ET-1 were detected in patients (n = 151) with unfavourable prognostic factors and shorter time to first treatment. In conclusion, our data describe for the first time a role of ET-1/ETA R signaling in CLL pathobiology. ET-1 mediates survival, drug-resistance, and growth signals in CLL cells that can be blocked by ETA R inhibition. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
- View/download PDF
34. Clinical impact of small TP53 mutated subclones in chronic lymphocytic leukemia.
- Author
-
Rossi, Davide, Khiabanian, Hossein, Spina, Valeria, Ciardullo, Carmela, Bruscaggin, Alessio, Famà, Rosella, Rasi, Silvia, Monti, Sara, Deambrogi, Clara, De Paoli, Lorenzo, Jiguang Wang, Gattei, Valter, Guarini, Anna, Foà, Robin, Rabadan, Raul, and Gaidano, Gianluca
- Subjects
- *
CHRONIC lymphocytic leukemia , *LEUKEMIA , *LEUCOCYTOSIS , *CHRONIC leukemia , *HAIRY cell leukemia - Abstract
TP53 mutations are strong predictors of poor survival and refractoriness in chronic lymphocytic leukemia (CLL) and have direct implications for disease management. Clinical information on TP53 mutations is limited to lesions represented in >20% leukemic cells. Here, we tested the clinical impact and prediction of chemorefractoriness of very small TP53 mutated subclones. The TP53 gene underwent ultra-deep-next generation sequencing (NGS) in 309 newly diagnosed CLL. A robust bioinformatic algorithm was established for the highly sensitive detection of few TP53 mutated cells (down to 3 out of ∼1000 wild-type cells). Minor subclones were validated by independent approaches. Ultra-deep-NGS identified small TP53 mutated subclones in 28/309 (9%) untreated CLL that, due to their very low abundance (median allele frequency: 2.1%), were missed by Sanger sequencing. Patients harboring small TP53 mutated subclones showed the same clinical phenotype and poor survival (hazard ratio = 2.01; P = .0250) as those of patients carrying clonal TP53 lesions. By longitudinal analysis, small TP53 mutated subclones identified before treatment became the predominant population at the time of CLL relapse and anticipated the development of chemorefractoriness. This study provides a proof-of-principle that very minor leukemia subclones detected at diagnosis are an important driver of the subsequent disease course. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
35. Genetic aberrations of signaling pathways in lymphomagenesis: Revelations from next generation sequencing studies.
- Author
-
Rossi, Davide, Ciardullo, Carmela, and Gaidano, Gianluca
- Subjects
- *
GENETIC mutation , *CELLULAR signal transduction , *LYMPHOMAS , *TUMOR growth , *NUCLEOTIDE sequence , *CHRONIC lymphocytic leukemia - Abstract
Abstract: Next generation sequencing (NGS) technology has led to a burst of disease-relevant molecular information in a variety of lymphoid tumors, including chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, Burkitt lymphoma, Waldenström macroglobulinemia, hairy cell leukemia, and splenic marginal zone lymphoma. Beside disclosing comprehensive catalogs of somatic mutations and new insights into the genes that contribute to cellular transformation, NGS has also provided molecular clues useful for addressing a number of unmet clinical needs in the field of B-cell tumor management, including biomarkers for disease diagnosis and classification improvement (i.e. mutations of BRAF, MYD88 and NOTCH2), and new targets to be translated into therapeutic interventions (i.e. BCR, TLR, NOTCH, NF-κB and MAPK signaling pathways). This review summarizes the molecular lesions of signaling pathways that have been discovered in B-cell lymphoproliferative disorders by NGS studies. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
36. Molecular bases of chronic lymphocytic leukemia in light of new treatments.
- Author
-
Rossi, Davide, Ciardullo, Carmela, Spina, Valeria, and Gaidano, Gianluca
- Subjects
- *
CHRONIC lymphocytic leukemia treatment , *CANCER genetics , *NUCLEOTIDE sequence , *CELL transformation , *B cell lymphoma , *PROTEIN-tyrosine kinases - Abstract
Abstract: The human genome era heralded a fundamental progress in the field of cancer genetics that shifted from a candidate gene approach toward global views of genomes and transcriptomes. Whole genome/exome sequencing has disclosed the genetic landscape of several hematologic tumors, providing comprehensive catalogs of somatic mutations and new insights into the genes that contribute to cellular transformation. Thanks to these technical progresses, research on the molecular pathogenesis of chronic lymphocytic leukemia (CLL) has also advanced at a sustained pace in recent times revealing NOTCH1, SF3B1, BIRC3, and MYD88 as the most recurrently (>5%) mutated genes that have been identified in CLL. Beside mutations of cancer related genes, another mechanism involved in disease initiation and progression of mature B-cell tumors, including CLL, is represented by B cell receptor (BCR) signaling. The BCR plays a central role in disease pathogenesis and, consequently, BCR signaling might represent a suitable target for therapy in many patients. Currently, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, which acts downstream the BCR signaling pathway, appears to be particularly promising and shows important clinical activity in CLL. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
37. rs2072135, a low-penetrance variant for chronic lymphocytic leukaemia?
- Author
-
Sava, Georgina P., Speedy, Helen E., Bernardo, Maria Chiara, Deaglio, Silvia, Karabon, Lidia, Frydecka, Irena, Woszczyk, Dariusz, Rossi, Davide, Gaidano, Gianluca, Mansouri, Larry, Smedby, Karin E., Juliusson, Gunnar, Rosenquist, Richard, Catovsky, Daniel, and Houlston, Richard S.
- Subjects
CHRONIC lymphocytic leukemia ,SINGLE nucleotide polymorphisms ,GENETIC code ,GENE expression ,CANCER cells ,LOCUS (Genetics) - Abstract
Recent multi-stage genome-wide association studies ( GWAS) have identified single nucleotide polymorphisms ( SNPs) that are robustly associated with chronic lymphocytic leukaemia ( CLL) risk. Given that most of these SNPs map to non-coding regions of the genome, it suggests that the functional basis of many GWAS signals will be through differential gene expression. By referencing publically accessible expression quantitative trait loci ( eQTL) data on lymphoblastoid cells lines ( LCLs) we have globally demonstrated an association between GWAS P-values and eQTLs, consistent with much of the variation in CLL risk being defined by variants impacting on gene expression. To explore using eQTL data to select GWAS SNPs for replication, we genotyped rs2072135 ( GWAS P-value = 0·0024, eQTL P-value = 1·510
−19 ) in five independent case-control series totalling 1968 cases and 3538 controls. While not attaining statistical significance (combined P-value = 1 × 10−4 ), rs2072135 defines a promising risk locus for CLL. Incorporating eQTL information offers an attractive strategy for selecting SNPs from GWAS for validation. [ABSTRACT FROM AUTHOR]- Published
- 2013
- Full Text
- View/download PDF
38. Association between molecular lesions and specific B-cell receptor subsets in chronic lymphocytic leukemia.
- Author
-
Rossi, Davide, Spina, Valeria, Bomben, Riccardo, Rasi, Silvia, Dal-Bo, Michele, Bruscaggin, Alessio, Rossi, Francesca Maria, Monti, Sara, Degan, Massimo, Ciardullo, Carmela, Serra, Roberto, Zucchetto, Antonella, Nomdedeu, Josep, Bulian, Pietro, Grossi, Alberto, Zaja, Francesco, Pozzato, Gabriele, Laurenti, Luca, Efremov, Dimitar G., and Di-Raimondo, Francesco
- Subjects
- *
CHRONIC lymphocytic leukemia , *B cell receptors , *ONCOGENES , *MEDICAL genetics , *RICHTER syndrome - Abstract
Genetic lesions and B-cell receptor (BCR) signaling are both oncogenic drivers in chronic lymphocytic leukemia (CLL). However, scant data are available on preferential associations between specific genetic alterations and stereotyped BCR subsets. By analyzing 1419 cases, 2 CLL subsets (2 and 8) harboring stereotyped BCR are enriched in specific molecular alterations influencing disease course. SF3B1 mutations are the genetic hallmark of IGHV3-21-CLL belonging to subset 2 (52%) but are evenly represented in nonstereotyped IGHV3-21-CLL. Trisomy 12 (87%) and NOTCH1 mutations (62%) characterize IGHV4-39-CLL belonging to subset 8 but occur with the expected frequency in IGHV4-39-CLL with heterogeneous BCR. Clinically, co-occurrence of SF3B1 mutations and subset 2 BCR configuration prompts disease progression in IGHV3-21-CLL, whereas cooperation between NOTCH1 mutations, + 12, and subset 8 BCR configuration invariably primes CLL transformation into Richter syndrome. These findings provide a proof of concept that specific stereotyped BCR may promote or select molecular lesions influencing outcome. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
39. MGA, a suppressor of MYC, is recurrently inactivated in high risk chronic lymphocytic leukemia.
- Author
-
De Paoli, Lorenzo, Cerri, Michaela, Monti, Sara, Rasi, Silvia, Spina, Valeria, Bruscaggin, Alessio, Greco, Mariangela, Ciardullo, Carmela, Famà, Rosella, Cresta, Stefania, Maffei, Rossana, Ladetto, Marco, Martini, Maurizio, Laurenti, Luca, Forconi, Francesco, Marasca, Roberto, Larocca, Luigi M., Bertoni, Francesco, Gaidano, Gianluca, and Rossi, Davide
- Subjects
CHRONIC lymphocytic leukemia ,LEUKEMIA - Abstract
A letter to the editor is presented in response to the research study "MGA, a suppressor of MYC, Is Recurrently Inactivated in High Risk Chronic Lymphocytic Leukemia," which appeared in the previous issue.
- Published
- 2013
- Full Text
- View/download PDF
40. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia.
- Author
-
Rossi, Davide, Rasi, Silvia, Spina, Valeria, Bruscaggin, Alessio, Monti, Sara, Ciardullo, Carmela, Deambrogi, Clara, Khiabanian, Hossein, Serra, Roberto, Bertoni, Francesco, Forconi, Francesco, Laurenti, Luca, Marasca, Roberto, Dal-Bo, Michele, Rossi, Francesca Maria, Bulian, Pietro, Nomdedeu, Josep, Del-Poeta, Giovanni, Gattei, Valter, and Pasqualucci, Laura
- Subjects
- *
CHRONIC lymphocytic leukemia , *GENETIC mutation , *KARYOTYPES , *CHROMOSOME abnormalities , *HUMAN cytogenetics , *GENETIC models - Abstract
The identification of new genetic lesions in chronic lymphocytic leukemia (CLL) prompts a comprehensive and dynamic prognostic algorithm including gene mutations, chromosomal abnormalities, and their changes during clonal evolution. By integrating mutational and cytogenetic analysis in 1274 CLL samples, and by using both a training-validation and a time-dependent design, four CLL subgroups were hierarchically classified: i) high-risk, harboring TP53 and/or BIRC3 abnormalities (10-year survival:29%); ii) intermediate-risk, harboring NOTCH1 and/or SF3B1 mutations and/or del11q22-q23 (10-year survival:37%); iii) low-risk, harboring +12 or a normal genetics (10-year survival:57%); iv) very low-risk, harboring del13q14 only, whose 10-year survival (69.3%) did not significantly differ from a matched general population. This integrated mutational and cytogenetic model independently predicted survival, improved CLL prognostication accuracy compared to FISH karyotype (p<0.0001), and was externally validated in an independent CLL cohort. Clonal evolution from lower to higher risk implicated the emergence of NOTCH1, SF3B1 and BIRC3 abnormalities in addition to TP53 and 11q22-q23 lesions. By taking into account clonal evolution through time-dependent analysis, the genetic model maintained its prognostic relevance at any time from diagnosis. These findings may have relevant implications for the design of clinical trials aimed at assessing the use of mutational profiling to inform therapeutic decisions. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
41. Different impact of NOTCH1 and SF3B1 mutations on the risk of chronic lymphocytic leukemia transformation to Richter syndrome.
- Author
-
Rossi, Davide, Rasi, Silvia, Spina, Valeria, Fangazio, Marco, Monti, Sara, Greco, Mariangela, Ciardullo, Carmela, Famà, Rosella, Cresta, Stefania, Bruscaggin, Alessio, Laurenti, Luca, Martini, Maurizio, Musto, Pellegrino, Forconi, Francesco, Marasca, Roberto, Larocca, Luigi M., Foà, Robin, and Gaidano, Gianluca
- Subjects
- *
CHRONIC lymphocytic leukemia , *NOTCH genes , *LYMPHOMAS , *MULTIVARIATE analysis , *GENETIC mutation - Abstract
The article presents a study on 605 patients with chronic lymphocytic leukemia (CLL) focusing on the impact of NOTCH1 and SFB3 mutations on the risk of transformation of CLL to Richter syndrome (RS). Techniques like Sanger sequencing, flow cytometry and multivariate analysis were used during the study. The SFB3 mutations showed no impact on RS development and were absent in all the CLL patients. 40 to 50 percent of NOTCH1 mutated patients developed RS.
- Published
- 2012
- Full Text
- View/download PDF
42. Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis.
- Author
-
Rossi, Davide, Spina, Valeria, Forconi, Francesco, Capello, Daniela, Fangazio, Marco, Rasi, Silvia, Martini, Maurizio, Gattei, Valter, Ramponi, Antonio, Larocca, Luigi M., Bertoni, Francesco, and Gaidano, Gianluca
- Abstract
Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia to aggressive lymphoma. We explored intraclonal diversification (ID) of immunoglobulin genes in order to ( i) follow the evolutionary history of the RS clone ( ii) compare the role of ID in clonally related RS vs. clonally unrelated cases. Most (10/11, 90.9%) clonally related RS stem from the predominant clone observed at CLL diagnosis. One single RS had a transformation pattern compatible with sequential evolution from a secondary CLL subclone. Once RS transformation had occurred, all secondary CLL subclones disappeared and were substituted by the dominant RS clone with its own descendants. These observations suggest that genetic lesions associated with RS transformation are acquired by a cell belonging to the original CLL clone, rather than being progressively accumulated by later CLL subclones. Accordingly, most (9/11, 81.1%) clonally related RS harbored a genetic lesion disrupting TP53 that was already present, though at subclonal levels, in 5/11 (45.5%) samples of the paired CLL phase. A fraction of clonally related RS switched off ID (4/11, 36.4%) or reduced the levels of ID (5/11, 45.4%) at transformation. Conversely, all clonally unrelated RS harbored ID and were characterized by a significantly higher mutation frequency compared to clonally related RS (median: 1.18 × 10
−3 vs. 0.13 × 10-3 ; p =0.002). These data indicate that ( i) clonally related RS stems from a cell that is already present within the initial CLL clone and ( ii) clonally unrelated and clonally related RS are biologically distinct disorders also in terms of antigen affinity maturation. [ABSTRACT FROM AUTHOR]- Published
- 2012
- Full Text
- View/download PDF
43. The Spectrum of Genetic Defects in Chronic Lymphocytic Leukemia.
- Author
-
Rossi, Davide, Fangazio, Marco, and Gaidano, Gianluca
- Subjects
- *
CHRONIC lymphocytic leukemia , *HETEROGENEITY , *LEUKEMIA etiology , *BIOMARKERS , *CANCER invasiveness , *DISEASE risk factors - Abstract
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and shows a remarkable heterogeneity in the clinical course. Understand the genetic basis of CLL may help in clarifying the molecular bases of this clinical heterogeneity. Recurrent chromosomal aberrations at 13q14, 12q, 11q22-q23 and 17p13, and TP53 mutations are the first genetic lesions identified as drivers of the disease. While some of these lesions are associated with poor outcome (17p13 deletion, TP53 mutations and, to a lesser extent, 11q22-q23 deletion) others are linked to a favorable course (13q14 deletion as sole aberration). Recently, next generation sequencing has revealed additional recurrent alterations in CLL targeting the NOTCH1, SF3B1, and BIRC3 genes. NOTCH1, SF3B1, and BIRC3 lesions provide: i) new insights on the mechanisms of leukemogenesis, tumor progression and chemoresistance in this leukemia; ii) new biomarkers for the identification of poor risk patients, having individually shown correlations with survival in CLL; and iii) new therapeutic targets, especially in the setting of high risk disease. This review will summarize the most important genetic aberrations in CLL and how our improved knowledge of the genome of leukemic cells may translate into improved patients' management. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
44. Hepatitis B virus and lymphomagenesis: Novel insights into an occult relationship.
- Author
-
Pinato, David J., Rossi, Davide, Minh, Margherita Tran, Toniutto, Pierluigi, Boccato, Elisa, Minisini, Rosalba, Gaidano, Gianluca, and Pirisi, Mario
- Subjects
HEPATITIS B virus ,LYMPHOMAS ,MULTIPLE myeloma ,B cell lymphoma ,CHRONIC lymphocytic leukemia ,BLOOD cells - Abstract
Abstract: Background: Increasing evidence shows that Hepatitis B virus infection associates with B-cell but not T-cell malignancies. It remains unclear (a) whether this association is restricted to discrete subtypes of B-cell neoplasms and (b) if occult hepatitis B virus infection can impact on the risk of B-cell malignancy. Methods: We analysed the prevalence of occult hepatitis B virus infection in three age and sex matched groups: patients with multiple myeloma, chronic lymphocytic leukaemia and healthy volunteers (N =80 each group). Hepatitis B virus sequences were detected by PCR in blood mononuclear cells isolated prior to treatment. Results: Fifteen subjects tested positive for occult hepatitis B virus infection and its distribution significantly favoured chronic lymphocytic leukaemia (p <0.02) over the other groups. No difference in age, gender and proportion of anti-HBc seropositivity was noted according to occult hepatitis B virus infection status. Chronic lymphocytic leukaemia had an odds ratio of 4.6 (95% CI 1.5–13.9) for the presence of occult hepatitis B virus infection in comparison to multiple myeloma and controls. Most occult hepatitis B virus infection cases (10/15, 67%) were detected in completely hepatitis B virus seronegative subjects. Conclusions: Our data support a potentially causal relationship for hepatitis B virus in chronic lymphocytic leukaemia but not in multiple myeloma. HBsAg seropositivity alone may bias the study of this association, potentially leading to underestimation. Primary occult hepatitis B virus infection appears the most frequent setting in our patients, extending the clinical relevance of hepatitis B virus vaccination to a preventative measure for B-cell neoplasms. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
- View/download PDF
45. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia.
- Author
-
Rossi, Davide, Rasi, Silvia, Fabbri, Giulia, Spina, Valeria, Fangazio, Marco, Forconi, Francesco, Marasca, Roberto, Laurenti, Luca, Bruscaggin, Alessio, Cern, Michaela, Monti, Sara, Cresta, Stefania, Famà, Rosella, De Paoli, Lorenzo, Bulian, Pietro, Gattei, Valter, Guarini, Anna, Deaglio, Silvia, Capello, Daniela, and Rabadan, Raul
- Subjects
- *
CHRONIC lymphocytic leukemia , *GENETIC mutation , *MULTIVARIATE analysis , *PROGNOSIS , *GENOMES , *FLOW cytometry - Abstract
Analysis of the chronic lymphocytic leukemia (CLL) coding genome has recently disclosed that the NOTCH1 proto-oncogene is recurrently mutated at CLL presentation. Here we assessed the prognostic role of NOTCH1 mutations in CLL. Two series of newly diagnosed CLL were utilized as training (n=309) and validation (n=230) cohorts. NOTCH1 mutations occurred in 11.0% and 11.3% CLL of the training and validation series, respectively. In the training series, NOTCH1 mutations led to a 3.77 fold increase in the hazard of death and to shorter overall survival (OS) (p<.001). Multivariate analysis selected NOTCH1 mutations as an independent predictor of OS after controlling for confounding clinical and biological variables. The independent prognostic value of NOTCH1 mutations was externally confirmed in the validation series. The poor prognosis conferred by NOTCH1 mutations was attributable, at least in part, to shorter treatment-free survival and higher risk of Richter transformation. Although NOTCH1 mutated patients were devoid of TP53 disruption in >90% cases in both training and validation series, the OS predicted by NOTCH1 mutations was similar to that of TP53 mutated/deleted CLL. NOTCH1 mutations are an independent predictor of CLL OS, tend to be mutually exclusive with TP53 abnormalities and identify cases with a dismal prognosis. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
46. Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness.
- Author
-
Rossi, Davide, Bruscaggin, Alessio, Spina, Valeria, Rasi, Silvia, Khiabanian, Hossein, Messina, Monica, Fangazio, Marco, Vaisitti, Tiziana, Monti, Sara, Chiaretti, Sabina, Guarini, Anna, Del Giudice, Ilaria, Cerri, Michaela, Cresta, Stefania, Deambrogi, Clara, Gargiulo, Ernesto, Gattei, Valter, Forconi, Francesco, Bertoni, Francesco, and Deaglio, Silvia
- Subjects
- *
CHRONIC lymphocytic leukemia , *GENETIC engineering , *GENETIC regulation , *GENE expression , *FLUDARABINE , *GENETIC code - Abstract
The genetic lesions identified in chronic lymphocytic leukemia (CLL) do not entirely recapitulate the disease pathogenesis and the development of serious complications, such as chemorefractoriness. While investigating the coding genome of fludarabine-refractory CLL, we observed that mutations of SF3B1, encoding a splicing factor and representing a critical component of the cell spliceosome, were recurrent in 10 of 59 (17%) fludarabine-refractory cases, with a frequency significantly greater than that observed in a consecutive CLL cohort sampled at diagnosis (17/301, 5%; P = .002). Mutations were somatically acquired, were generally represented by missense nucleotide changes, clustered in selected HEAT repeats of the SF3B1 protein, recurrently targeted 3 hotspots (codons 662, 666, and 700), and were predictive of a poor prognosis. In fludarabine-refractory CLL, SF3B1 mutations and TP53 disruption distributed in a mutually exclusive fashion (P = .046). The identification of SF3B1 mutations points to splicing regulation as a novel pathogenetic mechanism of potential clinical relevance in CLL. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
47. Genome-wide DNA profiling better defines the prognosis of chronic lymphocytic leukaemia.
- Author
-
Rinaldi, Andrea, Mian, Michael, Kwee, Ivo, Rossi, Davide, Deambrogi, Clara, Mensah, Afua A., Forconi, Francesco, Spina, Valeria, Cencini, Emanuele, Drandi, Daniela, Ladetto, Marco, Santachiara, Rita, Marasca, Roberto, Gattei, Valter, Cavalli, Franco, Zucca, Emanuele, Gaidano, Gianluca, and Bertoni, Francesco
- Subjects
CHRONIC lymphocytic leukemia ,LYMPHOPROLIFERATIVE disorders ,MULTIVARIATE analysis ,DNA fingerprinting ,FLUORESCENCE in situ hybridization ,CHRONIC diseases ,LYMPHOCYTIC leukemia - Abstract
Summary The integration of molecular and clinical information to tailor treatments remains an important research challenge in chronic lymphocytic leukaemia (CLL). This study aimed to identify genomic lesions associated with a poor outcome and a higher risk of histological transformation. A mono-institutional cohort of 147 cases was used as the test series, and a multi-institutional cohort of 176 cases as a validation series. Genomic profiles were obtained using Affymetrix SNP 6.0. The impact of the recurrent minimal common regions (MCRs) on overall survival was evaluated by univariate analysis followed by multiple-test correction. The independent prognostic significance was assessed by multivariate analysis. Eight MCRs showed a prognostic impact: gains at 2p25.3-p22.3 ( MYCN), 2p22.3, 2p16.2-p14 ( REL), 8q23.3-q24.3 ( MYC), losses at 8p23.1-p21.2, 8p21.2, and of the TP53 locus. Gains at 2p and 8q and TP53 inactivation maintained prognostic significance in multivariate analysis and a hierarchical model confirmed their relevance. Gains at 2p also determined a higher risk of Richter syndrome transformation. The prediction of outcome for CLL patients might be improved by evaluating the presence of gains at 2p and 8q as novel genomic regions besides those included in the 'standard' fluorescence in situ hybridization panel. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
48. Common genetic variation at 15q25.2 impacts on chronic lymphocytic leukaemia risk.
- Author
-
Crowther-Swanepoel, Dalemari, Di Bernardo, Maria Chiara, Jamroziak, Krzysztof, Karabon, Lidia, Frydecka, Irena, Deaglio, Silvia, D'Arena, Giovanni, Rossi, Davide, Gaidano, Gianluca, Olver, Bianca, Lloyd, Amy, Broderick, Peter, Laurenti, Luca, Szemraj-Rogucka, Zofia, Robak, Tadeusz, Catovsky, Daniel, and Houlston, Richard S.
- Subjects
CHRONIC lymphocytic leukemia ,LYMPHOCYTIC leukemia ,LEUKEMIA ,LYMPHOPROLIFERATIVE disorders ,CHRONIC diseases - Abstract
A genome-wide association study of chronic lymphocytic leukaemia (CLL) suggested that common variants at 15q25.2 (rs783540) and 18q21.1 (rs1036935) influence CLL. To validate these associations and explore their relationship with CLL risk we genotyped case-control datasets from Poland, UK and Italy totalling 1428 cases and 1920 controls. Combined data from these and previously genotyped series (2503 cases and 5789 controls) provided evidence for an association between 15q25.2 and 18q21.1 loci and CLL risk ( P = 1·10 × 10 and 1·30 × 10 respectively). These data provide further evidence for the involvement of common genetic variants in CLL risk and insight into the biological basis of disease development. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
49. B-cell receptor, clinical course and prognosis in chronic lymphocytic leukaemia: the growing saga of the IGHV3 subgroup gene usage.
- Author
-
Dal-Bo, Michele, Del Giudice, Ilaria, Bomben, Riccardo, Capello, Daniela, Bertoni, Francesco, Forconi, Francesco, Laurenti, Luca, Rossi, Davide, Zucchetto, Antonella, Pozzato, Gabriele, Marasca, Roberto, Efremov, Dimitar G., Guarini, Anna, Del Poeta, Giovanni, Foà, Robin, Gaidano, Gianluca, and Gattei, Valter
- Subjects
B cells ,CELL receptors ,IMMUNOGLOBULINS ,GENES ,CHRONIC lymphocytic leukemia ,PROGNOSIS - Abstract
The immunoglobulin heavy chain variable gene ( IGHV) mutational status has been recognized as an important predictor of prognosis in chronic lymphocytic leukaemia (CLL) since 1999. More recently, other features of the B-cell receptor, such as stereotypy, have been identified as capable of refining the prognostic potential of IGHV status in the clinical assessment of CLL patients. In this context, different genes belonging to the IGHV3 subgroup, the most frequently used subgroup in CLL, have been shown to denote disease subsets that either display a bad prognosis (i.e. IGHV3-21, IGHV3-23) or are associated with particularly good clinical outcomes, including a highly stable/indolent clinical course, even prone to spontaneous regression (i.e. IGHV3-72, IGHV3-30). The present review focuses on the molecular and biological features of CLL-expressing specific genes belonging to the IGHV3 subgroup that are known to mark disease subsets with completely different clinical courses, and may be possibly related to CLL pathogenesis via antigen and/or superantigen involvement. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
50. IGHD3-3 fails to behave as unfavourable prognostic marker in chronic lymphocytic leukaemia.
- Author
-
Bomben, Riccardo, Dal Bo, Michele, Capello, Daniela, Forconi, Francesco, Bertoni, Francesco, Maffei, Rossana, Laurenti, Luca, Rossi, Davide, Zucca, Emanuele, Degan, Massimo, Marasca, Roberto, Efremov, Dimitar G., Del Poeta, Giovanni, Gaidano, Gianluca, and Gattei, Valter
- Subjects
LETTERS to the editor ,CHRONIC lymphocytic leukemia - Abstract
A letter to the editor discussing prognostic marker in chronic lymphocytic leukaemia is presented.
- Published
- 2010
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.