39 results on '"University of Eastern Piedmont"'
Search Results
2. Tafasitamab for patients with relapsed or refractory diffuse large B-cell lymphoma: final 5-year efficacy and safety findings in the phase II L-MIND study.
- Author
-
Duell J, Abrisqueta P, Andre M, Gaidano G, Gonzales-Barca E, Jurczak W, Kalakonda N, Liberati AM, Maddocks KJ, Menne T, Nagy Z, Tournilhac O, Kuffer C, Bakuli A, Amin A, Gurbanov K, and Salles G
- Subjects
- Humans, Lenalidomide therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Lymphoma, Non-Hodgkin drug therapy, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse pathology
- Abstract
Tafasitamab, an anti-CD19 immunotherapy, is used with lenalidomide for patients with autologous stem cell transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma based on the results of the phase II L-MIND study (NCT02399085). We report the final 5-year analysis of this study. Eighty patients ≥18 years who had received one to three prior systemic therapies, and had Eastern Cooperative Oncology Group performance status 0-2 received up to 12 cycles of co-administered tafasitamab and lenalidomide, followed by tafasitamab monotherapy until disease progression or unacceptable toxicity. The primary endpoint was the best objective response rate. Secondary endpoints included duration of response, progression-free survival, overall survival, and safety. Exploratory analyses evaluated efficacy endpoints by prior lines of therapy. At data cutoff on November 14, 2022, the objective response rate was 57.5%, with a complete response rate of 41.3% (n=33), which was consistent with prior analyses. With a median follow-up of 44.0 months, the median duration of response was not reached. The median progression-free survival was 11.6 months (95% confidence interval [95% CI]: 5.7-45.7) with a median follow-up of 45.6 months. The median overall survival was 33.5 months (95% CI: 18.3-not reached) with a median follow-up of 65.6 months. Patients who had received one prior line of therapy (n=40) showed a higher objective response rate (67.5%; 52.5% complete responses) compared to patients who had received two or more prior lines of therapy (n=40; 47.5%; 30% complete responses), but the median duration of response was not reached in either subgroup. Other exploratory analyses revealed consistent long-term efficacy results across subgroups. Adverse events were consistent with those described in previous reports, were manageable, and their frequency decreased during tafasitamab monotherapy, with no new safety concerns. This final 5-year analysis of L-MIND demonstrates that the immunotherapy combination of tafasitamab and lenalidomide is well tolerated and has long-term clinical benefit with durable responses.
- Published
- 2024
- Full Text
- View/download PDF
3. SARS-CoV-2 vaccination in 361 non-transplanted patients with aplastic anemia and/or paroxysmal nocturnal hemoglobinuria.
- Author
-
Griffin M, Eikema DJ, Verheggen I, Kulagin A, Tjon JM, Fattizzo B, Ingram W, Zaidi U, Desnica L, Giammarco S, Drozd-Sokolowska J, Xicoy B, Patriarca A, Loschi M, Szmigielska-Kaplon A, Beier F, Cignetti A, Drexler B, Gavriilaki E, Lanza F, Orvain C, Risitano AM, De la Camara R, and De Latour RP
- Subjects
- Humans, Vaccination, Anemia, Aplastic complications, Anemia, Aplastic therapy, COVID-19 prevention & control, COVID-19 Vaccines administration & dosage, Hemoglobinuria, Paroxysmal complications, Hemoglobinuria, Paroxysmal therapy
- Published
- 2024
- Full Text
- View/download PDF
4. Elotuzumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: a multicenter, retrospective, real-world experience with 200 cases outside of controlled clinical trials.
- Author
-
Gentile M, Vigna E, Palmieri S, Galli M, Derudas D, Mina R, Della Pepa R, Zambello R, Martino EA, Bruzzese A, Mangiacavalli S, Zamagni E, Califano C, Musso M, Conticello C, Cerchione C, Mele G, Di Renzo N, Offidani M, Tarantini G, Casaluci GM, Rago A, Ria R, Uccello G, Barilà G, Palumbo G, Pompa A, Vincelli D, Brunori M, Accardi F, Amico V, Amendola A, Fontana R, Bongarzoni V, Rossini B, Cotzia E, Gozzetti A, Rizzi R, Sgherza N, Ferretti E, Bertuglia G, Nappi D, Petrucci MT, Di Raimondo F, Neri A, Morabito F, and Musto P
- Subjects
- Humans, Antineoplastic Combined Chemotherapy Protocols adverse effects, Dexamethasone therapeutic use, Lenalidomide therapeutic use, Proteasome Inhibitors therapeutic use, Retrospective Studies, Controlled Clinical Trials as Topic, Multiple Myeloma diagnosis, Multiple Myeloma drug therapy, Multiple Myeloma etiology
- Abstract
In the ELOQUENT-3 trial, the combination of elotuzumab, pomalidomide and dexamethasone (EloPd) proved to have a superior clinical benefit over pomalidomide and dexamethasone with a manageable toxicity profile, leading to its approval for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. We report here a real-world experience of 200 cases of RRMM treated with EloPd in 35 Italian centers outside of clinical trials. In our dataset, the median number of prior lines of therapy was two, with 51% of cases undergoing autologous stem cell transplant and 73% having been exposed to daratumumab. After a median follow-up of 9 months, 126 patients had stopped EloPd, most of them (88.9%) because of disease progression. The overall response rate was 55.4%, a finding in line with the pivotal trial results. Regarding adverse events, the toxicity profile in our cohort was similar to that in the ELOQUENT-3 trial, with no significant differences between younger (<70 years) and older patients. The median progression-free survival was 7 months, which was shorter than that observed in ELOQUENT-3, probably because of the different clinical characteristics of the two cohorts. Interestingly, International Staging System stage III disease was associated with worse progression-free survival (hazard ratio=2.55). Finally, the median overall survival of our series was shorter than that observed in the ELOQUENT-3 trial (17.5 vs. 29.8 months). In conclusion, our real-world study confirms that EloPd is a safe and possible therapeutic choice for patients with RRMM who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.
- Published
- 2024
- Full Text
- View/download PDF
5. The immunomodulatory molecule TIGIT is expressed by chronic lymphocytic leukemia cells and contributes to anergy.
- Author
-
Arruga F, Rubin M, Papazoglou D, Iannello A, Ioannou N, Moia R, Rossi D, Gaidano G, Coscia M, Laurenti L, D'Arena G, Allan JN, Furman RR, Vaisitti T, Ramsay AG, and Deaglio S
- Subjects
- Humans, Antigens, Differentiation, T-Lymphocyte metabolism, Cytokines metabolism, CD8-Positive T-Lymphocytes metabolism, Receptors, Immunologic genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell metabolism
- Abstract
T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory checkpoint receptor that negatively regulates Tcell responses. CD226 competes with TIGIT for binding to the CD155 ligand, delivering a positive signal to the T cell. Here we studied the expression of TIGIT and CD226 in a cohort of 115 patients with chronic lymphocytic leukemia (CLL) and report expression of TIGIT and CD226 by leukemic cells. By devising a TIGIT/CD226 ratio, we showed that CLL cells favoring TIGIT over CD226 are typical of a more indolent disease, while those favoring CD226 are characterized by a shorter time to first treatment and shorter progression-free survival after first treatment. TIGIT expression was inversely correlated to the B-cell receptor (BCR) signaling capacity, as determined by studying BTK phosphorylation, cell proliferation and interleukin- 10 production. In CLL cells treated with ibrutinib, in which surface IgM and BCR signaling capacity are temporarily increased, TIGIT expression was downmodulated, in line with data indicating transient recovery from anergy. Lastly, cells from patients with Richter syndrome were characterized by high levels of CD226, with low to undetectable TIGIT, in keeping with their high proliferative drive. Together, these data suggest that TIGIT contributes to CLL anergy by downregulating BCR signaling, identifying novel and actionable molecular circuits regulating anergy and modulating CLL cell functions.
- Published
- 2023
- Full Text
- View/download PDF
6. Results from a phase I/II trial of cusatuzumab combined with azacitidine in patients with newly diagnosed acute myeloid leukemia who are ineligible for intensive chemotherapy.
- Author
-
Pabst T, Vey N, Adès L, Bacher U, Bargetzi M, Fung S, Gaidano G, Gandini D, Hultberg A, Johnson A, Ma X, Müller R, Nottage K, Papayannidis C, Recher C, Riether C, Shah P, Tryon J, Xiu L, and Ochsenbein AF
- Subjects
- Humans, Azacitidine adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents therapeutic use, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy
- Abstract
Cusatuzumab is a high-affinity, anti-CD70 monoclonal antibody under investigation in acute myeloid leukemia (AML). This two-part, open-label, multicenter, phase I/II trial evaluated cusatuzumab plus azacitidine in patients with newly diagnosed AML ineligible for intensive chemotherapy. Patients received a single dose of cusatuzumab at one of four dose levels (1, 3, 10, or 20 mg/kg) 14 days before starting combination therapy. In phase I dose escalation, cusatuzumab was then administered on days 3 and 17, in combination with azacitidine (75 mg/m2) on days 1-7, every 28 days. The primary objective in phase I was to determine the recommended phase II dose (RP2D) of cusatuzumab plus azacitidine. The primary objective in phase II was efficacy at the RP2D (selected as 10 mg/kg). Thirty-eight patients were enrolled: 12 in phase I (three per dose level; four with European LeukemiaNet 2017 adverse risk) and 26 in phase II (21 with adverse risk). An objective response (≥partial remission) was achieved by 19/38 patients (including 8/26 in phase II); 14/38 achieved complete remission. Eleven patients (37.9%) achieved an objective response among the 29 patients in phase I and phase II treated at the RP2D. At a median follow-up of 10.9 months, median duration of first response was 4.5 months and median overall survival was 11.5 months. The most common treatment-emergent adverse events were infections (84.2%) and hematologic toxicities (78.9%). Seven patients (18.4%) reported infusion-related reactions, including two with grade 3 events. Thus, cusatuzumab/azacitidine appears generally well tolerated and shows preliminary efficacy in this setting. Investigation of cusatuzumab combined with current standard-of-care therapy, comprising venetoclax and azacitidine, is ongoing.
- Published
- 2023
- Full Text
- View/download PDF
7. Risk of hepatitis B virus reactivation in chronic lymphocytic leukemia patients receiving ibrutinib with or without antiviral prophylaxis. A retrospective multicentric GIMEMA study.
- Author
-
Innocenti I, Reda G, Visentin A, Coscia M, Motta M, Murru R, Moia R, Gentile M, Pennese E, Quaglia FM, Albano F, Cassin R, Deodato M, Ielo C, Frustaci AM, Piciocchi A, Rughini A, Arena V, Di Sevo D, Tomasso A, Autore F, Del Poeta G, Scarfò L, Mauro FR, Tedeschi A, Trentin L, Pompili M, Foà R, Ghia P, Cuneo A, and Laurenti L
- Subjects
- Adenine analogs & derivatives, Antiviral Agents adverse effects, Hepatitis B virus physiology, Humans, Piperidines, Retrospective Studies, Virus Activation, Hepatitis B, Chronic drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell complications, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Published
- 2022
- Full Text
- View/download PDF
8. Long-term outcomes from the Phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma.
- Author
-
Duell J, Maddocks KJ, González-Barca E, Jurczak W, Liberati AM, De Vos S, Nagy Z, Obr A, Gaidano G, Abrisqueta P, Kalakonda N, André M, Dreyling M, Menne T, Tournilhac O, Augustin M, Rosenwald A, Dirnberger-Hertweck M, Weirather J, Ambarkhane S, and Salles G
- Subjects
- Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols adverse effects, Humans, Lenalidomide therapeutic use, Transplantation, Autologous, Treatment Outcome, Hematopoietic Stem Cell Transplantation, Lymphoma, Large B-Cell, Diffuse diagnosis, Lymphoma, Large B-Cell, Diffuse drug therapy
- Abstract
Tafasitamab (MOR208), an Fc-modified, humanized, anti-CD19 monoclonal antibody, combined with the immunomodulatory drug lenalidomide was clinically active with a good tolerability profile in the open-label, single-arm, phase II L-MIND study of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem-cell transplantation. To assess long-term outcomes, we report an updated analysis with ≥35 months' follow-up. Patients were aged >18 years, had received one to three prior systemic therapies (including ≥1 CD20-targeting regimen) and Eastern Cooperative Oncology Group performance status 0-2. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during cycles 1-3, then every 2 weeks during cycles 4-12. Lenalidomide (25 mg orally) was administered on days 1-21 of cycles 1-12. After cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. The primary endpoint was best objective response rate. After ≥35 months' follow-up (data cut-off: October 30, 2020), the objective response rate was 57.5% (n=46/80), including a complete response in 40.0% of patients (n=32/80) and a partial response in 17.5% of patients (n=14/80). The median duration of response was 43.9 months (95% confidence interval [95% CI]: 26.1-not reached), the median overall survival was 33.5 months (95% CI: 18.3-not reached) and the median progression-free survival was 11.6 months (95% CI: 6.3-45.7). There were no unexpected toxicities. Subgroup analyses revealed consistent long-term efficacy results across most subgroups of patients. This extended follow-up of L-MIND confirms the long duration of response, meaningful overall survival, and well-defined safety profile of tafasitamab plus lenalidomide followed by tafasitamab monotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplantation. ClinicalTrials.gov identifier: NCT02399085.
- Published
- 2021
- Full Text
- View/download PDF
9. Long-term outcomes from the phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma.
- Author
-
Duell J, Maddocks KJ, González-Barca E, Jurczak W, Liberati AM, De Vos S, Nagy Z, Obr A, Gaidano G, Abrisqueta P, Kalakonda N, André M, Dreyling M, Menne T, Tournilhac O, Augustin M, Rosenwald A, Dirnberger-Hertweck M, Weirather J, Ambarkhane S, and Salles G
- Abstract
Not available.
- Published
- 2021
- Full Text
- View/download PDF
10. A step ahead toward precision medicine for chronic lymphocytic leukemia.
- Author
-
Patriarca A and Gaidano G
- Subjects
- Humans, Mutation, Precision Medicine, Prognosis, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Published
- 2020
- Full Text
- View/download PDF
11. KMT2D mutations and TP53 disruptions are poor prognostic biomarkers in mantle cell lymphoma receiving high-dose therapy: a FIL study.
- Author
-
Ferrero S, Rossi D, Rinaldi A, Bruscaggin A, Spina V, Eskelund CW, Evangelista A, Moia R, Kwee I, Dahl C, Di Rocco A, Stefoni V, Diop F, Favini C, Ghione P, Mahmoud AM, Schipani M, Kolstad A, Barbero D, Novero D, Paulli M, Zamò A, Jerkeman M, da Silva MG, Santoro A, Molinari A, Ferreri A, Grønbæk K, Piccin A, Cortelazzo S, Bertoni F, Ladetto M, and Gaidano G
- Subjects
- Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Humans, Mutation, Prognosis, Prospective Studies, Transplantation, Autologous, DNA-Binding Proteins genetics, Hematopoietic Stem Cell Transplantation, Lymphoma, Mantle-Cell diagnosis, Lymphoma, Mantle-Cell drug therapy, Lymphoma, Mantle-Cell genetics, Neoplasm Proteins genetics, Tumor Suppressor Protein p53 genetics
- Abstract
In recent years, the outcome of mantle cell lymphoma (MCL) has improved, especially in younger patients, receiving cytarabine-containing chemoimmunotherapy and autologous stem cell transplantation. Nevertheless, a proportion of MCL patients still experience early failure. To identify biomarkers anticipating failure of intensive chemotherapy in MCL, we performed target resequencing and DNA profiling of purified tumor samples collected from patients enrolled in the prospective FIL-MCL0208 phase 3 trial (high-dose chemoimmunotherapy followed by autologous transplantation and randomized lenalidomide maintenance). Mutations of KMT2D and disruption of TP53 by deletion or mutation associated with an increased risk of progression and death, both in univariate and multivariate analysis. By adding KMT2D mutations and TP53 disruption to the MIPI-c backbone, we derived a new prognostic index, the "MIPI-genetic" ("MIPI- g"). The "MIPI-g" improved the model discrimination ability compared to the MIPI-c alone, defining three risk groups: i) low-risk patients (4-year progression free survival and overall survival of 72.0% and 94.5%); ii) inter-mediate-risk patients (4-year progression free survival and overall survival of 42.2% and 65.8%) and iii) high-risk patients (4-year progression free survival and overall survival of 11.5% and 44.9%). Our results: i) confirm that TP53 disruption identifies a high-risk population characterized by poor sensitivity to conventional or intensified chemotherapy; ii) provide the pivotal evidence that patients harboring KMT2D mutations share the same poor outcome as patients harboring TP53 disruption; and iii) allow to develop a tool for the identification of high-risk MCL patients for whom novel therapeutic strategies need to be investigated. ( Trial registered at clinicaltrials.gov identifier: NCT02354313 )., (Copyright© 2020 Ferrata Storti Foundation.)
- Published
- 2020
- Full Text
- View/download PDF
12. A cross-trial comparison of single-agent ibrutinib versus chlorambucil-obinutuzumab in previously untreated patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.
- Author
-
Tedeschi A, Greil R, Demirkan F, Robak T, Moreno C, Barr PM, Anz B, Simpson D, Gaidano G, Bairey O, Stevens D, Gill D, Flinn IW, Kipps TJ, Burger JA, Lin J, Webb T, Fedorov V, Styles L, and Gribben JG
- Subjects
- Adenine analogs & derivatives, Humans, Piperidines, Antibodies, Monoclonal, Humanized therapeutic use, Chlorambucil therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Published
- 2020
- Full Text
- View/download PDF
13. HIF-1α is over-expressed in leukemic cells from TP53 -disrupted patients and is a promising therapeutic target in chronic lymphocytic leukemia.
- Author
-
Griggio V, Vitale C, Todaro M, Riganti C, Kopecka J, Salvetti C, Bomben R, Bo MD, Magliulo D, Rossi D, Pozzato G, Bonello L, Marchetti M, Omedè P, Kodipad AA, Laurenti L, Del Poeta G, Mauro FR, Bernardi R, Zenz T, Gattei V, Gaidano G, Foà R, Massaia M, Boccadoro M, and Coscia M
- Subjects
- Animals, Humans, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Mice, Phosphatidylinositol 3-Kinases genetics, Tumor Microenvironment, Tumor Suppressor Protein p53 genetics, Von Hippel-Lindau Tumor Suppressor Protein, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
In chronic lymphocytic leukemia (CLL), the hypoxia-inducible factor 1 (HIF-1) regulates the response of tumor cells to hypoxia and their protective interactions with the leukemic microenvironment. In this study, we demonstrate that CLL cells from TP53 -disrupted ( TP53 ) patients have constitutively higher expression levels of the α-subunit of HIF-1 (HIF-1α) and increased HIF-1 transcriptional activity compared to the wild-type counterpart. In the
dis subset, HIF-1α upregulation is due to reduced expression of the HIF-1α ubiquitin ligase von Hippel-Lindau protein (pVHL). Hypoxia and stromal cells further enhance HIF-1α accumulation, independently of TP53 status. Hypoxia acts through the downmodulation of pVHL and the activation of the PI3K/AKT and RAS/ERK1-2 pathways, whereas stromal cells induce an increased activity of the RAS/ERK1-2, RHOA/RHOA kinase and PI3K/AKT pathways, without affecting pVHL expression. Interestingly, we observed that higher levels ofdis mRNA correlate with a lower susceptibility of leukemic cells to spontaneous apoptosis, and associate with the fludarabine resistance that mainly characterizes TP53 tumor cells. The HIF-1α inhibitor BAY87-2243 exerts cytotoxic effects toward leukemic cells, regardless of the HIF-1A status, and has anti-tumor activity in Em-TCL1 mice. BAY87-2243 also overcomes the constitutive fludarabine resistance of TP53dis tumor cells. The HIF-1α inhibitor BAY87-2243 exerts cytotoxic effects toward leukemic cells, regardless of the TP53 status, and has anti-tumor activity in Em-TCL1 mice. BAY87-2243 also overcomes the constitutive fludarabine resistance of TP53dis leukemic cells and elicits a strongly synergistic cytotoxic effect in combination with ibrutinib, thus providing preclinical evidence to stimulate further investigation into use as a potential new drug in CLL., (Copyright© 2020 Ferrata Storti Foundation.)- Published
- 2020
- Full Text
- View/download PDF
14. Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia.
- Author
-
Diop F, Moia R, Favini C, Spaccarotella E, De Paoli L, Bruscaggin A, Spina V, Terzi-di-Bergamo L, Arruga F, Tarantelli C, Deambrogi C, Rasi S, Adhinaveni R, Patriarca A, Favini S, Sagiraju S, Jabangwe C, Kodipad AA, Peroni D, Mauro FR, Giudice ID, Forconi F, Cortelezzi A, Zaja F, Bomben R, Rossi FM, Visco C, Chiarenza A, Rigolin GM, Marasca R, Coscia M, Perbellini O, Tedeschi A, Laurenti L, Motta M, Donaldson D, Weir P, Mills K, Thornton P, Lawless S, Bertoni F, Poeta GD, Cuneo A, Follenzi A, Gattei V, Boldorini RL, Catherwood M, Deaglio S, Foà R, Gaidano G, and Rossi D
- Subjects
- Antineoplastic Combined Chemotherapy Protocols, Baculoviral IAP Repeat-Containing 3 Protein, Cyclophosphamide therapeutic use, Humans, Mutation, Prognosis, Retrospective Studies, Rituximab therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
BIRC3 is a recurrently mutated gene in chronic lymphocytic leukemia (CLL) but the functional implications of BIRC3 mutations are largely unexplored. Furthermore, little is known about the prognostic impact of BIRC3 mutations in CLL cohorts homogeneously treated with first-line fludarabine, cyclophosphamide, and rituximab (FCR). By immunoblotting analysis, we showed that the non-canonical nuclear factor-κB pathway is active in BIRC3 -mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, BIRC3 -mutated primary CLL cells are less sensitive to flu-darabine. In order to confirm in patients that BIRC3 mutations confer resistance to fludarabine-based chemoimmunotherapy, a retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed by targeted next-generation sequencing of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons BIRC3 mutations identify a poor prognostic subgroup of patients in whom FCR treatment fails (median progression-free survival: 2.2 years, P <0.001) similar to cases harboring TP53 mutations (median progression-free survival: 2.6 years, P <0.0001). BIRC3 mutations maintained an independent association with an increased risk of progression with a hazard ratio of 2.8 (95% confidence interval 1.4-5.6, P =0.004) in multivariate analysis adjusted for TP53 mutation, 17p deletion and IGHV mutation status. If validated, BIRC3 mutations may be used as a new molecular predictor to select high-risk patients for novel frontline therapeutic approaches., (Copyright© 2020 Ferrata Storti Foundation.)
- Published
- 2020
- Full Text
- View/download PDF
15. Outcome of paraosseous extra-medullary disease in newly diagnosed multiple myeloma patients treated with new drugs.
- Author
-
Montefusco V, Gay F, Spada S, De Paoli L, Di Raimondo F, Ribolla R, Musolino C, Patriarca F, Musto P, Galieni P, Ballanti S, Nozzoli C, Cascavilla N, Ben-Yehuda D, Nagler A, Hajek R, Offidani M, Liberati AM, Sonneveld P, Cavo M, Corradini P, and Boccadoro M
- Subjects
- Humans, Lenalidomide therapeutic use, Progression-Free Survival, Proportional Hazards Models, Multiple Myeloma diagnosis, Multiple Myeloma drug therapy, Pharmaceutical Preparations
- Abstract
Extramedullary disease is relatively frequent in multiple myeloma, but our knowledge on the subject is limited and mainly relies on small case series or single center experiences. Little is known regarding the role of new drugs in this setting. We performed a meta-analysis of eight trials focused on the description of extramedullary disease characteristics, clinical outcome, and response to new drugs. A total of 2,332 newly diagnosed myeloma patients have been included; 267 (11.4%) had extramedullary disease, defined as paraosseous in 243 (10.4%), extramedullary plasmocytoma in 12 (0.5%), and not classified in 12 (0.5%) patients. Median progression-free survival was 25.3 months and 25.2 in extramedullary disease and non-extramedullary disease patients, respectively. In multivariate analysis the presence of extramedullary disease did not impact on progression-free survival (hazard ratio 1.15, P =0.06), while other known prognostic factors retained their significance. Patients treated with immunomodulatory drugs, mainly lenalidomide, or proteasome inhibitors had similar progression-free survival and progression-free survival-2 regardless of extramedullary disease presence. Median overall survival was 63.5 months and 79.9 months ( P =0.01) in extramedullary and non-extramedullary disease patients, respectively, and in multivariate analysis the presence of extramedullary disease was associated with a reduced overall survival (hazard ratio 1.41, P <0.001), in line with other prognostic factors. With the limits of the use of low sensitivity imaging techniques, that lead to an underestimation of extramedullary disease, we conclude that in patients treated with new drugs the detrimental effect of extramedullary disease at diagnosis is limited, that lenalidomide is effective as are proteasome inhibitors, and that these patients tend to acquire a more aggressive disease in later stages. (EUDRACT2005-004714-32, NCT01063179 NCT00551928, NCT01091831, NCT01093196, NCT01190787, NCT01346787, NCT01857115)., (Copyright© 2020 Ferrata Storti Foundation.)
- Published
- 2020
- Full Text
- View/download PDF
16. Novel insights into the genetics and epigenetics of MALT lymphoma unveiled by next generation sequencing analyses.
- Author
-
Cascione L, Rinaldi A, Bruscaggin A, Tarantelli C, Arribas AJ, Kwee I, Pecciarini L, Mensah AA, Spina V, Chung EYL, di Bergamo LT, Dirnhofer S, Tzankov A, Miranda RN, Young KH, Traverse-Glehen A, Gaidano G, Swerdlow SH, Gascoyne R, Rabadan R, Ponzoni M, Bhagat G, Rossi D, Zucca E, and Bertoni F
- Subjects
- Humans, Lymphoma, B-Cell, Marginal Zone classification, Prognosis, Biomarkers, Tumor genetics, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, High-Throughput Nucleotide Sequencing methods, Lymphoma, B-Cell, Marginal Zone genetics, Lymphoma, B-Cell, Marginal Zone pathology
- Published
- 2019
- Full Text
- View/download PDF
17. The involvement of microRNA in the pathogenesis of Richter syndrome.
- Author
-
Van Roosbroeck K, Bayraktar R, Calin S, Bloehdorn J, Dragomir MP, Okubo K, Bertilaccio MTS, Zupo S, You MJ, Gaidano G, Rossi D, Chen SS, Chiorazzi N, Thompson PA, Ferrajoli A, Bertoni F, Stilgenbauer S, Keating MJ, and Calin GA
- Subjects
- Adult, Aged, Animals, Apoptosis, Cell Proliferation, Cell Transformation, Neoplastic genetics, Female, Follow-Up Studies, Humans, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Male, Mice, Mice, Inbred NOD, Mice, SCID, Middle Aged, Prognosis, Syndrome, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Biomarkers, Tumor genetics, Cell Transformation, Neoplastic pathology, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Leukemia, Lymphocytic, Chronic, B-Cell pathology, MicroRNAs genetics
- Abstract
Richter syndrome is the name given to the transformation of the most frequent type of leukemia, chronic lymphocytic leukemia, into an aggressive lymphoma. Patients with Richter syndrome have limited response to therapies and dismal survival. The underlying mechanisms of transformation are insufficiently understood and there is a major lack of knowledge regarding the roles of microRNA that have already proven to be causative for most cases of chronic lymphocytic leukemia. Here, by using four types of genomic platforms and independent sets of patients from three institutions, we identified microRNA involved in the transformation of chronic lymphocytic leukemia to Richter syndrome. The expression signature is composed of miR-21, miR-150, miR-146b and miR-181b, with confirmed targets significantly enriched in pathways involved in cancer, immunity and inflammation. In addition, we demonstrated that genomic alterations may account for microRNA deregulation in a subset of cases of Richter syndrome. Furthermore, network analysis showed that Richter transformation leads to a complete rearrangement, resulting in a highly connected microRNA network. Functionally, ectopic overexpression of miR-21 increased proliferation of malignant B cells in multiple assays, while miR-150 and miR-26a were downregulated in a chronic lymphocytic leukemia xenogeneic mouse transplantation model. Together, our results suggest that Richter transformation is associated with significant expression and genomic loci alterations of microRNA involved in both malignancy and immunity., (Copyright© 2019 Ferrata Storti Foundation.)
- Published
- 2019
- Full Text
- View/download PDF
18. Liquid biopsy in lymphoma.
- Author
-
Rossi D, Spina V, Bruscaggin A, and Gaidano G
- Subjects
- Female, Humans, Liquid Biopsy, Male, Circulating Tumor DNA blood, Lymphoma blood, Lymphoma diagnosis, Lymphoma pathology
- Published
- 2019
- Full Text
- View/download PDF
19. Tailored approaches grounded on immunogenetic features for refined prognostication in chronic lymphocytic leukemia.
- Author
-
Baliakas P, Moysiadis T, Hadzidimitriou A, Xochelli A, Jeromin S, Agathangelidis A, Mattsson M, Sutton LA, Minga E, Scarfò L, Rossi D, Davis Z, Villamor N, Parker H, Kotaskova J, Stalika E, Plevova K, Mansouri L, Cortese D, Navarro A, Delgado J, Larrayoz M, Young E, Anagnostopoulos A, Smedby KE, Juliusson G, Sheehy O, Catherwood M, Strefford JC, Stavroyianni N, Belessi C, Pospisilova S, Oscier D, Gaidano G, Campo E, Haferlach C, Ghia P, Rosenquist R, and Stamatopoulos K
- Subjects
- Aged, Aged, 80 and over, Chromosome Aberrations, Female, Humans, Immunogenetics, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Male, Mutation, Neoplasm Staging, Prognosis, Time-to-Treatment, Biomarkers, Tumor, Disease Susceptibility, Leukemia, Lymphocytic, Chronic, B-Cell etiology, Leukemia, Lymphocytic, Chronic, B-Cell mortality
- Abstract
Chronic lymphocytic leukemia (CLL) patients with differential somatic hypermutation status of the immunoglobulin heavy variable genes, namely mutated or unmutated, display fundamental clinico-biological differences. Considering this, we assessed prognosis separately within mutated (M-CLL) and unmutated (U-CLL) CLL in 3015 patients, hypothesizing that the relative significance of relevant indicators may differ between these two categories. Within Binet A M-CLL patients, besides TP53 abnormalities, trisomy 12 and stereotyped subset #2 membership were equivalently associated with the shortest time-to-first-treatment and a treatment probability at five and ten years after diagnosis of 40% and 55%, respectively; the remaining cases exhibited 5-year and 10-year treatment probability of 12% and 25%, respectively. Within Binet A U-CLL patients, besides TP53 abnormalities, del(11q) and/or SF3B1 mutations were associated with the shortest time-to-first-treatment (5- and 10-year treatment probability: 78% and 98%, respectively); in the remaining cases, males had a significantly worse prognosis than females. In conclusion, the relative weight of indicators that can accurately risk stratify early-stage CLL patients differs depending on the somatic hypermutation status of the immunoglobulin heavy variable genes of each patient. This finding highlights the fact that compartmentalized approaches based on immunogenetic features are necessary to refine and tailor prognostication in CLL., (Copyright © 2019 Ferrata Storti Foundation.)
- Published
- 2019
- Full Text
- View/download PDF
20. A B-cell receptor-related gene signature predicts survival in mantle cell lymphoma: results from the Fondazione Italiana Linfomi MCL-0208 trial.
- Author
-
Bomben R, Ferrero S, D'Agaro T, Dal Bo M, Re A, Evangelista A, Carella AM, Zamò A, Vitolo U, Omedè P, Rusconi C, Arcaini L, Rigacci L, Luminari S, Piccin A, Liu D, Wiestner A, Gaidano G, Cortelazzo S, Ladetto M, and Gattei V
- Subjects
- Adult, Aged, Female, Follow-Up Studies, Humans, Lymphoma, Mantle-Cell pathology, Lymphoma, Mantle-Cell therapy, Male, Middle Aged, Prognosis, Prospective Studies, Survival Rate, Biomarkers, Tumor genetics, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Lymphoma, Mantle-Cell genetics, Lymphoma, Mantle-Cell mortality, Receptors, Antigen, B-Cell genetics
- Abstract
Mantle cell lymphoma patients have variable clinical courses, ranging from indolent cases that do not require immediate treatment to aggressive, rapidly progressing diseases. Thus, diagnostic tools capable of stratifying patients according to their risk of relapse and death are needed. This study included 83 samples from the Fondazione Italiana Linfomi MCL-0208 clinical trial. Through gene expression profiling and quantitative real-time PCR we analyzed 46 peripheral blood and 43 formalin-fixed paraffin-embedded lymph node samples. A prediction model to classify patients was developed. By analyzing the transcriptome of 27 peripheral blood samples, two subgroups characterized by a differential expression of genes from the B-cell receptor pathway (B-cell receptor
low and B-cell receptorhigh ) were identified. The prediction model based on the quantitative real-time PCR values of six representative genes ( AKT3, BCL2, BTK, CD79B, PIK3CD , and SYK ), was used to classify the 83 cases (43 B-cell receptorlow and 40 B-cell receptorhigh ). The B-cell receptorhigh signature associated with shorter progression-free survival ( P =0.0074), selected the mantle cell lymphoma subgroup with the shortest progression-free survival and overall survival ( P =0.0014 and P =0.029, respectively) in combination with high (>30%) Ki-67 staining, and was an independent predictor of short progression- free survival along with the Mantle Cell Lymphoma International Prognostic Index-combined score. Moreover, the clinical impact of the 6- gene signature related to the B-cell receptor pathway identified a mantle cell lymphoma subset with shorter progression-free survival intervals also in an external independent mantle cell lymphoma cohort homogenously treated with different schedules. In conclusion, this 6-gene signature associates with a poor clinical response in the context of the MCL- 0208 clinical trial. ( clinicaltrials.gov identifier: 02354313 )., (Copyright © 2018 Ferrata Storti Foundation.)- Published
- 2018
- Full Text
- View/download PDF
21. Mutational status of IGHV is the most reliable prognostic marker in trisomy 12 chronic lymphocytic leukemia.
- Author
-
Bulian P, Bomben R, Bo MD, Zucchetto A, Rossi FM, Degan M, Pozzo F, Bittolo T, Bravin V, D'Agaro T, Cerri M, Chiarenza A, Chaffee KG, Condoluci A, D'Arena G, Spina M, Zaja F, Pozzato G, Di Raimondo F, Rossi D, Poeta GD, Gaidano G, Shanafelt TD, and Gattei V
- Subjects
- Biomarkers, Humans, Kaplan-Meier Estimate, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Prognosis, Proportional Hazards Models, Chromosomes, Human, Pair 12, Genes, Immunoglobulin Heavy Chain, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Mutation, Trisomy
- Published
- 2017
- Full Text
- View/download PDF
22. Mutations in the 3' untranslated region of NOTCH1 are associated with low CD20 expression levels chronic lymphocytic leukemia.
- Author
-
Bittolo T, Pozzo F, Bomben R, D'Agaro T, Bravin V, Bulian P, Rossi FM, Zucchetto A, Degan M, Macor P, D'Arena G, Chiarenza A, Zaja F, Pozzato G, Di Raimondo F, Rossi D, Gaidano G, Del Poeta G, Gattei V, and Dal Bo M
- Subjects
- Humans, Immunotherapy methods, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Mutation, Treatment Failure, 3' Untranslated Regions genetics, Antigens, CD20 metabolism, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Receptor, Notch1 genetics
- Published
- 2017
- Full Text
- View/download PDF
23. Integration of B-cell receptor-induced ERK1/2 phosphorylation and mutations of SF3B1 gene refines prognosis in treatment-naïve chronic lymphocytic leukemia.
- Author
-
Cavallini C, Visco C, Putta S, Rossi D, Mimiola E, Purvis N, Lovato O, Perbellini O, Falisi E, Facco M, Trentin L, Romanelli MG, Semenzato G, Ambrosetti A, Gaidano G, Pizzolo G, Cesano A, and Scupoli MT
- Subjects
- ADP-ribosyl Cyclase 1 genetics, ADP-ribosyl Cyclase 1 immunology, Disease Progression, Humans, Immunoglobulin Heavy Chains genetics, Immunoglobulin Heavy Chains metabolism, Immunoglobulin Variable Region genetics, Immunoglobulin Variable Region metabolism, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Membrane Glycoproteins genetics, Membrane Glycoproteins immunology, Mitogen-Activated Protein Kinase 1 immunology, Mitogen-Activated Protein Kinase 3 immunology, Mutation, Phosphoproteins immunology, Phosphorylation, Prognosis, RNA Splicing Factors immunology, Receptor, Notch1 genetics, Receptor, Notch1 immunology, Receptors, Antigen, B-Cell immunology, Signal Transduction, Survival Analysis, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 immunology, Gene Expression Regulation, Leukemic, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Mitogen-Activated Protein Kinase 1 genetics, Mitogen-Activated Protein Kinase 3 genetics, Phosphoproteins genetics, RNA Splicing Factors genetics, Receptors, Antigen, B-Cell genetics
- Published
- 2017
- Full Text
- View/download PDF
24. Clinical impact of recurrently mutated genes on lymphoma diagnostics: state-of-the-art and beyond.
- Author
-
Rosenquist R, Rosenwald A, Du MQ, Gaidano G, Groenen P, Wotherspoon A, Ghia P, Gaulard P, Campo E, and Stamatopoulos K
- Subjects
- Clinical Decision-Making, Gene Frequency, Genomics methods, High-Throughput Nucleotide Sequencing, Humans, Lymphoma mortality, Lymphoma therapy, Mutation Rate, Prognosis, Biomarkers, Tumor, Genetic Association Studies, Genetic Predisposition to Disease, Lymphoma diagnosis, Lymphoma genetics, Mutation
- Abstract
Similar to the inherent clinical heterogeneity of most, if not all, lymphoma entities, the genetic landscape of these tumors is markedly complex in the majority of cases, with a rapidly growing list of recurrently mutated genes discovered in recent years by next-generation sequencing technology. Whilst a few genes have been implied to have diagnostic, prognostic and even predictive impact, most gene mutations still require rigorous validation in larger, preferably prospective patient series, to scrutinize their potential role in lymphoma diagnostics and patient management. In selected entities, a predominantly mutated gene is identified in almost all cases (e.g. Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma and hairy-cell leukemia), while for the vast majority of lymphomas a quite diverse mutation pattern is observed, with a limited number of frequently mutated genes followed by a seemingly endless tail of genes with mutations at a low frequency. Herein, the European Expert Group on NGS-based Diagnostics in Lymphomas (EGNL) summarizes the current status of this ever-evolving field, and, based on the present evidence level, segregates mutations into the following categories: i) immediate impact on treatment decisions, ii) diagnostic impact, iii) prognostic impact, iv) potential clinical impact in the near future, or v) should only be considered for research purposes. In the coming years, coordinated efforts aiming to apply targeted next-generation sequencing in large patient series will be needed in order to elucidate if a particular gene mutation will have an immediate impact on the lymphoma classification, and ultimately aid clinical decision making., (Copyright© Ferrata Storti Foundation.)
- Published
- 2016
- Full Text
- View/download PDF
25. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors.
- Author
-
Sutton LA, Young E, Baliakas P, Hadzidimitriou A, Moysiadis T, Plevova K, Rossi D, Kminkova J, Stalika E, Pedersen LB, Malcikova J, Agathangelidis A, Davis Z, Mansouri L, Scarfò L, Boudjoghra M, Navarro A, Muggen AF, Yan XJ, Nguyen-Khac F, Larrayoz M, Panagiotidis P, Chiorazzi N, Niemann CU, Belessi C, Campo E, Strefford JC, Langerak AW, Oscier D, Gaidano G, Pospisilova S, Davi F, Ghia P, Stamatopoulos K, and Rosenquist R
- Subjects
- Complementarity Determining Regions genetics, Cytogenetic Analysis, Female, Gene Frequency, Gene Rearrangement, B-Lymphocyte, Genes, Immunoglobulin, Humans, Immunoglobulin Heavy Chains genetics, Immunoglobulin Joining Region genetics, Immunoglobulin Variable Region genetics, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Male, Polymorphism, Single Nucleotide, Prognosis, Biomarkers, Tumor, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Mutation, Receptors, Antigen, B-Cell genetics, Receptors, Antigen, B-Cell metabolism
- Abstract
We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22-34%), often in association with trisomy 12, and was significantly different (P<0.001) to the frequency observed in subset #2 (4%, aggressive disease, variable somatic hypermutation status) and subset #4 (1%, indolent disease, mutated immunoglobulin genes). Interestingly, subsets harboring a high frequency of NOTCH1 mutations were found to carry few (if any) SF3B1 mutations. This starkly contrasts with subsets #2 and #3 where, despite their immunogenetic differences, SF3B1 mutations occurred in 45% and 46% of cases, respectively. In addition, mutations within TP53, whilst enriched in subset #1 (16%), were rare in subsets #2 and #8 (both 2%), despite all being clinically aggressive. All subsets were negative for MYD88 mutations, whereas BIRC3 mutations were infrequent. Collectively, this striking bias and skewed distribution of mutations and cytogenetic aberrations within specific chronic lymphocytic leukemia subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s)., (Copyright© Ferrata Storti Foundation.)
- Published
- 2016
- Full Text
- View/download PDF
26. RNA sequencing unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications.
- Author
-
Gianfelici V, Chiaretti S, Demeyer S, Di Giacomo F, Messina M, La Starza R, Peragine N, Paoloni F, Geerdens E, Pierini V, Elia L, Mancini M, De Propris MS, Apicella V, Gaidano G, Testi AM, Vitale A, Vignetti M, Mecucci C, Guarini A, Cools J, and Foà R
- Subjects
- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cell Cycle Proteins metabolism, Child, Cluster Analysis, Cohort Studies, Drug Resistance, Neoplasm, F-Box Proteins metabolism, F-Box-WD Repeat-Containing Protein 7, Female, Gene Expression Profiling, Humans, Janus Kinases metabolism, Male, Middle Aged, Mutation, Oncogene Proteins, Fusion genetics, PTEN Phosphohydrolase metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma mortality, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma therapy, Prognosis, Receptor, Notch1 genetics, Receptor, Notch1 metabolism, Recurrence, STAT Transcription Factors metabolism, Signal Transduction, Survival Analysis, Treatment Outcome, Ubiquitin-Protein Ligases metabolism, Young Adult, ras Proteins metabolism, Genetic Variation, High-Throughput Nucleotide Sequencing, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Sequence Analysis, RNA
- Abstract
Despite therapeutic improvements, a sizable number of patients with T-cell acute lymphoblastic leukemia still have a poor outcome. To unravel the genomic background associated with refractoriness, we evaluated the transcriptome of 19 cases of refractory/early relapsed T-cell acute lymphoblastic leukemia (discovery cohort) by performing RNA-sequencing on diagnostic material. The incidence and prognostic impact of the most frequently mutated pathways were validated by Sanger sequencing on genomic DNA from diagnostic samples of an independent cohort of 49 cases (validation cohort), including refractory, relapsed and responsive cases. Combined gene expression and fusion transcript analyses in the discovery cohort revealed the presence of known oncogenes and identified novel rearrangements inducing overexpression, as well as inactivation of tumor suppressor genes. Mutation analysis identified JAK/STAT and RAS/PTEN as the most commonly disrupted pathways in patients with chemorefractory disease or early relapse, frequently in association with NOTCH1/FBXW7 mutations. The analysis on the validation cohort documented a significantly higher risk of relapse, inferior overall survival, disease-free survival and event-free survival in patients with JAK/STAT or RAS/PTEN alterations. Conversely, a significantly better survival was observed in patients harboring only NOTCH1/FBXW7 mutations: this favorable prognostic effect was abrogated by the presence of concomitant mutations. Preliminary in vitro assays on primary cells demonstrated sensitivity to specific inhibitors. These data document the negative prognostic impact of JAK/STAT and RAS/PTEN mutations in T-cell acute lymphoblastic leukemia and suggest the potential clinical application of JAK and PI3K/mTOR inhibitors in patients harboring mutations in these pathways., (Copyright© Ferrata Storti Foundation.)
- Published
- 2016
- Full Text
- View/download PDF
27. Clinical impact of small subclones harboring NOTCH1, SF3B1 or BIRC3 mutations in chronic lymphocytic leukemia.
- Author
-
Rasi S, Khiabanian H, Ciardullo C, Terzi-di-Bergamo L, Monti S, Spina V, Bruscaggin A, Cerri M, Deambrogi C, Martuscelli L, Biasi A, Spaccarotella E, De Paoli L, Gattei V, Foà R, Rabadan R, Gaidano G, and Rossi D
- Subjects
- Alleles, Antineoplastic Agents therapeutic use, B-Lymphocytes metabolism, B-Lymphocytes pathology, Baculoviral IAP Repeat-Containing 3 Protein, Clone Cells, Gene Expression, Gene Frequency, High-Throughput Nucleotide Sequencing, Humans, Inhibitor of Apoptosis Proteins metabolism, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Phosphoproteins metabolism, Prospective Studies, RNA Splicing Factors metabolism, Receptor, Notch1 metabolism, Survival Analysis, Ubiquitin-Protein Ligases metabolism, Inhibitor of Apoptosis Proteins genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Mutation, Phosphoproteins genetics, RNA Splicing Factors genetics, Receptor, Notch1 genetics, Ubiquitin-Protein Ligases genetics
- Published
- 2016
- Full Text
- View/download PDF
28. Innovation in the prognostication of chronic lymphocytic leukemia: how far beyond TP53 gene analysis can we go?
- Author
-
Pospisilova S, Sutton LA, Malcikova J, Tausch E, Rossi D, Montserrat E, Moreno C, Stamatopoulos K, Gaidano G, Rosenquist R, and Ghia P
- Subjects
- Adenine analogs & derivatives, Agammaglobulinaemia Tyrosine Kinase, Alleles, Biomarkers, Tumor metabolism, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors, Class I Phosphatidylinositol 3-Kinases genetics, Class I Phosphatidylinositol 3-Kinases metabolism, Gene Expression, Gene Frequency, High-Throughput Nucleotide Sequencing, Humans, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Molecular Targeted Therapy, Piperidines, Prognosis, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases genetics, Protein-Tyrosine Kinases metabolism, Purines therapeutic use, Pyrazoles therapeutic use, Pyrimidines therapeutic use, Quinazolinones therapeutic use, Sulfonamides therapeutic use, Tumor Suppressor Protein p53 deficiency, Antineoplastic Agents therapeutic use, Biomarkers, Tumor genetics, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Tumor Suppressor Protein p53 genetics
- Published
- 2016
- Full Text
- View/download PDF
29. The genotype of MLH1 identifies a subgroup of follicular lymphoma patients who do not benefit from doxorubicin: FIL-FOLL study.
- Author
-
Rossi D, Bruscaggin A, La Cava P, Galimberti S, Ciabatti E, Luminari S, Rigacci L, Tucci A, Pulsoni A, Bertoldero G, Vallisa D, Rusconi C, Spina M, Arcaini L, Angrilli F, Stelitano C, Merli F, Gaidano G, Federico M, and Palumbo GA
- Subjects
- Aged, Antibiotics, Antineoplastic administration & dosage, Antibiotics, Antineoplastic therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Doxorubicin administration & dosage, Doxorubicin therapeutic use, Female, Humans, Kaplan-Meier Estimate, Lymphoma, Follicular diagnosis, Lymphoma, Follicular drug therapy, Lymphoma, Follicular mortality, Male, Middle Aged, MutL Protein Homolog 1, Neoplasm Grading, Neoplasm Metastasis, Neoplasm Staging, Polymorphism, Single Nucleotide, Prognosis, Receptors, IgG genetics, Treatment Failure, Treatment Outcome, Adaptor Proteins, Signal Transducing genetics, Genotype, Lymphoma, Follicular genetics, Nuclear Proteins genetics
- Abstract
Though most follicular lymphoma biomarkers rely on tumor features, the host genetic background may also be relevant for outcome. Here we aimed at verifying the contribution of candidate polymorphisms of FCγ receptor, DNA repair and detoxification genes to prognostic stratification of follicular lymphoma treated with immunochemotherapy. The study was based on 428 patients enrolled in the FOLL05 prospective trial that compared three standard-of-care regimens (rituximab-cyclophosphamide-vincristine-prednisone versus rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone versus rituximab-fludarabine-mitoxantrone) for the first line therapy of advanced follicular lymphoma. Polymorphisms were genotyped on peripheral blood DNA samples. The primary endpoint was time to treatment failure. Polymorphisms of FCGR2A and FCGR3A, which have been suggested to influence the activity of rituximab as a single agent, did not affect time to treatment failure in the pooled analysis of the three FOLL05 treatment arms that combined rituximab with chemotherapy (P=0.742, P=0.252, respectively). These results were consistent even when the analysis was conducted by intention to treat, indicating that different chemotherapy regimens and loads did not interact differentially with the FCGR2A and FCGR3A genotypes. The genotype of MLH1, which regulates the genotoxic effect of doxorubicin, significantly affected time to treatment failure in patients in the rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone arm (P=0.001; q<0.1), but not in arms in which patients did not receive doxorubicin (i.e., the rituximab-cyclophosphamide-vincristine-prednisone and rituximab-fludarabine-mitoxantrone arms). The impact of MLH1 on time to treatment failure was independent after adjusting for the Follicular Lymphoma International Prognostic Index and other potential confounding variables by multivariate analysis. These data indicate that MLH1 genotype is a predictor of failure to benefit from rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone treatment in advanced follicular lymphoma and confirm that FCGR2A and FCGR3A polymorphisms have no impact when follicular lymphoma is treated with rituximab plus chemotherapy (clinicaltrials.gov identifier: NCT00774826)., (Copyright© Ferrata Storti Foundation.)
- Published
- 2015
- Full Text
- View/download PDF
30. The NOTCH pathway is recurrently mutated in diffuse large B-cell lymphoma associated with hepatitis C virus infection.
- Author
-
Arcaini L, Rossi D, Lucioni M, Nicola M, Bruscaggin A, Fiaccadori V, Riboni R, Ramponi A, Ferretti VV, Cresta S, Casaluci GM, Bonfichi M, Gotti M, Merli M, Maffi A, Arra M, Varettoni M, Rattotti S, Morello L, Guerrera ML, Sciarra R, Gaidano G, Cazzola M, and Paulli M
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor genetics, DNA-Binding Proteins, Female, Follow-Up Studies, Hepacivirus isolation & purification, Hepatitis C mortality, Hepatitis C pathology, Hepatitis C virology, Humans, Lymphoma, Large B-Cell, Diffuse mortality, Lymphoma, Large B-Cell, Diffuse pathology, Lymphoma, Large B-Cell, Diffuse virology, Male, Middle Aged, Neoplasm Grading, Neoplasm Recurrence, Local mortality, Neoplasm Recurrence, Local pathology, Neoplasm Recurrence, Local virology, Polymerase Chain Reaction, Prognosis, RNA-Binding Proteins, Survival Rate, Hepatitis C genetics, Homeodomain Proteins genetics, Lymphoma, Large B-Cell, Diffuse genetics, Mutation genetics, Neoplasm Recurrence, Local genetics, Nuclear Proteins genetics, Receptor, Notch1 genetics, Receptor, Notch2 genetics
- Abstract
Hepatitis C virus has been found to be associated with B-cell non-Hodgkin lymphomas, mostly marginal zone lymphomas and diffuse large B-cell lymphoma. Deregulation of signaling pathways involved in normal marginal zone development (NOTCH pathway, NF-κB, and BCR signaling) has been demonstrated in splenic marginal zone lymphoma. We studied mutations of NOTCH pathway signaling in 46 patients with hepatitis C virus-positive diffuse large B-cell lymphoma and in 64 patients with diffuse large B-cell lymphoma unrelated to HCV. NOTCH2 mutations were detected in 9 of 46 (20%) hepatitis C virus-positive patients, and NOTCH1 mutations in 2 of 46 (4%). By contrast, only one of 64 HCV-negative patients had a NOTCH1 or NOTCH2 mutation. The frequency of the NOTCH pathway lesions was significantly higher in hepatitis C virus-positive patients (P=0.002). The 5-year overall survival was 27% (95%CI: 5%-56%) for hepatitis C virus-positive diffuse large B-cell lymphoma patients carrying a NOTCH pathway mutation versus 62% (95%CI: 42%-77%) for those without these genetic lesions. By univariate analysis, age over 60 years, NOTCH2 mutation, and any mutation of the NOTCH pathway (NOTCH2, NOTCH1, SPEN) were associated with shorter overall survival. Mutation of the NOTCH pathway retained an independent significance (P=0.029). In conclusion, a subset of patients with hepatitis C virus-positive diffuse large B-cell lymphoma displays a molecular signature of splenic marginal zone and has a worse clinical outcome., (Copyright© Ferrata Storti Foundation.)
- Published
- 2015
- Full Text
- View/download PDF
31. Bendamustine and subcutaneous alemtuzumab combination is an effective treatment in relapsed/refractory chronic lymphocytic leukemia patients.
- Author
-
Montillo M, Tedeschi A, Gaidano G, Coscia M, Petrizzi VB, Orlandi E, Cascavilla N, Ghia P, Motta M, Gallamini A, Frustaci AM, Rossi D, De Paoli L, Nichelatti M, Morra E, and Massaia M
- Subjects
- Adolescent, Adult, Aged, Alemtuzumab, Bendamustine Hydrochloride, Drug Administration Schedule, Drug Combinations, Female, Humans, Injections, Intravenous, Injections, Subcutaneous, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Recurrence, Survival Analysis, Treatment Outcome, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents, Alkylating therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Nitrogen Mustard Compounds therapeutic use
- Published
- 2014
- Full Text
- View/download PDF
32. MDM2 promotor polymorphism and disease characteristics in chronic lymphocytic leukemia: results of an individual patient data-based meta-analysis.
- Author
-
Benner A, Mansouri L, Rossi D, Majid A, Willander K, Parker A, Bond G, Pavlova S, Nückel H, Merkel O, Ghia P, Montserrat E, Kaderi MA, Rosenquist R, Gaidano G, Dyer MJ, Söderkvist P, Linderholm M, Oscier D, Tvaruzkova Z, Pospisilova S, Dührsen U, Greil R, Döhner H, Stilgenbauer S, and Zenz T
- Subjects
- Adult, Aged, Aged, 80 and over, Cohort Studies, Female, Humans, Male, Middle Aged, Young Adult, Databases, Factual trends, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Polymorphism, Single Nucleotide genetics, Promoter Regions, Genetic genetics, Proto-Oncogene Proteins c-mdm2 genetics
- Abstract
A number of single nucleotide polymorphisms have been associated with disease predisposition in chronic lymphocytic leukemia. A single nucleotide polymorphism in the MDM2 promotor region, MDM2SNP309, was shown to soothe the p53 pathway. In the current study, we aimed to clarify the effect of the MDM2SNP309 on chronic lymphocytic leukemia characteristics and outcome. We performed a meta-analysis of data from 2598 individual patients from 10 different cohorts. Patients' data and genetic analysis for MDM2SNP309 genotype, immunoglobulin heavy chain variable region mutation status and fluorescence in situ hybridization results were collected. There were no differences in overall survival based on the polymorphism (log rank test, stratified by study cohort; P=0.76; GG genotype: cohort-adjusted median overall survival of 151 months; TG: 153 months; TT: 149 months). In a multivariable Cox proportional hazards regression analysis, advanced age, male sex and unmutated immunoglobulin heavy chain variable region genes were associated with inferior survival, but not the MDM2 genotype. The MDM2SNP309 is unlikely to influence disease characteristics and prognosis in chronic lymphocytic leukemia. Studies investigating the impact of individual single nucleotide polymorphisms on prognosis are often controversial. This may be due to selection bias and small sample size. A meta-analysis based on individual patient data provides a reasonable strategy for prognostic factor analyses in the case of small individual studies. Individual patient data-based meta-analysis can, therefore, be a powerful tool to assess genetic risk factors in the absence of large studies., (Copyright© Ferrata Storti Foundation.)
- Published
- 2014
- Full Text
- View/download PDF
33. CD49d expression is an independent risk factor of progressive disease in early stage chronic lymphocytic leukemia.
- Author
-
Rossi D, Zucchetto A, Rossi FM, Capello D, Cerri M, Deambrogi C, Cresta S, Rasi S, De Paoli L, Bodoni CL, Bulian P, Del Poeta G, Ladetto M, Gattei V, and Gaidano G
- Subjects
- Aged, Biomarkers, Tumor blood, Female, Humans, Male, Neoplasm Staging, Risk Factors, Survival Rate, Time Factors, Disease Progression, Integrin alpha4 blood, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell pathology
- Abstract
Identification of prognosticators for Binet A chronic lymphocytic leukemia is important for selecting patients with dismal prognosis. We analyzed CD49d expression in 140 consecutive Binet A chronic lymphocytic leukemia. At diagnosis, CD49d >or=30% (54/140, 38.6%) associated with proliferation markers, namely CD38 >or=30% (p=3.9 x 10(-6)), LDH (p=0.007) and beta2-microglobulin (p=0.020). Univariate log-rank analysis identified CD49d >or=30% as a risk factor of treatment free survival (p=8.3 x 10(-5)), time to progression to a more advanced stage (p=4.7 x 10(-4)), and time to lymphocyte doubling (p=0.009). Multivariate analysis selected CD49d >or=30% as an independent treatment free survival predictor after adjustment for biological (HR 2.28; 95% CI 1.71-4.45, p=0.015) and both biological and clinical variables analyzed together (HR 3.33, 95% CI 1.61-6.90, p=0.001). Within Binet A subgroups harboring favorable biological variables (IGHV homology <98%, favorable karyotype, CD38 <30%, ZAP70 <20%) or clinical variables, CD49d >or=30% consistently identified a subset of patients with short treatment free survival. Our observations indicate CD49d >or=30% as a new marker for the initial prognostic assessment of Binet A chronic lymphocytic leukemia.
- Published
- 2008
- Full Text
- View/download PDF
34. Molecular analysis of immunoglobulin variable genes in human immunodeficiency virus-related non-Hodgkin's lymphoma reveals implications for disease pathogenesis and histogenesis.
- Author
-
Capello D, Martini M, Gloghini A, Cerri M, Rasi S, Deambrogi C, Rossi D, Spina M, Tirelli U, Larocca LM, Carbone A, and Gaidano G
- Subjects
- Bathing Beaches, Burkitt Lymphoma genetics, Burkitt Lymphoma immunology, Burkitt Lymphoma pathology, Gene Amplification, Gene Rearrangement, HIV Infections immunology, HIV Infections pathology, Humans, Lymphoma, Non-Hodgkin pathology, Polymerase Chain Reaction, Receptors, Antigen, B-Cell genetics, Somatic Hypermutation, Immunoglobulin genetics, HIV Infections complications, Immunoglobulin Variable Region genetics, Lymphoma, Non-Hodgkin genetics, Lymphoma, Non-Hodgkin immunology
- Abstract
Background: Human immunodeficiency virus (HIV)-related non-Hodgkin's lymphomas (HIV-NHL) are heterogeneous and associated with distinct molecular pathways. Analysis of immunoglobulin variable genes (IGV) may provide insights into the pathogenesis and histogenesis of HIV-NHL., Design and Methods: IGV rearrangements were amplified from genomic DNA by polymerase chain reaction and directly sequenced in 87 cases of HIV-NHL (17 Burkitt/Burkitt-like lymphomas, 38 diffuse large B-cell lymphomas, and 32 primary central nervous system lymphomas)., Results: A skewed IGHV repertoire in specific HIV-NHL clinico-pathological categories was observed. Systemic HIV-diffuse large B-cell lymphomas displayed underrepresentation of the IGHV3 family (11/38, 28.9%; p=0.0047) and, in particular, of the IGHV3-23 gene (0/38; p<0.001). These same cases were also characterized by significant overrepresentation of the IGHV4 family (18/38; 47.4%; p=0.0044) and, in particular, of the IGHV4-34 gene (10/38; 26.3%; p=0.003). HIV-primary central nervous system lymphomas displayed a preferential usage of IGLV6-57, with stereotyped B-cell receptor in two cases. Somatic hypermutation of IGHV genes was detected in 81/87 (93.1%) HIV-NHL. Unmutated cases were restricted to six HIV-primary central nervous system lymphomas with immunoblastic plasmacytoid morphology. A mutational profile suggesting a tendency to maintain antigen binding and antigen selection was observed in more than 50% of the cases of IGV mutated HIV-NHL., Conclusions: Our data show evidence of a skewed IGHV repertoire in specific HIV-NHL categories and suggest B-cell receptor restriction in some HIV-primary central nervous system lymphomas. The heterogeneous representation of IGHV genes in HIV-NHL may be related to specific pathways of antigen stimulation, or to differences in host's immune dysregulation and lymphoma histogenesis.
- Published
- 2008
- Full Text
- View/download PDF
35. Aberrant somatic hypermutation in transformation of follicular lymphoma and chronic lymphocytic leukemia to diffuse large B-cell lymphoma.
- Author
-
Rossi D, Berra E, Cerri M, Deambrogi C, Barbieri C, Franceschetti S, Lunghi M, Conconi A, Paulli M, Matolcsy A, Pasqualucci L, Capello D, and Gaidano G
- Subjects
- Gene Frequency, Humans, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, Gene Rearrangement, B-Lymphocyte, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Lymphoma, B-Cell genetics, Lymphoma, Follicular genetics, Somatic Hypermutation, Immunoglobulin genetics
- Abstract
The molecular mechanisms involved in histologic transformation of follicular lymphoma (FL) and B-chronic lymphocytic leukemia (B-CLL) to diffuse large B-cell lymphoma (DLBCL) are heterogeneous and largely unknown. Here we explored whether aberrant somatic hypermutation, leading to the acquisition of new mutations in PIM-1, PAX-5, RhoH/TTF and c-MYC genes, is involved in transformation from FL or B-CLL to DLBCL. Eighteen sequential pairs of FL/DLBCL (n=9) and B-CLL/DLBCL (n=9) were investigated. Our findings demonstrate that acquisition of novel mutations due to aberrant somatic hypermutation was associated with DLBCL transformation in 5/9 (55.5%) cases of FL and 2/9 (22.2%) cases of B-CLL.
- Published
- 2006
36. Aberrant promoter methylation of multiple genes throughout the clinico-pathologic spectrum of B-cell neoplasia.
- Author
-
Rossi D, Capello D, Gloghini A, Franceschetti S, Paulli M, Bhatia K, Saglio G, Vitolo U, Pileri SA, Esteller M, Carbone A, and Gaidano G
- Subjects
- Acyltransferases genetics, Aneuploidy, Apoptosis genetics, Apoptosis Regulatory Proteins, Blast Crisis genetics, Calcium-Calmodulin-Dependent Protein Kinases genetics, Caspase 8, Caspases genetics, Cell Cycle genetics, DNA Repair genetics, DNA-Binding Proteins genetics, Death-Associated Protein Kinases, Disease Progression, Follow-Up Studies, Genes, Tumor Suppressor, Humans, Inactivation, Metabolic genetics, Leukemia, B-Cell classification, Leukemia, B-Cell pathology, Lymphoma, B-Cell classification, Lymphoma, B-Cell pathology, Nuclear Proteins genetics, O(6)-Methylguanine-DNA Methyltransferase genetics, Promoter Regions, Genetic genetics, Tumor Protein p73, Tumor Suppressor Proteins, CpG Islands, DNA Methylation, Gene Silencing, Leukemia, B-Cell genetics, Lymphoma, B-Cell genetics
- Abstract
Background and Objectives: Aberrant promoter methylation targets CpG islands causing gene silencing. We explored aberrant promoter methylation of genes potentially involved in B-cell malignancies and encoding proteins implicated in DNA repair (O6-methylguanine-DNA methyltransferase, MGMT), detoxification of environmental xenobiotics (glutathione S-transferase P1, GSTP1), apoptosis regulation (death associated protein kinase, DAP-k and caspase 8, CASP8) and cell cycle control (p73)., Design and Methods: Three hundred and seventeen B-cell malignancies were investigated by methylation-specific polymerase chain reaction (MSP) of MGMT, GSTP1, DAP-k, CASP8 and p73 genes. In selected cases, MSP results were matched to protein expression studies by immunohistochemistry or Western blotting., Results: DAP-k promoter methylation occurred at highest frequency in follicular lymphoma (85.0%) and MALT-lymphoma (72.2%). MGMT methylation targeted both precursor B-cell neoplasia (23.8%) and mature B-cell tumors (27.6%). GSTP1 methylation was commonest in hairy cell leukemia (75.0%), follicular lymphoma (55.5%), Burkitt s lymphoma (52.0%), and MALT lymphoma (50.0%). Methylation of p73 and CASP8 was rare or absent. DAP-k and MGMT methylation caused absent protein expression., Interpretation and Conclusions: Methylation of MGMT, DAP-k and GSTP1 represents a major pathogenetic event in several B-cell malignancies. In follicular lymphoma and MALT lymphoma, frequent inactivation of the apoptosis extrinsic pathway through DAP-k methylation may reinforce the survival advantage already conferred by deregulation of the intrinsic apoptotic pathway. Inactivation of GSTP1 in gastric MALT lymphoma represents an additional mechanism favoring accumulation of reactive oxygen species and lymphomagenesis. Finally, the frequency of GSTP1 aberrant methylation in diffuse large B-cell lymphoma prompts studies aimed at verifying the prognostic impact of this epigenetic lesion in these lymphomas.
- Published
- 2004
37. Messengers of cell death: apoptotic signaling in health and disease.
- Author
-
Rossi D and Gaidano G
- Subjects
- Animals, Apoptosis Regulatory Proteins, Humans, Lymphoma etiology, Lymphoma metabolism, Membrane Glycoproteins metabolism, Membrane Glycoproteins physiology, Proto-Oncogene Proteins c-bcl-2 metabolism, Proto-Oncogene Proteins c-bcl-2 physiology, Receptors, TNF-Related Apoptosis-Inducing Ligand, Receptors, Tumor Necrosis Factor metabolism, Receptors, Tumor Necrosis Factor physiology, TNF-Related Apoptosis-Inducing Ligand, Tumor Necrosis Factor-alpha metabolism, Tumor Necrosis Factor-alpha physiology, fas Receptor metabolism, fas Receptor physiology, Apoptosis, Lymphoma pathology, Signal Transduction
- Abstract
Background and Objectives: Apoptosis is a genetically controlled mechanism of cell death involved in the regulation of tissue homeostasis. Understanding the molecular basis of apoptosis signaling may reveal novel clues for lymphomagenesis., Evidence and Information Sources: Pro-apoptotic signaling is mediated by specific ligands and surface death receptors (extrinsic pathway of apoptosis regulation), which are capable of delivering a death signal from the microenvironment and can activate the execution of apoptosis in the cell cytoplasm and organelles. Death receptors include tumor necrosis factor-receptor 1, Fas, death receptor (DR) 3, DR4, DR5 and DR6, whereas death ligands include tumor necrosis factor-a, lymphotoxin, Fas-Ligand, Apo3-Ligand and TRAIL (TNF-Related Apoptosis-Inducing Ligand). Once activated, death receptors recruit adaptor proteins, which in turn recruit initiator caspases, giving rise to a pro-apoptotic complex termed the death-inducing signaling complex (DISC). Besides being triggered from microenvironmental signals, apoptosis can also be activated from inside the cell through specific cell sensors residing in the cell nucleus and cytoplasm (intrinsic pathway of apoptosis regulation). The intrinsic pathway of apoptosis leads to the formation of a pro-apoptotic complex termed an apoptosome. Both the extrinsic and the intrinsic pathways of apoptosis signaling converge into a common pathway causing the activation of the effector enzymes caspases. Consistent with the role of apoptosis as a main regulator of B-cell homeostasis in the germinal center, the pathogenesis of several germinal-center-derived lymphomas is characterized by deregulation of one or more steps of the apoptosis signaling pathways., Perspectives: Tumor-specific alterations in the apoptotic machinery may represent new potential targets for molecular therapy of lymphoma.
- Published
- 2003
38. Molecular pathophysiology of indolent lymphoma.
- Author
-
Capello D and Gaidano G
- Subjects
- Chromosome Aberrations, DNA, Neoplasm, Humans, Lymphoma etiology, Lymphoma genetics, Lymphoma pathology, Lymphoma physiopathology
- Abstract
Indolent lymphomas are a markedly heterogeneous group of lymphoproliferative disorders including B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mantle cell lymphoma and mucosa-associated lymphoid tissue (MALT) lymphoma. The molecular pathophysiology of indolent lymphoma is characterized by distinct genetic pathways which selectively associate with different clinico-pathologic categories of the disease. At diagnosis, B-cell chronic lymphocytic leukemia frequently display deletions of 13q14, trisomy 12 and alterations of the ATM gene, whereas evolution to Richter's syndrome is associated with disruption of p53. Lymphoplasmacytoid lymphoma carries t(9;14) (p13;q32) in approximately 50% of cases, leading to the deregulated expression of the PAX-5 gene. Follicular lymphoma consistently harbors rearrangement of BCL-2. With time, a fraction of follicular lymphoma accumulates mutations of p53 and of p16 and evolves into a high grade lymphoma. MALT-lymphoma frequently associates with alterations of API2/MLT and, in some cases, of p53, BCL-6 and BCL-10. Studies of genotypic and phenotypic markers of histogenesis have shown that mantle cell lymphoma and a fraction of B-CLL/SLL derive from naive B-cells, whereas follicular lymphoma, lymphoplasmacytoid lymphoma and MALT-lymphoma originate from germinal center (GC) or post-GC B-cells. The identification of distinct genetic categories of indolent lymphoma may help in the therapeutic stratification of these disorders. In addition, genetic lesions of indolent lymphoma provide useful molecular markers for disease monitoring by high sensitivity techniques.
- Published
- 2000
39. Frequent mutation of bcl-6 proto-oncogene in high grade, but not low grade, MALT lymphomas of the gastrointestinal tract.
- Author
-
Gaidano G, Capello D, Gloghini A, Fassone L, Vivenza D, Ariatti C, Migliazza A, Saglio G, and Carbone A
- Subjects
- Gene Frequency, Humans, Mutation, Proto-Oncogene Mas, Proto-Oncogene Proteins c-bcl-6, DNA-Binding Proteins genetics, Gastrointestinal Neoplasms genetics, Gastrointestinal Neoplasms pathology, Lymphoma, B-Cell, Marginal Zone genetics, Lymphoma, B-Cell, Marginal Zone pathology, Proto-Oncogene Proteins genetics, Transcription Factors genetics
- Abstract
Background and Objective: Knowledge regarding the molecular pathogenesis and histogenesis of gastrointestinal mucosa-associated lymphoid tissue non-Hodgkin's lymphomas (MALT-NHL) is limited. Mutations of BCL-6, a zinc finger transcription factor implicated in lymphoid development, occur frequently in lymphomas and represent a histogenetic marker of B-cell transit through the germinal center. The distribution of BCL-6 mutations in gastrointestinal MALT-NHL was analyzed in this study., Design and Methods: This study was based on 26 gastrointestinal MALT-NHL, including 16 cases of low grade histology and 10 cases of high grade histology. Mutations of BCL-6 were investigated by a combination of polymerase chain reaction-single strand conformation polymorphism and DNA direct sequencing analysis., Results: Mutations of BCL-6 occurred in 6/10 high grade MALT-NHL, whereas they were absent from all low grade cases tested (n = 16; p = 0.001). MALT-NHL harboring BCL-6 mutations included 5 cases of gastric MALT-NHL and 1 case of jejunal MALT-NHL. Mutations were predominantly represented by single nucleotide substitutions which were multiple in most cases. All sequence alterations were unique to individual cases of gastrointestinal MALT-NHL., Interpretation and Conclusions: Mutations of BCL-6 occur frequently in high grade gastrointestinal MALT-NHL and display characteristics similar to those of BCL-6 mutations harbored by other B-cell lymphomas. The association of high grade MALT-NHL with BCL-6 mutations corroborates their histogenetic derivation from germinal center-related B-cells and may be of potential pathogenetic relevance for these disorders.
- Published
- 1999
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.