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2. The recombinome of IKZF1 deletions in B-cell precursor ALL

Author

Lopes, Bruno A., Meyer, Claus, Bouzada, Heloysa, Külp, Marius, Maciel, Ana Luiza Tardem, Larghero, Patrizia, Barbosa, Thayana C., Poubel, Caroline P., Barbieri, Caroline, Venn, Nicola C., Pozza, Luciano Dalla, Barbaric, Draga, Palmi, Chiara, Fazio, Grazia, Saitta, Claudia, Aguiar, Thais F., Lins, Mecneide M., Ikoma-Colturato, Maura R. V., Schramm, Marcia, Chapchap, Eduardo, Cazzaniga, Gianni, Sutton, Rosemary, Marschalek, Rolf, and Emerenciano, Mariana

Published
2023
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3. PAX5 fusion genes are frequent in poor risk childhood acute lymphoblastic leukaemia and can be targeted with BIBF1120

Author

Fazio, Grazia, Bresolin, Silvia, Silvestri, Daniela, Quadri, Manuel, Saitta, Claudia, Vendramini, Elena, Buldini, Barbara, Palmi, Chiara, Bardini, Michela, Grioni, Andrea, Rigamonti, Silvia, Galbiati, Marta, Mecca, Stefano, Savino, Angela Maria, Peloso, Alberto, Tu, Jia-Wey, Bhatia, Sanil, Borkhardt, Arndt, Micalizzi, Concetta, Lo Nigro, Luca, Locatelli, Franco, Conter, Valentino, Rizzari, Carmelo, Valsecchi, Maria Grazia, te Kronnie, Geertruij, Biondi, Andrea, and Cazzaniga, Giovanni

Published
2022
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6. Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor Acute Lymphoblastic Leukemia

Author

Palmi, Chiara, primary, Bresolin, Silvia, additional, Junk, Stefanie, additional, Fazio, Grazia, additional, Silvestri, Daniela, additional, Zaliova, Marketa, additional, Oikonomou, Athanasios, additional, Scharov, Katerina, additional, Stanulla, Martin, additional, Moericke, Anja, additional, Zimmermann, Martin, additional, Schrappe, Martin, additional, Buldini, Barbara, additional, Bhatia, Sanil, additional, Borkhardt, Arndt, additional, Saitta, Claudia, additional, Galbiati, Marta, additional, Bardini, Michela, additional, Lo Nigro, Luca, additional, Conter, Valentino, additional, Valsecchi, Maria Grazia, additional, Biondi, Andrea, additional, te Kronnie, Geertruy, additional, Cario, Gunnar, additional, and Cazzaniga, Giovanni, additional

Published
2023
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7. The recombinome of IKZF1 deletions in B-ALL

Author

Lopes, Bruno, primary, Meyer, Claus, additional, Bouzada, Heloysa, additional, Külp, Marius, additional, Maciel, Ana Luiza, additional, Larghero, Patrizia, additional, Barbosa, Thayana, additional, Poubel, Caroline, additional, Blunck, Caroline, additional, Venn, Nicola, additional, Dalla-Pozza, Luciano, additional, Barbaric, Draga, additional, Palmi, Chiara, additional, Fazio, Grazia, additional, Saitta, Claudia, additional, Aguiar, Thais, additional, Lins, Mecneide, additional, Ikoma-Colturato, Maura, additional, Schramm, Marcia, additional, Chapchap, Eduardo, additional, Cazzaniga, Giovanni, additional, Sutton, Rosemary, additional, Marschalek, Rolf, additional, and Emerenciano, Mariana, additional

Published
2023
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9. Ph-like and IKZF1plus Features in Children with Down Syndrome and B Cell Precursor Acute Lymphoblastic Leukemia

Author

Palmi, Chiara, primary, Bresolin, Silvia, additional, Junk, Stefanie V., additional, Fazio, Grazia, additional, Silvestri, Daniela, additional, Zaliova, Marketa, additional, Oikonomou, Athanasios, additional, Scharov, Katerina, additional, Stanulla, Martin, additional, Moericke, Anja, additional, Zimmermann, Martin, additional, Schrappe, Martin, additional, Buldini, Barbara, additional, Saitta, Claudia, additional, Galbiati, Marta, additional, Bardini, Michela, additional, Bhatia, Sanil, additional, Borkhardt, Arndt, additional, Lo Nigro, Luca, additional, Conter, Valentino, additional, Valsecchi, Maria Grazia, additional, Biondi, Andrea, additional, Te Kronnie, Geertruij, additional, Cario, Gunnar, additional, and Cazzaniga, Giovanni, additional

Published
2022
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12. Potential role of STAG1 mutations in genetic predisposition to childhood hematological malignancies

Author

Saitta, C, Rebellato, S, Bettini, L, Giudici, G, Panini, N, Erba, E, Massa, V, Auer, F, Friedrich, U, Hauer, J, Biondi, A, Fazio, G, Cazzaniga, G, Saitta, Claudia, Rebellato, Stefano, Bettini, Laura Rachele, Giudici, Giovanni, Panini, Nicolò, Erba, Eugenio, Massa, Valentina, Auer, Franziska, Friedrich, Ulrike, Hauer, Julia, Biondi, Andrea, Fazio, Grazia, Cazzaniga, Giovanni, Saitta, C, Rebellato, S, Bettini, L, Giudici, G, Panini, N, Erba, E, Massa, V, Auer, F, Friedrich, U, Hauer, J, Biondi, A, Fazio, G, Cazzaniga, G, Saitta, Claudia, Rebellato, Stefano, Bettini, Laura Rachele, Giudici, Giovanni, Panini, Nicolò, Erba, Eugenio, Massa, Valentina, Auer, Franziska, Friedrich, Ulrike, Hauer, Julia, Biondi, Andrea, Fazio, Grazia, and Cazzaniga, Giovanni

Published
2022

13. Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma

Author

Schedel, Anne, Friedrich, Ulrike Anne, Morcos, Mina N.F., Wagener, Rabea, Mehtonen, Juha, Watrin, Titus, Saitta, Claudia, Brozou, Triantafyllia, Michler, Pia, Walter, Carolin, Försti, Asta, Baksi, Arka, Menzel, Maria, Horak, Peter, Paramasivam, Nagarajan, Fazio, Grazia, Autry, Robert J., Fröhling, Stefan, Suttorp, Meinolf, Gertzen, Christoph, Gohlke, Holger, Bhatia, Sanil, Wadt, Karin, Schmiegelow, Kjeld, Dugas, Martin, Richter, Daniela, Glimm, Hanno, Heinäniemi, Merja, Jessberger, Rolf, Cazzaniga, Gianni, Borkhardt, Arndt, Hauer, Julia, Auer, Franziska, Schedel, Anne, Friedrich, Ulrike Anne, Morcos, Mina N.F., Wagener, Rabea, Mehtonen, Juha, Watrin, Titus, Saitta, Claudia, Brozou, Triantafyllia, Michler, Pia, Walter, Carolin, Försti, Asta, Baksi, Arka, Menzel, Maria, Horak, Peter, Paramasivam, Nagarajan, Fazio, Grazia, Autry, Robert J., Fröhling, Stefan, Suttorp, Meinolf, Gertzen, Christoph, Gohlke, Holger, Bhatia, Sanil, Wadt, Karin, Schmiegelow, Kjeld, Dugas, Martin, Richter, Daniela, Glimm, Hanno, Heinäniemi, Merja, Jessberger, Rolf, Cazzaniga, Gianni, Borkhardt, Arndt, Hauer, Julia, and Auer, Franziska

Abstract

Somatic loss of function mutations in cohesin genes are frequently associated with various cancer types, while cohesin disruption in the germline causes cohesinopathies such as Cornelia‐de‐ Lange syndrome (CdLS). Here, we present the discovery of a recurrent heterozygous RAD21 germline aberration at amino acid position 298 (p.P298S/A) identified in three children with lymphoblastic leukemia or lymphoma in a total dataset of 482 pediatric cancer patients. While RAD21 p.P298S/A did not disrupt the formation of the cohesin complex, it altered RAD21 gene expression, DNA damage response and primary patient fibroblasts showed increased G2/M arrest after irradiation and Mitomycin‐C treatment. Subsequent single‐cell RNA‐sequencing analysis of healthy human bone marrow confirmed the upregulation of distinct cohesin gene patterns during hematopoiesis, highlighting the importance of RAD21 expression within proliferating B‐ and T‐cells. Our clinical and functional data therefore suggest that RAD21 germline variants can predispose to childhood lymphoblastic leukemia or lymphoma without displaying a CdLS phenotype.

Published
2022

14. PAX5 fusion genes are frequent in poor risk childhood acute lymphoblastic leukaemia and can be targeted with BIBF1120

Author

Fazio, G, Bresolin, S, Silvestri, D, Quadri, M, Saitta, C, Vendramini, E, Buldini, B, Palmi, C, Bardini, M, Grioni, A, Rigamonti, S, Galbiati, M, Mecca, S, Savino, A, Peloso, A, Tu, J, Bhatia, S, Borkhardt, A, Micalizzi, C, Lo Nigro, L, Locatelli, F, Conter, V, Rizzari, C, Valsecchi, M, Te Kronnie, G, Biondi, A, Cazzaniga, G, Fazio, Grazia, Bresolin, Silvia, Silvestri, Daniela, Quadri, Manuel, Saitta, Claudia, Vendramini, Elena, Buldini, Barbara, Palmi, Chiara, Bardini, Michela, Grioni, Andrea, Rigamonti, Silvia, Galbiati, Marta, Mecca, Stefano, Savino, Angela Maria, Peloso, Alberto, Tu, Jia-Wey, Bhatia, Sanil, Borkhardt, Arndt, Micalizzi, Concetta, Lo Nigro, Luca, Locatelli, Franco, Conter, Valentino, Rizzari, Carmelo, Valsecchi, Maria Grazia, Te Kronnie, Geertruij, Biondi, Andrea, Cazzaniga, Giovanni, Fazio, G, Bresolin, S, Silvestri, D, Quadri, M, Saitta, C, Vendramini, E, Buldini, B, Palmi, C, Bardini, M, Grioni, A, Rigamonti, S, Galbiati, M, Mecca, S, Savino, A, Peloso, A, Tu, J, Bhatia, S, Borkhardt, A, Micalizzi, C, Lo Nigro, L, Locatelli, F, Conter, V, Rizzari, C, Valsecchi, M, Te Kronnie, G, Biondi, A, Cazzaniga, G, Fazio, Grazia, Bresolin, Silvia, Silvestri, Daniela, Quadri, Manuel, Saitta, Claudia, Vendramini, Elena, Buldini, Barbara, Palmi, Chiara, Bardini, Michela, Grioni, Andrea, Rigamonti, Silvia, Galbiati, Marta, Mecca, Stefano, Savino, Angela Maria, Peloso, Alberto, Tu, Jia-Wey, Bhatia, Sanil, Borkhardt, Arndt, Micalizzi, Concetta, Lo Nigro, Luca, Locatelli, Franco, Conter, Valentino, Rizzari, Carmelo, Valsecchi, Maria Grazia, Te Kronnie, Geertruij, Biondi, Andrea, and Cazzaniga, Giovanni

Abstract

Background: Despite intensive risk-based treatment protocols, 15% of paediatric patients with B-Cell Precursor Acute Lymphoblastic Leukaemia (BCP-ALL) experience relapse. There is urgent need of novel strategies to target poor prognosis subgroups, like PAX5 translocated. Methods: We considered 289 childhood BCP-ALL cases consecutively enrolled in Italy in the AIEOP-BFM ALL2000/R2006 protocols and we performed extensive molecular profiling, integrating gene expression, copy number analyses and fusion genes discovery by target-capture NGS. We developed preclinical strategies to target PAX5 fusion genes. Findings: We identified 135 cases without recurrent genetic rearrangements. Among them, 59 patients (43·7%) had a Ph-like signature; the remaining cases were identified as ERG-related (26%), High-Hyperdiploid-like (17%), ETV6::RUNX1-like (8·9%), MEF2D-rearranged (2·2%) or KMT2A-like (1·5%). A poor prognosis was associated with the Ph-like signature, independently from other high-risk features. Interestingly, PAX5 was altered in 54·4% of Ph-like compared to 16·2% of non-Ph-like cases, with 7 patients carrying PAX5 fusions (PAX5t), involving either novel (ALDH18A1, IKZF1, CDH13) or known (FBRSL1, AUTS2, DACH2) partner genes. PAX5t cases have a specific driver activity signature, extending to multiple pathways including LCK hyperactivation. Among FDA-approved drugs and inhibitors, we selected Dasatinib, Bosutinib and Foretinib, in addition to Nintedanib, known to be LCK ligands. We demonstrated the efficacy of the LCK-inhibitor BIBF1120/Nintedanib, as single agent or in combination with conventional chemotherapy, both ex vivo and in patient-derived xenograft model, showing a synergistic effect with dexamethasone. Interpretation: This study provides new insights in high-risk Ph-like leukaemia and identifies a potential therapy for targeting PAX5-fusion poor risk group. Funding: Ricerca Finalizzata-Giovani Ricercatori (Italian Ministry of Health), AIRC, Transcall, Fondazion

Published
2022

15. Predisposition to hematological malignancies in children and adults: from genetic profiling to clonal evolution

Author

CAZZANIGA, GIOVANNI, Saitta, C, SAITTA, CLAUDIA, CAZZANIGA, GIOVANNI, Saitta, C, and SAITTA, CLAUDIA

Abstract

Recenti evidenze hanno dimostrato come la predisposizione rivesta un ruolo cruciale nel 5-10% dei tumori pediatrici. Ciò nonostante, è ancora un ambito nebuloso, che va ulteriormente investigato. Nell’adulto, l’evoluzione clonale agisce in modo simile: l’accumulo di mutazioni somatiche dovuto all’età, aumenta la prevalenza di neoplasie mieloidi tra gli individui più anziani. Come specifici pathway di co-occorrenza predispongano a tumori ematologici, è da indagare in modo più approfondito. In questo studio, ci siamo focalizzati sul ruolo della predisposizione genetica nei tumori ematologici del bambino e dell’adulto, allo scopo di migliorare le conoscenze riguardo alle alterazioni genetiche che agiscono nella fase pre-leucemica. Abbiamo realizzato il nostro studio attraverso diverse tasks, caratterizzate dall’obiettivo comune di scandagliare il ruolo della predisposizione genetica nel promuovere la trasformazione neoplastica. Innanzitutto, abbiamo sequenziato una corte di 120 diagnosi consecutive di pazienti pediatrici affetti da Leucemia Linfoblastica Acuta e casi sporadici con altri tumori ematologici, così come casi con ricorrenza familiare. Il profiling genetico ha confermato il ruolo cruciale di alcuni geni nella Leucemogenesi, come quelli appartenenti al pathway di RAS, sia in termini di incidenza, sia di patogenicità. Inoltre, ha fatto luce sulle mutazioni germinali nelle Coesine: queste alterazioni, solitamente associate a sindromi genetiche denominate Coesinopatie, non sono eventi sporadici, ma si presentano con una frequenza non trascurabile (6%) e degna di ulteriori approfondimenti. Considerando questa evidenza, ci siamo focalizzati sulle varianti germinali dei geni STAG1 e RAD21. I nostri risultati hanno dimostrato che queste alterazioni sono responsabili di una scarsa coesione cromatinica, promuovono quindi instabilità genetica spontanea e sono caratterizzati da meccanismi di riparo al danno del DNA difettivi. Pertanto, geni che non sono classic, Despite genetic predisposition occurs in 5-10 % of pediatric cancer, it is still a nebulous field, that has to be better characterized. In the adult setting, clonal evolution acts similarly, and age-dependent accumulation of somatic mutations increases the prevalence of myeloid neoplasms among older individuals. How the specific co-occurrence of somatic events predisposes to hematological malignancies have to be further clarified. In the present project, we focused our attention in dissecting the role of genetic predisposition in both childhood and adult hematological malignancies, with the purpose of improving knowledge about genetic alterations that act in pre-leukemic phase. We planned and developed our study through several tasks, characterized by the joint purpose of investigating the contribution of genetic predisposition in promote tumor transformation. Firstly, we screened a cohort of 120 consecutive diagnosis of pediatric patients affected by Acute Lymphoblastic Leukemia and sporadic cases with other hematological malignancies, as well as cases with familiar recurrence. Genetic profiling confirmed the crucial role of some genes in Leukemogenesis, like those belonging to Ras pathway, both in term of incidence and pathogenicity. Moreover, it shed light on germline mutations in Cohesins: these alterations, usually associated to genetic syndromes called Cohesinopathies, are not random or sporadic events, but occur with a frequency (6%) that is not negligible and worthy of further study. Considering this evidence, we made a focus on STAG1 and RAD21 germline variants. Our results demonstrated that they lead to a poor chromosomal strength and promote spontaneous instability, resulting in a lowered response to exogenous and endogenous agents, as well as defective DNA repair mechanisms. So, genes that are not classically related to full-blown stage of hematological disease, promote cancer prone conditions in pediatric patients, aggravating the risk of somatic events

Published
2022

16. Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma

Author

Schedel, Anne, primary, Friedrich, Ulrike, additional, Morcos, Mina, additional, Wagener, Rabea, additional, Mehtonen, Juha, additional, Watrin, Titus, additional, Saitta, Claudia, additional, Brozou, Triantafyllia, additional, Michler, Pia, additional, Walter, Carolin, additional, Försti, Asta, additional, Baksi, Arka, additional, Menzel, Maria, additional, Horak, Peter, additional, Paramasivam, Nagarajan, additional, Fazio, Grazia, additional, Autry, Robert, additional, Fröhling, Stefan, additional, Suttorp, Meinolf, additional, Gertzen, Christoph, additional, Gohlke, Holger, additional, Bhatia, Sanil, additional, Wadt, Karin, additional, Schmiegelow, Kjeld, additional, Dugas, Martin, additional, Richter, Daniela, additional, Glimm, Hanno, additional, Heinäniemi, Merja, additional, Jessberger, Rolf, additional, Cazzaniga, Gianni, additional, Borkhardt, Arndt, additional, Hauer, Julia, additional, and Auer, Franziska, additional

Published
2022
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17. Predisposition to hematological malignancies in children and adults: from genetic profiling to clonal evolution

Author

SAITTA, CLAUDIA and Saitta, C

Subjects
Clonal Evolution, Myelodisplasia, MED/15 - MALATTIE DEL SANGUE, Predisposizione, Evoluzione Clonale, Mielodisplasie, Leucemia pediatrica, Pediatric Leukemia, Predisposition, Coesine
Abstract

Recenti evidenze hanno dimostrato come la predisposizione rivesta un ruolo cruciale nel 5-10% dei tumori pediatrici. Ciò nonostante, è ancora un ambito nebuloso, che va ulteriormente investigato. Nell’adulto, l’evoluzione clonale agisce in modo simile: l’accumulo di mutazioni somatiche dovuto all’età, aumenta la prevalenza di neoplasie mieloidi tra gli individui più anziani. Come specifici pathway di co-occorrenza predispongano a tumori ematologici, è da indagare in modo più approfondito. In questo studio, ci siamo focalizzati sul ruolo della predisposizione genetica nei tumori ematologici del bambino e dell’adulto, allo scopo di migliorare le conoscenze riguardo alle alterazioni genetiche che agiscono nella fase pre-leucemica. Abbiamo realizzato il nostro studio attraverso diverse tasks, caratterizzate dall’obiettivo comune di scandagliare il ruolo della predisposizione genetica nel promuovere la trasformazione neoplastica. Innanzitutto, abbiamo sequenziato una corte di 120 diagnosi consecutive di pazienti pediatrici affetti da Leucemia Linfoblastica Acuta e casi sporadici con altri tumori ematologici, così come casi con ricorrenza familiare. Il profiling genetico ha confermato il ruolo cruciale di alcuni geni nella Leucemogenesi, come quelli appartenenti al pathway di RAS, sia in termini di incidenza, sia di patogenicità. Inoltre, ha fatto luce sulle mutazioni germinali nelle Coesine: queste alterazioni, solitamente associate a sindromi genetiche denominate Coesinopatie, non sono eventi sporadici, ma si presentano con una frequenza non trascurabile (6%) e degna di ulteriori approfondimenti. Considerando questa evidenza, ci siamo focalizzati sulle varianti germinali dei geni STAG1 e RAD21. I nostri risultati hanno dimostrato che queste alterazioni sono responsabili di una scarsa coesione cromatinica, promuovono quindi instabilità genetica spontanea e sono caratterizzati da meccanismi di riparo al danno del DNA difettivi. Pertanto, geni che non sono classicamente correlati alla fase conclamata delle neoplasie ematologiche pediatriche promuovono condizioni che predispongono al cancro, aggravando infatti il rischio di eventi somatici responsabili dell’insorgere della neoplasia. Al fine di valutare il contributo della predisposizione genetica considerando tutto l’arco della vita, abbiamo investigato il ruolo dell’Evoluzione Clonale nell’adulto. Nonostante sia considerato un fenomeno fisiologico nell’invecchiamento, è anche significativamente associato a malattie cardiovascolari, tumori solidi e neoplasie ematologiche. Lo screening mutazionale di 1794 individui anziani (oltre 80 anni) ha permesso di stabilire un modello basato su tre gruppi di rischio, in cui l’accumulo differenziale di mutazioni somatiche dipendente dall’età aumenta la prevalenza di neoplasie mieloidi o malattie associate all’infiammazione. Nello specifico, le mutazioni dei geni dello Splicing, di JAK2, o la presenza di mutazioni multiple (DNMT3A, TET2, ASXL1 con lesioni genetiche aggiuntive), nonché le varianti con frequenza allelica ≥ 0,096, hanno un valore predittivo positivo per le neoplasie mieloidi. Infine, abbiamo sottolineato il ruolo delle mutazioni dei geni dello Splicing non solo come eventi precoci nella patogenesi, ma anche in una fase precedente, figure chiave nel determinare l’insorgenza della malattia mielodisplasica. In conclusione, una migliore conoscenza e caratterizzazione di queste alterazioni può avere impatti clinici differenti. In primo luogo, può garantire una migliore comprensione del processo di tumorigenesi, aprendo nuovi scenari in merito al contributo della Predisposizione genetica e dell’Evoluzione Clonale nelle neoplasie ematologiche. Inoltre, può avere conseguenze significative sia nella terapia dei pazienti, sia nella consulenza genetica familiare: consentirebbe quindi strategie di sorveglianza mirate e aggiustamenti terapeutici paziente-specifici. Despite genetic predisposition occurs in 5-10 % of pediatric cancer, it is still a nebulous field, that has to be better characterized. In the adult setting, clonal evolution acts similarly, and age-dependent accumulation of somatic mutations increases the prevalence of myeloid neoplasms among older individuals. How the specific co-occurrence of somatic events predisposes to hematological malignancies have to be further clarified. In the present project, we focused our attention in dissecting the role of genetic predisposition in both childhood and adult hematological malignancies, with the purpose of improving knowledge about genetic alterations that act in pre-leukemic phase. We planned and developed our study through several tasks, characterized by the joint purpose of investigating the contribution of genetic predisposition in promote tumor transformation. Firstly, we screened a cohort of 120 consecutive diagnosis of pediatric patients affected by Acute Lymphoblastic Leukemia and sporadic cases with other hematological malignancies, as well as cases with familiar recurrence. Genetic profiling confirmed the crucial role of some genes in Leukemogenesis, like those belonging to Ras pathway, both in term of incidence and pathogenicity. Moreover, it shed light on germline mutations in Cohesins: these alterations, usually associated to genetic syndromes called Cohesinopathies, are not random or sporadic events, but occur with a frequency (6%) that is not negligible and worthy of further study. Considering this evidence, we made a focus on STAG1 and RAD21 germline variants. Our results demonstrated that they lead to a poor chromosomal strength and promote spontaneous instability, resulting in a lowered response to exogenous and endogenous agents, as well as defective DNA repair mechanisms. So, genes that are not classically related to full-blown stage of hematological disease, promote cancer prone conditions in pediatric patients, aggravating the risk of somatic events that are responsible of the disease’ onset. In order to evaluate the contribution of genetic predisposition in cancer considering overall the time of life, we investigated the role of clonal evolution in the adult setting. Despite it is considered normal in aging, it is also significantly associated with cardiovascular disease, as well as solid tumors and hematological malignancies. The mutational screening of 1794 oldest-old individuals allowed to establish a model based on 3 risk groups, in which differential age-dependent accumulation of somatic mutations increases prevalence of myeloid malignancies or inflammatory-associated diseases. Specifically, mutations in Splicing genes, JAK2 or the presence of multiple mutations (DNMT3A, TET2, ASXL1 with additional genetic lesions), as well as variants with allele frequency ≥0.096, have a positive predictive value for myeloid neoplasms. Finally, we underlined the role of Splicing genes mutations not only as early events in pathogenesis, but also in a previous phase, as key players in determine the onset of myelodysplastic disease. Overall, a better knowledge and characterization of these alterations will have different impacts: it will improve the understanding of tumorigenesis, opening new scenarios regarding the contribution of genetic predisposition and clonal evolution to hematological malignancies. Moreover, it could have significative effects on both patients’ care and familial genetic counseling, enabling targeted surveillance strategies, and tailored therapeutical adjustments that include familiar screening in case of familiar donor in hematopoietic stem cell transplantation.

Published
2022

18. The recombinome of IKZF1deletions in B-cell precursor ALL

Author

Lopes, Bruno A., Meyer, Claus, Bouzada, Heloysa, Külp, Marius, Maciel, Ana Luiza Tardem, Larghero, Patrizia, Barbosa, Thayana C., Poubel, Caroline P., Barbieri, Caroline, Venn, Nicola C., Pozza, Luciano Dalla, Barbaric, Draga, Palmi, Chiara, Fazio, Grazia, Saitta, Claudia, Aguiar, Thais F., Lins, Mecneide M., Ikoma-Colturato, Maura R. V., Schramm, Marcia, Chapchap, Eduardo, Cazzaniga, Gianni, Sutton, Rosemary, Marschalek, Rolf, and Emerenciano, Mariana

Published
2023
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19. 3159 – PH-LIKE AND IKZF1PLUS FEATURES IN CHILDREN WITH DOWN SYNDROME ACUTE LYMPHOBLASTIC LEUKAEMIA

Author

Palmi, Chiara, primary, Bresolin, Silvia, additional, Junk, Stefanie, additional, Fazio, Grazia, additional, Silvestri, Daniela, additional, Zaliova, Marketa, additional, Stanulla, Martin, additional, Moericke, Anja, additional, Zimmermann, Martin, additional, Schrappe, Martin, additional, Buldini, Barbara, additional, Saitta, Claudia, additional, Galbiati, Marta, additional, Bardini, Michela, additional, Nigro, Luca Lo, additional, Conter, Valentino, additional, Valsecchi, Maria Grazia, additional, Biondi, Andrea, additional, Kronnie, Geertruy Te, additional, Cario, Gunnar, additional, and Cazzaniga, Giovanni, additional

Published
2022
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20. PAX5 Fusion Genes are Frequent in Poor Risk Childhood Acute Lymphoblastic Leukaemia and Can Be Targeted with BIBF1120

Author

Fazio, Grazia, primary, Bresolin, Silvia, additional, Silvestri, Daniela, additional, Quadri, Manuel, additional, Saitta, Claudia, additional, Vendramini, Elena, additional, Buldini, Barbara, additional, Palmi, Chiara, additional, Bardini, Michela, additional, Grioni, Andrea, additional, Rigamonti, Silvia, additional, Galbiati, Marta, additional, Mecca, Stefano, additional, Savino, Angela Maria, additional, Peloso, Alberto, additional, Micalizzi, Concetta, additional, Lo Nigro, Luca, additional, Locatelli, Franco, additional, Conter, Valentino, additional, Rizzari, Carmelo, additional, Valsecchi, Maria Grazia, additional, te Kronnie, Geertruij, additional, Biondi, Andrea, additional, and Cazzaniga, Giovanni, additional

Published
2022
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21. Clinical relevance of clonal hematopoiesis in persons aged ≥80 years

Author

Rossi, Marianna, primary, Meggendorfer, Manja, additional, Zampini, Matteo, additional, Tettamanti, Mauro, additional, Riva, Emma, additional, Travaglino, Erica, additional, Bersanelli, Matteo, additional, Mandelli, Sara, additional, Antonella Galbussera, Alessia, additional, Mosca, Ettore, additional, Saba, Elena, additional, Chiereghin, Chiara, additional, Manes, Nicla, additional, Milanesi, Chiara, additional, Ubezio, Marta, additional, Morabito, Lucio, additional, Peano, Clelia, additional, Soldà, Giulia, additional, Asselta, Rosanna, additional, Duga, Stefano, additional, Selmi, Carlo, additional, De Santis, Maria, additional, Malik, Karolina, additional, Maggioni, Giulia, additional, Bicchieri, Marilena, additional, Campagna, Alessia, additional, Tentori, Cristina A., additional, Russo, Antonio, additional, Civilini, Efrem, additional, Allavena, Paola, additional, Piazza, Rocco, additional, Corrao, Giovanni, additional, Sala, Claudia, additional, Termanini, Alberto, additional, Giordano, Laura, additional, Detoma, Paolo, additional, Malabaila, Aurelio, additional, Sala, Luca, additional, Rosso, Stefano, additional, Zanetti, Roberto, additional, Saitta, Claudia, additional, Riva, Elena, additional, Condorelli, Gianluigi, additional, Passamonti, Francesco, additional, Santoro, Armando, additional, Sole, Francesc, additional, Platzbecker, Uwe, additional, Fenaux, Pierre, additional, Bolli, Niccolò, additional, Castellani, Gastone, additional, Kern, Wolfgang, additional, Vassiliou, George S., additional, Haferlach, Torsten, additional, Lucca, Ugo, additional, and Della Porta, Matteo G., additional

Published
2021
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23. Recurrent Germline Variant in the Cohesin Complex Gene RAD21 Predisposes Children to Lymphoblastic Leukemia and Lymphoma

Author

Schedel, Anne, primary, Friedrich, Ulrike Anne, additional, Wagener, Rabea, additional, Mehtonen, Juha, additional, Saitta, Claudia, additional, Brozou, Triantafyllia, additional, Michler, Pia, additional, Walter, Carolin, additional, Horak, Peter, additional, Paramasivam, Nagarajan, additional, Fazio, Grazia, additional, Fröhling, Stefan, additional, Dugas, Martin, additional, Richter, Daniela, additional, Glimm, Hanno, additional, Heinäniemi, Merja, additional, Jessberger, Rolf, additional, Cazzaniga, Giovanni, additional, Borkhardt, Arndt, additional, Hauer, Julia, additional, and Auer, Franziska, additional

Published
2021
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26. Clinical relevance of clonal hematopoiesis in persons aged ≥80 years

Author

Rossi, M, Meggendorfer, M, Zampini, M, Tettamanti, M, Riva, E, Travaglino, E, Bersanelli, M, Mandelli, S, Galbussera, A, Mosca, E, Saba, E, Chiereghin, C, Manes, N, Milanesi, C, Ubezio, M, Morabito, L, Peano, C, Soldà, G, Asselta, R, Duga, S, Selmi, C, De Santis, M, Malik, K, Maggioni, G, Bicchieri, M, Campagna, A, Tentori, C, Russo, A, Civilini, E, Allavena, P, Piazza, R, Corrao, G, Sala, C, Termanini, A, Giordano, L, Detoma, P, Malabaila, A, Sala, L, Rosso, S, Zanetti, R, Saitta, C, Condorelli, G, Passamonti, F, Santoro, A, Sole, F, Platzbecker, U, Fenaux, P, Bolli, N, Castellani, G, Kern, W, Vassiliou, G, Haferlach, T, Lucca, U, Della Porta, M, Rossi, Marianna, Meggendorfer, Manja, Zampini, Matteo, Tettamanti, Mauro, Riva, Emma, Travaglino, Erica, Bersanelli, Matteo, Mandelli, Sara, Galbussera, Alessia Antonella, Mosca, Ettore, Saba, Elena, Chiereghin, Chiara, Manes, Nicla, Milanesi, Chiara, Ubezio, Marta, Morabito, Lucio, Peano, Clelia, Soldà, Giulia, Asselta, Rosanna, Duga, Stefano, Selmi, Carlo, De Santis, Maria, Malik, Karolina, Maggioni, Giulia, Bicchieri, Maria Elena, Campagna, Alessia, Tentori, Cristina Astrid, Russo, Antonio, Civilini, Efrem, Allavena, Paola, Piazza, Rocco, Corrao, Giovanni, Sala, Claudia, Termanini, Alberto, Giordano, Laura, Detoma, Paolo, Malabaila, Aurelio, Sala, Luca, Rosso, Stefano, Zanetti, Roberto, Saitta, Claudia, Riva, Elena, Condorelli, Gianluigi, Passamonti, Francesco, Santoro, Armando, Sole, Francesc, Platzbecker, Uwe, Fenaux, Pierre, Bolli, Niccolo, Castellani, Gastone, Kern, Wolfgang, Vassiliou, George, Haferlach, Torsten, Lucca, Ugo, Della Porta, Matteo G, Rossi, M, Meggendorfer, M, Zampini, M, Tettamanti, M, Riva, E, Travaglino, E, Bersanelli, M, Mandelli, S, Galbussera, A, Mosca, E, Saba, E, Chiereghin, C, Manes, N, Milanesi, C, Ubezio, M, Morabito, L, Peano, C, Soldà, G, Asselta, R, Duga, S, Selmi, C, De Santis, M, Malik, K, Maggioni, G, Bicchieri, M, Campagna, A, Tentori, C, Russo, A, Civilini, E, Allavena, P, Piazza, R, Corrao, G, Sala, C, Termanini, A, Giordano, L, Detoma, P, Malabaila, A, Sala, L, Rosso, S, Zanetti, R, Saitta, C, Condorelli, G, Passamonti, F, Santoro, A, Sole, F, Platzbecker, U, Fenaux, P, Bolli, N, Castellani, G, Kern, W, Vassiliou, G, Haferlach, T, Lucca, U, Della Porta, M, Rossi, Marianna, Meggendorfer, Manja, Zampini, Matteo, Tettamanti, Mauro, Riva, Emma, Travaglino, Erica, Bersanelli, Matteo, Mandelli, Sara, Galbussera, Alessia Antonella, Mosca, Ettore, Saba, Elena, Chiereghin, Chiara, Manes, Nicla, Milanesi, Chiara, Ubezio, Marta, Morabito, Lucio, Peano, Clelia, Soldà, Giulia, Asselta, Rosanna, Duga, Stefano, Selmi, Carlo, De Santis, Maria, Malik, Karolina, Maggioni, Giulia, Bicchieri, Maria Elena, Campagna, Alessia, Tentori, Cristina Astrid, Russo, Antonio, Civilini, Efrem, Allavena, Paola, Piazza, Rocco, Corrao, Giovanni, Sala, Claudia, Termanini, Alberto, Giordano, Laura, Detoma, Paolo, Malabaila, Aurelio, Sala, Luca, Rosso, Stefano, Zanetti, Roberto, Saitta, Claudia, Riva, Elena, Condorelli, Gianluigi, Passamonti, Francesco, Santoro, Armando, Sole, Francesc, Platzbecker, Uwe, Fenaux, Pierre, Bolli, Niccolo, Castellani, Gastone, Kern, Wolfgang, Vassiliou, George, Haferlach, Torsten, Lucca, Ugo, and Della Porta, Matteo G

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged ≥80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged ≥80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged ≥80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged ≥80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged ≥80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged ≥80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.

Published
2021

27. Classification and Personalized Prognostic Assessment on the Basis of Clinical and Genomic Features in Myelodysplastic Syndromes

Author

Bersanelli, Matteo, primary, Travaglino, Erica, additional, Meggendorfer, Manja, additional, Matteuzzi, Tommaso, additional, Sala, Claudia, additional, Mosca, Ettore, additional, Chiereghin, Chiara, additional, Di Nanni, Noemi, additional, Gnocchi, Matteo, additional, Zampini, Matteo, additional, Rossi, Marianna, additional, Maggioni, Giulia, additional, Termanini, Alberto, additional, Angelucci, Emanuele, additional, Bernardi, Massimo, additional, Borin, Lorenza, additional, Bruno, Benedetto, additional, Bonifazi, Francesca, additional, Santini, Valeria, additional, Bacigalupo, Andrea, additional, Voso, Maria Teresa, additional, Oliva, Esther, additional, Riva, Marta, additional, Ubezio, Marta, additional, Morabito, Lucio, additional, Campagna, Alessia, additional, Saitta, Claudia, additional, Savevski, Victor, additional, Giampieri, Enrico, additional, Remondini, Daniel, additional, Passamonti, Francesco, additional, Ciceri, Fabio, additional, Bolli, Niccolò, additional, Rambaldi, Alessandro, additional, Kern, Wolfgang, additional, Kordasti, Shahram, additional, Sole, Francesc, additional, Palomo, Laura, additional, Sanz, Guillermo, additional, Santoro, Armando, additional, Platzbecker, Uwe, additional, Fenaux, Pierre, additional, Milanesi, Luciano, additional, Haferlach, Torsten, additional, Castellani, Gastone, additional, and Della Porta, Matteo G., additional

Published
2021
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28. Incidence and Therapeutic Implications of Germline TP53 Mutations in Hypodiploid Childhood Acute Lymphoblastic Leukemia: A Retrospective Analysis of the Italian Cohort

Author

Bettini, Laura Rachele, primary, Saitta, Claudia, additional, Buldini, Barbara, additional, Te Kronnie, Geertruij, additional, Rebellato, Stefano, additional, Silvestri, Daniela, additional, Barisone, Elena, additional, Pession, Andrea, additional, Rabusin, Marco, additional, Micalizzi, Concetta, additional, Locatelli, Franco, additional, Rizzari, Carmelo, additional, Valsecchi, Maria Grazia, additional, Biondi, Andrea, additional, Fazio, Grazia, additional, and Cazzaniga, Giovanni, additional

Published
2020
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29. Dysregulation of NIPBL leads to impaired RUNX1 expression and haematopoietic defects

Author

Mazzola, Mara, primary, Pezzotta, Alex, additional, Fazio, Grazia, additional, Rigamonti, Alessandra, additional, Bresciani, Erica, additional, Gaudenzi, Germano, additional, Pelleri, Maria Chiara, additional, Saitta, Claudia, additional, Ferrari, Luca, additional, Parma, Matteo, additional, Fumagalli, Monica, additional, Biondi, Andrea, additional, Cazzaniga, Giovanni, additional, Marozzi, Anna, additional, and Pistocchi, Anna, additional

Published
2020
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30. Clinical Relevance of Clonal Hematopoiesis in the Oldest-Old Population

Author

Rossi, Marianna, primary, Meggendorfer, Manja, additional, Zampini, Matteo, additional, Tettamanti, Mauro, additional, Riva, Emma, additional, Travaglino, Erica, additional, Mandelli, Sara, additional, Galbussera, Alessia Antonella, additional, Saba, Elena, additional, Manes, Nicla, additional, Milanesi, Chiara, additional, Ubezio, Marta, additional, Morabito, Lucio, additional, Chiereghin, Chiara, additional, Peano, Clelia, additional, Solda, Giulia, additional, Asselta, Rosanna, additional, Duga, Stefano, additional, Selmi, Carlo, additional, De Santis, Maria, additional, Malik, Karolina, additional, Maggioni, Giulia, additional, Bicchieri, Marilena, additional, Campagna, Alessia, additional, Civilini, Efrem, additional, Allavena, Paola, additional, Piazza, Rocco, additional, Bersanelli, Matteo, additional, Mosca, Ettore, additional, Corrao, Giovanni, additional, Castellani, Gastone C., additional, Sala, Claudia, additional, Termanini, Alberto, additional, Giordano, Laura, additional, Detoma, Paolo, additional, Malabaila, Aurelio, additional, Sala, Luca, additional, Rosso, Stefano, additional, Zanetti, Roberto, additional, Saitta, Claudia, additional, Condorelli, Gianluigi, additional, Passamonti, Francesco, additional, Santoro, Armando, additional, Sole, Francesc, additional, Platzbecker, Uwe, additional, Fenaux, Pierre, additional, Bolli, Niccolo, additional, Kern, Wolfgang, additional, Vassiliou, George S., additional, Haferlach, Torsten, additional, Lucca, Ugo, additional, and Della Porta, Matteo, additional

Published
2020
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31. NIPBL: a new player in myeloid cells differentiation

Author

Mazzola, M, Deflorian, G, Pezzotta, A, Ferrari, L, Fazio, G, Bresciani, E, Saitta, C, Fumagalli, M, Parma, M, Marasca, F, Bodega, B, Riva, P, Cotelli, F, Biondi, A, Marozzi, A, Cazzaniga, G, Pistocchi, A, Mazzola, Mara, Deflorian, Gianluca, Pezzotta, Alex, Ferrari, Laura, Fazio, Grazia, Bresciani, Erica, SAITTA, CLAUDIA, Ferrari, Luca, Fumagalli, Monica, Parma, Matteo, Marasca, Federica, Bodega, Beatrice, Riva, Paola, Cotelli, Franco, Biondi, Andrea, Marozzi, Anna, Cazzaniga, Gianni, Pistocchi, Anna, Mazzola, M, Deflorian, G, Pezzotta, A, Ferrari, L, Fazio, G, Bresciani, E, Saitta, C, Fumagalli, M, Parma, M, Marasca, F, Bodega, B, Riva, P, Cotelli, F, Biondi, A, Marozzi, A, Cazzaniga, G, Pistocchi, A, Mazzola, Mara, Deflorian, Gianluca, Pezzotta, Alex, Ferrari, Laura, Fazio, Grazia, Bresciani, Erica, SAITTA, CLAUDIA, Ferrari, Luca, Fumagalli, Monica, Parma, Matteo, Marasca, Federica, Bodega, Beatrice, Riva, Paola, Cotelli, Franco, Biondi, Andrea, Marozzi, Anna, Cazzaniga, Gianni, and Pistocchi, Anna

Abstract

NUCLEOPHOSMIN1 (NPM1) is the most frequently mutated gene in acute myeloid leukemia. Notably, NPM1 mutations are always accompanied by additional mutations such as those in cohesin genes RAD21, SMC1A, SMC3, STAG2 but not in the cohesin regulator NIPBL. In this work, we analyze a cohort of adult patients with acute myeloid leukemia and NPM1 mutation and we observe specific reduction in the expression of NIPBL but not in other cohesin genes. In our zebrafish model, the overexpression of the mutated form of NPM1 also induced the down-regulation of nipblb, the zebrafish orthologue of the human NIPBL. To investigate the hematopoietic phenotype and the interaction between mutated NPM1 and nipblb, we generate a zebrafish model with nipblb down-regulation that shows an increased number of myeloid progenitors. This phenotype is due to a hyper activation of the canonical Wnt pathway: the rescue of myeloid cells blocked in an undifferentiated state is possible when the Wnt pathway is inhibited by ddk1b mRNA injection or indomethacin administration. Our results reveal for the first time a role for NIPBL during zebrafish hematopoiesis and suggest that NIPBL/NPM1 interplay may regulate myeloid differentiation in zebrafish and humans through the canonical Wnt pathway and that dysregulation of these interactions may drive to leukemic transformations

Published
2019

32. A simple RNA target capture NGS strategy for fusion genes assessment in the diagnostics of pediatric B-cell acute lymphoblastic leukemia

Author

Grioni, A, Fazio, G, Rigamonti, S, Bystry, V, Daniele, G, Dostalova, Z, Quadri, M, Saitta, C, Silvestri, D, Songia, S, Storlazzi, C, Biondi, A, Darzentas, N, Cazzaniga, G, Grioni, Andrea, Fazio, Grazia, Rigamonti, Silvia, Bystry, Vojtech, Daniele, Giulia, Dostalova, Zuzana, Quadri, Manuel, Saitta, Claudia, Silvestri, Daniela, Songia, Simona, Storlazzi, Clelia T., Biondi, Andrea, Darzentas, Nikos, Cazzaniga, Giovanni, Grioni, A, Fazio, G, Rigamonti, S, Bystry, V, Daniele, G, Dostalova, Z, Quadri, M, Saitta, C, Silvestri, D, Songia, S, Storlazzi, C, Biondi, A, Darzentas, N, Cazzaniga, G, Grioni, Andrea, Fazio, Grazia, Rigamonti, Silvia, Bystry, Vojtech, Daniele, Giulia, Dostalova, Zuzana, Quadri, Manuel, Saitta, Claudia, Silvestri, Daniela, Songia, Simona, Storlazzi, Clelia T., Biondi, Andrea, Darzentas, Nikos, and Cazzaniga, Giovanni

Abstract

Acute lymphoblastic leukemia (ALL) is the most frequent pediatric cancer. Fusion genes are hallmarks of ALL, and they are used as biomarkers for risk stratification as well as targets for precision medicine. Hence, clinical diagnostics pursues broad and comprehensive strategies for accurate discovery of fusion genes. Currently, the gold standard methodologies for fusion gene detection are fluorescence in situ hybridization and polymerase chain reaction; these, however, lack sensitivity for the identification of new fusion genes and breakpoints. In this study, we implemented a simple operating procedure (OP) for detecting fusion genes. The OP employs RNA CaptureSeq, a versatile and effortless next-generation sequencing assay, and an in-house as well as a purpose-built bioinformatics pipeline for the subsequent data analysis. The OP was evaluated on a cohort of 89 B-cell precursor ALL (BCP-ALL) pediatric samples annotated as negative for fusion genes by the standard techniques. The OP confirmed 51 samples as negative for fusion genes, and, more importantly, it identified known (KMT2A rearrangements) as well as new fusion events (JAK2 rearrangements) in the remaining 38 investigated samples, of which 16 fusion genes had prognostic significance. Herein, we describe the OP and its deployment into routine ALL diagnostics, which will allow substantial improvements in both patient risk stratification and precision medicine.

Published
2019

33. First evidence of a paediatric patient with Cornelia de Lange syndrome with acute lymphoblastic leukaemia

Author

Fazio, G, Massa, V, Grioni, A, Bystry, V, Rigamonti, S, Saitta, C, Galbiati, M, Rizzari, C, Consarino, C, Biondi, A, Selicorni, A, Cazzaniga, G, Fazio, Grazia, Massa, Valentina, GRIONI, ANDREA, Bystry, Vojtech, Rigamonti, Silvia, Saitta, Claudia, Galbiati, Marta, Rizzari, Carmelo, Consarino, Caterina, Biondi, Andrea, Selicorni, Angelo, Cazzaniga, Giovanni, Fazio, G, Massa, V, Grioni, A, Bystry, V, Rigamonti, S, Saitta, C, Galbiati, M, Rizzari, C, Consarino, C, Biondi, A, Selicorni, A, Cazzaniga, G, Fazio, Grazia, Massa, Valentina, GRIONI, ANDREA, Bystry, Vojtech, Rigamonti, Silvia, Saitta, Claudia, Galbiati, Marta, Rizzari, Carmelo, Consarino, Caterina, Biondi, Andrea, Selicorni, Angelo, and Cazzaniga, Giovanni

Abstract

Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant genetic disorder characterised by prenatal and postnatal growth and mental retardation, facial dysmorphism and upper limb abnormalities. Germline mutations of cohesin complex genes SMC1A, SMC3, RAD21 or their regulators NIPBL and HDAC8 have been identified in CdLS as well as somatic mutations in myeloid disorders. We describe the first case of a paediatric patient with CdLS with B-cell precursor Acute Lymphoblastic Leukaemia (ALL). The patient did not show any unusual cytogenetic abnormality, and he was enrolled into the high risk arm of AIEOP-BFM ALL2009 protocol because of slow early response, but 3 years after discontinuation, he experienced an ALL relapse. We identified a heterozygous mutation in exon 46 of NIPBL, causing frameshift and a premature stop codon (RNA-Targeted Next generation Sequencing Analysis). The analysis of the family indicated a de novo origin of this previously not reported deleterious variant. As for somatic cohesin mutations in acute myeloid leukaemia, also this ALL case was not affected by aneuploidy, thus suggesting a major impact of the non-canonical role of NIPBL in gene regulation. A potential biological role of NIPBL in leukaemia has still to be dissected.

Published
2019

34. Pre-Clinical Efficacy of the Novel Kinase Inhibitor Nintedanib on PAX5 Fusion Genes in Pediatric Ph-like B-Cell Precursor Acute Lymphoblastic Leukemia

Author

Fazio, Grazia, primary, Bresolin, Silvia, primary, Saitta, Claudia, primary, Silvestri, Daniela, primary, Vendramini, Elena, primary, Palmi, Chiara, primary, Rigamonti, Silvia, primary, Galbiati, Marta, primary, Quadri, Manuel, primary, Mecca, Stefano, primary, Savino, Angela Maria, primary, Bardini, Michela, primary, Grioni, Andrea, primary, Valsecchi, Maria Grazia, primary, te Kronnie, Geertruy, primary, Biondi, Andrea, primary, and Cazzaniga, Giovanni, primary

Published
2019
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35. A Simple RNA Target Capture NGS Strategy for Fusion Genes Assessment in the Diagnostics of Pediatric B-cell Acute Lymphoblastic Leukemia

Author

Grioni, Andrea, primary, Fazio, Grazia, additional, Rigamonti, Silvia, additional, Bystry, Vojtech, additional, Daniele, Giulia, additional, Dostalova, Zuzana, additional, Quadri, Manuel, additional, Saitta, Claudia, additional, Silvestri, Daniela, additional, Songia, Simona, additional, Storlazzi, Clelia T., additional, Biondi, Andrea, additional, Darzentas, Nikos, additional, and Cazzaniga, Giovanni, additional

Published
2019
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36. First evidence of a paediatric patient with Cornelia de Lange syndrome with acute lymphoblastic leukaemia

Author

Fazio, Grazia, primary, Massa, Valentina, additional, Grioni, Andrea, additional, Bystry, Vojtech, additional, Rigamonti, Silvia, additional, Saitta, Claudia, additional, Galbiati, Marta, additional, Rizzari, Carmelo, additional, Consarino, Caterina, additional, Biondi, Andrea, additional, Selicorni, Angelo, additional, and Cazzaniga, Giovanni, additional

Published
2019
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37. NIPBL: a new player in myeloid cell differentiation

Author

Mazzola, Mara, primary, Deflorian, Gianluca, additional, Pezzotta, Alex, additional, Ferrari, Laura, additional, Fazio, Grazia, additional, Bresciani, Erica, additional, Saitta, Claudia, additional, Ferrari, Luca, additional, Fumagalli, Monica, additional, Parma, Matteo, additional, Marasca, Federica, additional, Bodega, Beatrice, additional, Riva, Paola, additional, Cotelli, Franco, additional, Biondi, Andrea, additional, Marozzi, Anna, additional, Cazzaniga, Gianni, additional, and Pistocchi, Anna, additional

Published
2019
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38. P337: IKZF1 DELETIONS IN B‐ALL: FROM ITS GENETIC BASIS TO DIAGNOSTIC ENHANCEMENT.

Author

Lopes, Bruno A., Meyer, Claus, Bouzada, Heloysa, Külp, Marius, Luiza Tardem Maciel, Ana, Larghero, Patrizia, Da Conceição Barbosa, Thayana, Poubel, Caroline P., Barbieri, Caroline, Venn, Nicola C., Dalla‐Pozza, Luciano, Barbaric, Draga, Palmi, Chiara, Fazio, Grazia, Saitta, Claudia, Ferraz Aguiar, Thais, Lins, Mecneide M., Ikoma, Maura R. V., Schramm, Marcia, and Chapchap, Eduardo

Published
2023
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39. Somatic and Germline Cohesin Genes Alterations in Pediatric Acute Lymphoblastic Leukemia

Author

Rebellato, Stefano, Saitta, Claudia, Bettini, Laura Rachele, Silvestri, Daniela, Spinelli, Orietta, Pastorczak, Agata, Brandes, Danielle, Fischer, Ute, Borkhardt, Arndt, Strehl, Sabine, Lo Nigro, Luca, Buldini, Barbara, Hauer, Julia, Auer, Franziska, Kester, Lennart, Kuiper, Roland P., Vinti, Luciana, Locatelli, Franco, Biondi, Andrea, Fazio, Grazia, and Cazzaniga, Giovanni

Abstract

Leukemia is a complex disease and the molecular mechanisms of malignant transformation are not fully understood yet. Cohesins are essential proteins, forming a complex which plays critical roles in various cellular processes, not only by canonical DNA binding and chromosome segregation but also in non-canonical regulation of gene expression in both proliferating and post-mitotic cells.

Published
2023
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41. Ph-likeand IKZF1plusFeatures in Children with Down Syndrome and B Cell Precursor Acute Lymphoblastic Leukemia

Author

Palmi, Chiara, Bresolin, Silvia, Junk, Stefanie V., Fazio, Grazia, Silvestri, Daniela, Zaliova, Marketa, Oikonomou, Athanasios, Scharov, Katerina, Stanulla, Martin, Moericke, Anja, Zimmermann, Martin, Schrappe, Martin, Buldini, Barbara, Saitta, Claudia, Galbiati, Marta, Bardini, Michela, Bhatia, Sanil, Borkhardt, Arndt, Lo Nigro, Luca, Conter, Valentino, Valsecchi, Maria Grazia, Biondi, Andrea, Te Kronnie, Geertruij, Cario, Gunnar, and Cazzaniga, Giovanni

Published
2022
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42. Incidence and Therapeutic Implications of Germline TP53Mutations in Hypodiploid Childhood Acute Lymphoblastic Leukemia: A Retrospective Analysis of the Italian Cohort

Author

Bettini, Laura Rachele, Saitta, Claudia, Buldini, Barbara, Te Kronnie, Geertruij, Rebellato, Stefano, Silvestri, Daniela, Barisone, Elena, Pession, Andrea, Rabusin, Marco, Micalizzi, Concetta, Locatelli, Franco, Rizzari, Carmelo, Valsecchi, Maria Grazia, Biondi, Andrea, Fazio, Grazia, and Cazzaniga, Giovanni

Abstract

Background. Hypodiploid Acute Lymphoblastic Leukemia (ALL) is a rare subtype of childhood ALL known to be associated with a poor prognosis. Currently, intensive chemotherapy and haematopoietic stem cell transplantation are recommended as the main therapeutic strategy for these patients. Previous studies showed that low-hypodiploid ALL frequently carry TP53variants, the majority of which are germline mutations. This finding suggests that hypodiploid ALL may be a manifestation of underlying Li-Fraumeni syndrome, with an associated high risk for secondary tumors.

Published
2020
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43. Recurrent Germline Variant in the Cohesin Complex Gene RAD21Predisposes Children to Lymphoblastic Leukemia and Lymphoma

Author

Schedel, Anne, Friedrich, Ulrike Anne, Wagener, Rabea, Mehtonen, Juha, Saitta, Claudia, Brozou, Triantafyllia, Michler, Pia, Walter, Carolin, Horak, Peter, Paramasivam, Nagarajan, Fazio, Grazia, Fröhling, Stefan, Dugas, Martin, Richter, Daniela, Glimm, Hanno, Heinäniemi, Merja, Jessberger, Rolf, Cazzaniga, Giovanni, Borkhardt, Arndt, Hauer, Julia, and Auer, Franziska

Abstract

Introduction:Cohesin complex genes are commonly mutated in cancer particularly in myeloid malignancies. Yet patients with germline mutations in cohesin genes, leading to cohesinopathies like Cornelia-de-Lange syndrome (CdLS) are generally not known to be tumor-prone. The complex plays a major role in chromosome alignment and segregation (Uhlmann, Nature Reviews Molecular Cell Biology, 2016),homologous recombination-driven DNA repair (Ström et al., Molecular Cell, 2004) and regulation of gene expression (Busslinger et al., Nature, 2017). To deepen the understanding of cohesin variants in cancer predisposition, we performed TRIO Sequencing in two independent pediatric cancer cohorts. Thereby, we identified a novel recurrent heterozygous germline variant in the cohesin gene RAD21not described in CdLS patients ,located in the binding domain of the cofactors WAPL and PDS5B .

Published
2021
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44. Potential Role of STAG1Mutations in Genetic Predisposition to Childhood Hemato-Oncological Diseases

Author

Saitta, Claudia, Rebellato, Stefano, Bettini, Laura Rachele, Giudici, Giovanni, Panini, Nicolò, Erba, Eugenio, Songia, Simona, Massa, Valentina, Biondi, Andrea, Fazio, Grazia, and Cazzaniga, Giovanni

Abstract

Background.Genetic predisposition has been recently assessed in about 5-10% of pediatric tumors, including leukemias. Among genetic syndromes associated with an increased risk of developing leukemia, a possible link has been proposed for Cohesinopathies, like Cornelia de Lange Syndrome (CdLS), caused by mutations in Cohesin family genes. Somatic mutation in these genes, known for their fundamental role in cell cycle and DNA repair mechanisms, are described in myeloid malignancies (10-20% of AML, 50% of DS-AMKL, 5-15% of MDS and 10% of MPN) and solid tumours. We previously described the first germline variant of NIPBL in a CdL case with acute lymphoblastic leukemia (ALL). The identification of germline variants can provide new insights in the pathogenesis of hemato-oncological diseases.

Published
2021
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45. Targeting JAK2Gene Rearrangements with a Novel Kinase Inhibitor in a Preclinical Model of Pediatric Acute Lymphoblastic Leukemia

Author

Quadri, Manuel, Saitta, Claudia, Palamini, Sonia, Palmi, Chiara, Biondi, Andrea, Cazzaniga, Giovanni, and Fazio, Grazia

Abstract

Background.Although the Event Free Survival for Childhood Acute lymphoblastic leukemia (ALL) reaches 85%, the remaining 15% of patients relapse, and 25-40% of them die. Novel molecular targets may increase the efficacy of therapy and reduce treatment toxicity. Among B-other ALL patients, JAK/STAT pathway alterations represent about 7% of the ‘Philadelphia-like’ cases. JAK2gene encodes for a non-receptor tyrosine kinase fundamental for hematopoiesis, cellular proliferation and survival. In last years, JAK2 mutations have been widely studied in leukemia and lymphoma, whereas JAK2 fusion genes are still poorly characterized.

Published
2021
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46. Clinical relevance of clonal hematopoiesis in the oldest-old population

Author

Rossi, Marianna, Meggendorfer, Manja, Zampini, Matteo, Tettamanti, Mauro, Riva, Emma, Travaglino, Erica, Bersanelli, Matteo, Mandelli, Sara, Galbussera, Alessia Antonella, Mosca, Ettore, Saba, Elena, Chiereghin, Chiara, Manes, Nicla, Milanesi, Chiara, Ubezio, Marta, Morabito, Lucio, Peano, Clelia, Soldà, Giulia, Asselta, Rosanna, Duga, Stefano, Selmi, Carlo, De Santis, Maria, Malik, Karolina, Maggioni, Giulia, Bicchieri, Marilena, Campagna, Alessia, Tentori, Cristina A, Russo, Antonio, Civilini, Efrem, Allavena, Paola, Piazza, Rocco, Corrao, Giovanni, Sala, Claudia, Termanini, Alberto, Giordano, Laura, Detoma, Paolo, Malabaila, Aurelio, Sala, Luca, Rosso, Stefano, Zanetti, Roberto, Saitta, Claudia, Riva, Elena, Condorelli, Gianluigi, Passamonti, Francesco, Santoro, Armando, Sole, Francesc, Platzbecker, Uwe, Fenaux, Pierre, Bolli, Niccolo', Castellani, Gastone, Kern, Wolfgang, Vassiliou, George S, Haferlach, Torsten, Lucca, Ugo, and Porta, Matteo G Della

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes very common in oldest-old individuals, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 oldest-old individuals enrolled in two population-based studies and investigate the relationships between CHIP and associated pathologies. Clonal mutations were observed in one third of oldest-old individuals and were associated with reduced survival. Mutations in JAK2and splicing genes, multiple mutations (DNMT3A, TET2, ASXL1with additional genetic lesions) and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1or JAK2(most occurring as single lesion) were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was a common finding in oldest-old population, the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly-specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of oldest-old subjects with cytopenia had presumptive evidence of myeloid neoplasm. In conclusion, specific mutational patterns define different risk of developing myeloid neoplasms vs.inflammatory-associated diseases in oldest-old population. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.

Published
2021
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47. Pre-Clinical Efficacy of the Novel Kinase Inhibitor Nintedanib on PAX5Fusion Genes in Pediatric Ph-likeB-Cell Precursor Acute Lymphoblastic Leukemia

Author

Fazio, Grazia, Bresolin, Silvia, Saitta, Claudia, Silvestri, Daniela, Vendramini, Elena, Palmi, Chiara, Rigamonti, Silvia, Galbiati, Marta, Quadri, Manuel, Mecca, Stefano, Savino, Angela Maria, Bardini, Michela, Grioni, Andrea, Valsecchi, Maria Grazia, te Kronnie, Geertruy, Biondi, Andrea, and Cazzaniga, Giovanni

Abstract

Despite the current risk-based stratification protocol, 15% of pediatric patients with B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) still experience relapse. In the large subset of ‘B-other’ patients (negative for common fusion transcripts, non-high hyperdiploid and non-Down Syndrome), ‘Ph-like’ is a high risk subgroup with high incidence of relapses, which represents 30% of B-others or 10-15% of BCP-ALL patients. The PAX5gene, encoding for a B-cell related transcription factor, is frequently involved in several translocations in Ph-like patients, determining the formation of fusion genes encoding for aberrant proteins. Our previous studies showed that PAX5fusions sustain survival of leukemic cells by Lymphocyte kinase (LCK) hyperactivation, which can be targeted by the kinase inhibitor Nintedanib/BIBF1120.

Published
2019
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48. Classification and Personalized Prognostic Assessment on the Basis of Clinical and Genomic Features in Myelodysplastic Syndromes

Author

Andrea Bacigalupo, Pierre Fenaux, Alberto Termanini, Marianna Rossi, Lucio Morabito, Niccolo Bolli, Massimo Bernardi, Victor Savevski, Manja Meggendorfer, Daniel Remondini, Tommaso Matteuzzi, Torsten Haferlach, Luciano Milanesi, Matteo G. Della Porta, Ettore Mosca, Gastone Castellani, Valeria Santini, Alessandro Rambaldi, Giulia Maggioni, Guillermo Sanz, Claudia Sala, Wolfgang Kern, Marta Ubezio, Matteo Zampini, Emanuele Angelucci, Armando Santoro, Laura Palomo, Noemi Di Nanni, Lorenza Borin, Erica Travaglino, Alessia Campagna, Maria Teresa Voso, Francesc Solé, Francesca Bonifazi, Shahram Kordasti, Uwe Platzbecker, Matteo Bersanelli, Matteo Gnocchi, Esther Oliva, Marta Riva, Benedetto Bruno, Fabio Ciceri, Francesco Passamonti, Claudia Saitta, Enrico Giampieri, Chiara Chiereghin, Bersanelli, Matteo, Travaglino, Erica, Meggendorfer, Manja, Matteuzzi, Tommaso, Sala, Claudia, Mosca, Ettore, Chiereghin, Chiara, Di Nanni, Noemi, Gnocchi, Matteo, Zampini, Matteo, Rossi, Marianna, Maggioni, Giulia, Termanini, Alberto, Angelucci, Emanuele, Bernardi, Massimo, Borin, Lorenza, Bruno, Benedetto, Bonifazi, Francesca, Santini, Valeria, Bacigalupo, Andrea, Voso, Maria Teresa, Oliva, Esther, Riva, Marta, Ubezio, Marta, Morabito, Lucio, Campagna, Alessia, Saitta, Claudia, Savevski, Victor, Giampieri, Enrico, Remondini, Daniel, Passamonti, Francesco, Ciceri, Fabio, Bolli, Niccolò, Rambaldi, Alessandro, Kern, Wolfgang, Kordasti, Shahram, Sole, Francesc, Palomo, Laura, Sanz, Guillermo, Santoro, Armando, Platzbecker, Uwe, Fenaux, Pierre, Milanesi, Luciano, Haferlach, Torsten, Castellani, Gastone, and Della Porta, Matteo G

Subjects
Male, Cancer Research, SCORING SYSTEM, MODELS, disease classification, MEDLINE, ACUTE MYELOID-LEUKEMIA, Computational biology, 03 medical and health sciences, 0302 clinical medicine, Text mining, hemic and lymphatic diseases, MDS, medicine, CRITERIA, Humans, NGS, somatic mutations, myelodysplastic syndromes, prognosis, 030304 developmental biology, Retrospective Studies, 0303 health sciences, GENETIC LESIONS, business.industry, Myelodysplastic syndromes, Disease classification, Retrospective cohort study, SOMATIC MUTATIONS, Genomics, MDS, Artificial Intekkìlligence, machine learning, Settore MED/15, medicine.disease, Prognosis, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Myelodysplastic Syndromes, Female, prognostication, business
Abstract

PURPOSE Recurrently mutated genes and chromosomal abnormalities have been identified in myelodysplastic syndromes (MDS). We aim to integrate these genomic features into disease classification and prognostication. METHODS We retrospectively enrolled 2,043 patients. Using Bayesian networks and Dirichlet processes, we combined mutations in 47 genes with cytogenetic abnormalities to identify genetic associations and subgroups. Random-effects Cox proportional hazards multistate modeling was used for developing prognostic models. An independent validation on 318 cases was performed. RESULTS We identify eight MDS groups (clusters) according to specific genomic features. In five groups, dominant genomic features include splicing gene mutations ( SF3B1, SRSF2, and U2AF1) that occur early in disease history, determine specific phenotypes, and drive disease evolution. These groups display different prognosis (groups with SF3B1 mutations being associated with better survival). Specific co-mutation patterns account for clinical heterogeneity within SF3B1- and SRSF2-related MDS. MDS with complex karyotype and/or TP53 gene abnormalities and MDS with acute leukemia–like mutations show poorest prognosis. MDS with 5q deletion are clustered into two distinct groups according to the number of mutated genes and/or presence of TP53 mutations. By integrating 63 clinical and genomic variables, we define a novel prognostic model that generates personally tailored predictions of survival. The predicted and observed outcomes correlate well in internal cross-validation and in an independent external cohort. This model substantially improves predictive accuracy of currently available prognostic tools. We have created a Web portal that allows outcome predictions to be generated for user-defined constellations of genomic and clinical features. CONCLUSION Genomic landscape in MDS reveals distinct subgroups associated with specific clinical features and discrete patterns of evolution, providing a proof of concept for next-generation disease classification and prognosis.

Published
2021
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