Grazia Fazio
@fondazionetettamanti.it
Tettamanti Research Center
Fondazione M. Tettamanti
24
Scopus Publications
Scopus Publications
- Bone Marrow CD8 + Abundance Inversely Correlates with Progressive Marrow Fibrosis and Myelodysplastic Evolution in GATA2 Deficiency: Case Report
Francesca Vendemini, Samuele Roncareggi, Vincenzo L’Imperio, Fabiola Guerra, Federica Mottadelli, Marco Chiarini, Oscar Maglia, Simona Sala, Grazia Fazio, Rocco Piazza,et al.
Springer Science and Business Media LLC - Biallelic PI4KA Mutations Disrupt B-Cell Metabolism and Cause B-Cell Lymphopenia and Hypogammaglobulinemia
Francesco Saettini, Fabiola Guerra, Mario Mauri, Claire G. Salter, Margaret P. Adam, David Adams, Emma L. Baple, Estibaliz Barredo, Sanil Bhatia, Arndt Borkhardt,et al.
Springer Science and Business Media LLC - PAX5::AUTS2 childhood B-ALL: a relapse-prone genetic subtype with frequent central nervous system involvement and a poor outcome: ACUTE LYMPHOBLASTIC LEUKEMIA
Aurélie Caye-Eude, Grazia Fazio, Agata Pastorczak, Judith M. Boer, Doris Steinemann, Debdutta Ganguli, Edwin Sonneveld, Sabrina Haslinger, Lucía D’Andrea, Jutta Bradtke,et al.
Springer Science and Business Media LLC - Cohesins: Crossroad Between Cornelia de Lange Spectrum and Cancer Predisposition
Laura Rigotti, Stefano Rebellato, Antonella Lettieri, Silvia Castiglioni, Milena Mariani, Simona Totaro, Claudia Saitta, Cristina Gervasini, Grazia Fazio, Valentina Massa,et al.
Wiley
ABSTRACTThe cohesin complex plays crucial roles in DNA repair, chromatid separation, and gene transcription regulation. Pathogenic variants in cohesins or dysfunctional transcriptional regulators lead to cohesinopathies, a broader group of disorders including Cornelia de Lange Spectrum (CdLSp), for which the prevalence of cancer cases remains unclear. Here, we aimed to assess the prevalence of oncological events in CdLSp and elucidate the role of cohesin variants in cancer predisposition. We developed a custom next‐generation sequencing (NGS) panel targeting predisposition and pathogenic genes, which we applied on N = 120 samples of pediatric patients with acute lymphoblastic leukemia (ALL), identifying 11 out of 229 total—10 germline and 1 somatic—variants in cohesin genes. Data of N = 205 brain tumors were extracted by bioinformatic analysis of data from open‐source databases carrying 19 somatic variants. In a cohort of 54 CdLSp patients, the largest cohort from a single center, with a median age of 13 years, the hypothesis of an increased prevalence of cancer in CdLSp was not confirmed. Our findings highlight a significant involvement of germline NIPBL variants in CdLSp, whereas RAD21 and STAG1/2 are predominantly found as somatic variants in neoplasms. However, a distinct genetic or molecular pattern distinguishing variants leading to CdLSp from tumors was not identified. Hence, we advocate for further investigation into the relationship between cohesin variants and cancer predisposition in a larger cohort of patients, with a longer observation time and including different types of malignancies, with more focus on epigenetic approaches. - Diverse mechanisms of leukemogenesis associated with PAX5 germline mutation
Laura Rachele Bettini, Grazia Fazio, Claudia Saitta, Rocco Piazza, Sonia Palamini, Chiara Buracchi, Stefano Rebellato, Nicola Santoro, Cristiano Simone, Andrea Biondi,et al.
Springer Science and Business Media LLC - Prenatal origin of NUTM1 gene rearrangement in infant B-cell precursor acute lymphoblastic leukaemia
Michela Bardini, Grazia Fazio, Lilia Corral Abascal, Claus Meyer, Oscar Maglia, Simona Sala, Sonia Palamini, Stefano Rebellato, Rolf Marschalek, Carmelo Rizzari,et al.
Wiley
SummaryRearrangement of NUTM1 gene (NUTM1r) is one of the most frequent aberrations occurring in infants (younger than 1 year at diagnosis) with B‐cell precursor Acute Lymphoblastic Leukaemia (BCP‐ALL). In this study we had the unique opportunity to analyze the umbilical cord blood (UCB) sample from one infant patient with NUTM1r BCP‐ALL. Herein we reported for the first time that NUTM1r infant ALL arise prenatally, as both the patient‐specific CUX1::NUTM1 fusion gene, as well as two IG/TR leukaemic markers were already present and detectable in the patient's UCB at birth. Our results clearly demonstrate the prenatal origin of NUTM1r infant BCP‐ALL. - Extracellular vesicles from II trimester human amniotic fluid as paracrine conveyors counteracting oxidative stress
Giorgia Senesi, Laura Guerricchio, Maddalena Ghelardoni, Nadia Bertola, Stefano Rebellato, Nicole Grinovero, Martina Bartolucci, Ambra Costa, Andrea Raimondi, Cristina Grange,et al.
Elsevier BV - Synergistic drug interactions of the histone deacetylase inhibitor givinostat (ITF2357) in CRLF2-rearranged pediatric B-cell precursor acute lymphoblastic leukemia identified by high-throughput drug screening
Athanasios Oikonomou, Titus Watrin, Luigia Valsecchi, Katerina Scharov, Angela Maria Savino, Julian Schliehe-Diecks, Michela Bardini, Grazia Fazio, Silvia Bresolin, Andrea Biondi,et al.
Elsevier BV - Characterization of a novel HDAC2 pathogenetic variant: a missing puzzle piece for chromatinopathies
Elisabetta Di Fede, Antonella Lettieri, Esi Taci, Silvia Castiglioni, Stefano Rebellato, Chiara Parodi, Elisa Adele Colombo, Paolo Grazioli, Federica Natacci, Paola Marchisio,et al.
Springer Science and Business Media LLC
AbstractHistone deacetylases (HDACs) are enzymes pivotal for histone modification (i.e. acetylation marks removal), chromatin accessibility and gene expression regulation. Class I HDACs (including HDAC1, 2, 3, 8) are ubiquitously expressed and they often participate in multi-molecular protein complexes. To date, three neurodevelopmental disorders caused by mutations in genes encoding for HDACs (HDAC4, HDAC6 and HDAC8) and thus belonging to the group of chromatinopathies, have been described. We performed whole exome sequencing (WES) for a patient (#249) clinically diagnosed with the chromatinopathy Rubinstein-Taybi syndrome (RSTS) but negative for mutations in RSTS genes, identifying a de novo frameshift variant in HDAC2 gene. We then investigated its molecular effects in lymphoblastoid cell lines (LCLs) derived from the patient compared to LCLs from healthy donors (HD). As the variant was predicted to be likely pathogenetic and to affect the sequence of nuclear localization signal, we performed immunocytochemistry and lysates fractionation, observing a nuclear mis-localization of HDAC2 compared to HD LCLs. In addition, HDAC2 total protein abundance resulted altered in patient, and we found that newly identified variant in HDAC2 affects also acetylation levels, with significant difference in acetylation pattern among patient #249, HD and RSTS cells and in expression of a known molecular target. Remarkably, RNA-seq performed on #249, HD and RSTS cells shows differentially expressed genes (DEGs) common to #249 and RSTS. Interestingly, our reported patient was clinically diagnosed with RSTS, a chromatinopathy which known causative genes encode for enzymes antagonizing HDACs. These results support the role of HDAC2 as causative gene for chromatinopathies, strengthening the genotype-phenotype correlations in this relevant group of disorders. - Case report: An intriguing case of Philadelphia chromosome–positive acute lymphoblastic leukemia recurrence
Nicolò Peccatori, Elena Chiocca, Valentino Conter, Annalisa Tondo, Matilde Marzorati, Tommaso Casini, Marinella Veltroni, Andrea Biondi, and Grazia Fazio
Frontiers Media SA
The incorporation of tyrosine kinase inhibitors (TKIs) in the treatment of Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) led to significant improvement. However, in the pediatric setting, the outcomes of Ph+ ALL are still inferior compared to those of other ALL subtypes even in the TKI era due to higher relapse rate. Herein, we report a very peculiar case of late extramedullary Ph+ ALL relapse in a child, characterized by lymphomatous presentation in the tonsils and lymphoid lineage switch. The diagnostic dilemma between the occurrence of a second malignant neoplasm and the recurrence of the primary disease is further discussed, highlighting the importance of molecular backtracking analysis. This case report emphasizes the high plasticity and polyclonal nature of ALL and expands the heterogeneity of possible clinical presentation of Ph+ ALL at relapse. - Modeling skeletal dysplasia in Hurler syndrome using patient-derived bone marrow osteoprogenitor cells
Samantha Donsante, Alice Pievani, Biagio Palmisano, Melissa Finamore, Grazia Fazio, Alessandro Corsi, Andrea Biondi, Shunji Tomatsu, Rocco Piazza, Marta Serafini,et al.
American Society for Clinical Investigation
Dysostosis multiplex is a major cause of morbidity in Hurler syndrome (mucopolysaccharidosis type IH [MPS IH], OMIM #607014) because currently available therapies have limited success in its prevention and reversion. Unfortunately, the elucidation of skeletal pathogenesis in MPS IH is limited by difficulties in obtaining bone specimens from pediatric patients and poor reproducibility in animal models. Thus, the application of experimental systems that can be used to dissect cellular and molecular mechanisms underlying the skeletal phenotype of MPS IH patients and to identify effective therapies is highly needed. Here, we adopted in vitro/in vivo systems based on patient-derived bone marrow stromal cells to generate cartilaginous pellets and bone rudiments. Interestingly, we observed that heparan sulphate accumulation compromised the remodeling of MPS IH cartilage into other skeletal tissues and other critical aspects of the endochondral ossification process. We also noticed that MPS IH hypertrophic cartilage was characterized by dysregulation of signaling pathways controlling cartilage hypertrophy and fate, extracellular matrix organization, and glycosaminoglycan metabolism. Our study demonstrates that the cartilaginous pellet–based system is a valuable tool to study MPS IH dysostosis and to develop new therapeutic approaches for this hard-to-treat aspect of the disease. Finally, our approach may be applied for modeling other genetic skeletal disorders. - Correction to: Antibody Deficiency in Patients with Biallelic KARS1 Mutations (Journal of Clinical Immunology, (2023), 43, 8, (2115-2125), 10.1007/s10875-023-01584-7)
Francesco Saettini, Fabiola Guerra, Grazia Fazio, Cristina Bugarin, Hugh J. McMillan, Akira Ohtake, Anna Ardissone, Masayuki Itoh, Sabrina Giglio, Gerarda Cappuccio,et al.
Springer Science and Business Media LLC - Antibody Deficiency in Patients with Biallelic KARS1 Mutations
Francesco Saettini, Fabiola Guerra, Grazia Fazio, Cristina Bugarin, Hugh J McMillan, Akira Ohtake, Anna Ardissone, Masayuki Itoh, Sabrina Giglio, Gerarda Cappuccio,et al.
Springer Science and Business Media LLC - High-throughput screening as a drug repurposing strategy for poor outcome subgroups of pediatric B-cell precursor Acute Lymphoblastic Leukemia
Athanasios Oikonomou, Luigia Valsecchi, Manuel Quadri, Titus Watrin, Katerina Scharov, Simona Procopio, Jia-Wey Tu, Melina Vogt, Angela Maria Savino, Daniela Silvestri,et al.
Elsevier BV - miR-126 identifies a quiescent and chemo-resistant human B-ALL cell subset that correlates with minimal residual disease
Carolina Caserta, Silvia Nucera, Matteo Barcella, Grazia Fazio, Matteo Maria Naldini, Riccardo Pagani, Francesca Pavesi, Giacomo Desantis, Erika Zonari, Mariella D’Angiò,et al.
Springer Science and Business Media LLC - The recombinome of IKZF1 deletions in B-cell precursor ALL
Bruno A. Lopes, Claus Meyer, Heloysa Bouzada, Marius Külp, Ana Luiza Tardem Maciel, Patrizia Larghero, Thayana C. Barbosa, Caroline P. Poubel, Caroline Barbieri, Nicola C. Venn,et al.
Springer Science and Business Media LLC - Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor Acute Lymphoblastic Leukemia
Chiara Palmi, Silvia Bresolin, Stefanie Junk, Grazia Fazio, Daniela Silvestri, Marketa Zaliova, Athanasios Oikonomou, Katerina Scharov, Martin Stanulla, Anja Moericke,et al.
Wiley
Children with Down syndrome have an augmented risk for B-cell acute lymphoblastic leukemia (DS-ALL), which is associated with lower survival than in non-DS-ALL. It is known that cytogenetic abnormalities common in childhood ALL are less frequent in DS-ALL, while other genetic aberrancies (ie, CRLF2 overexpression and IKZF1 deletions) are increased. A possible cause for the lower survival of DS-ALL that we herewith evaluated for the first time was the incidence and prognostic value of the Philadelphia-like (Ph-like) profile and the IKZF1plus pattern. These features have been associated with poor outcome in non-DS ALL and therefore introduced in current therapeutic protocols. Forty-six out of 70 DS-ALL patients treated in Italy from 2000 to 2014 displayed Ph-like signature, mostly characterized by CRLF2 (n = 33) and IKZF1 (n = 16) alterations; only 2 cases were positive for ABL-class or PAX5-fusion genes. Moreover, in an Italian and German joint cohort of 134 DS-ALL patients, we observed 18% patients positive for IKZF1plus feature. Ph-like signature and IKZF1 deletion were associated with poor outcome (cumulative incidence of relapse: 27.7 ± 6.8% versus 13 ± 7%; P = 0.04 and 35.2 ± 8.6% versus 17 ± 3.9%; P = 0.007, respectively), which further worsens when IKZF1 deletion was co-occurring with P2RY8::CRLF2, qualifying for the IKZF1plus definition (13/15 patients had an event of relapse or treatment-related death). Notably, ex vivo drug screening revealed sensitivity of IKZF1plus blasts for drugs active against Ph-like ALL such as Birinapant and histone deacetylase inhibitors. We provided data in a large setting of a rare condition (DS-ALL) supporting that these patients, not associated with other high-risk features, need tailored therapeutic strategies. - The chemerin/CMKLR1 axis regulates intestinal graft-versus-host disease
Erica Dander, Paola Vinci, Stefania Vetrano, Camilla Recordati, Rocco Piazza, Grazia Fazio, Donatella Bardelli, Mattia Bugatti, Francesca Sozio, Andrea Piontini,et al.
American Society for Clinical Investigation
Gastrointestinal graft-versus-host disease (GvHD) is a major cause of mortality and morbidity following allogeneic bone marrow transplantation (allo-BMT). Chemerin is a chemotactic protein that recruits leukocytes to inflamed tissues by interacting with ChemR23/CMKLR1, a chemotactic receptor expressed by leukocytes, including macrophages. During acute GvHD, chemerin plasma levels were strongly increased in allo-BM-transplanted mice. The role of the chemerin/CMKLR1 axis in GvHD was investigated using Cmklr1-KO mice. WT mice transplanted with an allogeneic graft from Cmklr1-KO donors (t-KO) had worse survival and more severe GvHD. Histological analysis demonstrated that the gastrointestinal tract was the organ mostly affected by GvHD in t-KO mice. The severe colitis of t-KO mice was characterized by massive neutrophil infiltration and tissue damage associated with bacterial translocation and exacerbated inflammation. Similarly, Cmklr1-KO recipient mice showed increased intestinal pathology in both allogeneic transplant and dextran sulfate sodium–induced colitis. Notably, the adoptive transfer of WT monocytes into t-KO mice mitigated GvHD manifestations by decreasing gut inflammation and T cell activation. In patients, higher chemerin serum levels were predictive of GvHD development. Overall, these results suggest that CMKLR1/chemerin may be a protective pathway for the control of intestinal inflammation and tissue damage in GvHD. - Circulating cell-free DNA for target quantification in hematologic malignancies: Validation of a protocol to overcome pre-analytical biases
Roberta Soscia, Irene Della Starza, Lucia Anna De Novi, Caterina Ilari, Michela Ansuinelli, Marzia Cavalli, Vittorio Bellomarino, Luciana Cafforio, Mariangela Di Trani, Giovanni Cazzaniga,et al.
Wiley
AbstractCirculating tumor DNA (ctDNA) has become the most investigated analyte in blood. It is shed from the tumor into the circulation and represents a subset of the total cell‐free DNA (cfDNA) pool released into the peripheral blood. In order to define if ctDNA could represent a useful tool to monitor hematologic malignancies, we analyzed 81 plasma samples from patients affected by different diseases. The results showed that: (i) the comparison between two different extraction methods Qiagen (Hilden, Germany) and Promega (Madison, WI) showed no significant differences in cfDNA yield, though the first recovered higher amounts of larger DNA fragments; (ii) cfDNA concentrations showed a notable inter‐patient variability and differed among diseases: acute lymphoblastic leukemia and chronic myeloid leukemia released higher amounts of cfDNA than chronic lymphocytic leukemia, and diffuse large B‐cell lymphoma released higher cfDNA quantities than localized and advanced follicular lymphoma; (iii) focusing on the tumor fraction of cfDNA, the quantity of ctDNA released was insufficient for an adequate target quantification for minimal residual disease monitoring; (iv) an amplification system proved to be free of analytical biases and efficient in increasing ctDNA amounts at diagnosis and in follow‐up samples as shown by droplet digital PCR target quantification. The protocol has been validated by quality control rounds involving external laboratories. To conclusively document the feasibility of a ctDNA‐based monitoring of patients with hematologic malignancies, more post‐treatment samples need to be evaluated. This will open new possibilities for ctDNA use in the clinical practice. - PAX5 fusion genes are frequent in poor risk childhood acute lymphoblastic leukaemia and can be targeted with BIBF1120
Grazia Fazio, Silvia Bresolin, Daniela Silvestri, Manuel Quadri, Claudia Saitta, Elena Vendramini, Barbara Buldini, Chiara Palmi, Michela Bardini, Andrea Grioni,et al.
Elsevier BV - HDAC6 inhibition decreases leukemic stem cell expansion driven by Hedgehog hyperactivation by restoring primary ciliogenesis
Alex Pezzotta, Ilaria Gentile, Donatella Genovese, Maria Grazia Totaro, Cristina Battaglia, Anskar Yu-Hung Leung, Monica Fumagalli, Matteo Parma, Gianni Cazzaniga, Grazia Fazio,et al.
Elsevier BV - Conjoined Genes as Common Events in Childhood Acute Lymphoblastic Leukemia
Marco Severgnini, Mariella D’Angiò, Silvia Bungaro, Giovanni Cazzaniga, Ingrid Cifola, and Grazia Fazio
MDPI AG
Acute lymphoblastic leukemia (ALL) is the most frequent childhood cancer. For the last three decades, conventional cytogenetic and molecular approaches allowed the identification of genetic abnormalities having prognostic and therapeutic relevance. Although the current cure rate in pediatric B cell acute leukemia is approximately 90%, it remains one of the leading causes of mortality in childhood. Furthermore, in the contemporary protocols, chemotherapy intensity was raised to the maximal levels of tolerability, and further improvements in the outcome will depend on the characterization and reclassification of the disease, as well as on the development of new targeted drugs. The recent technological advances in genome-wide profiling techniques have allowed the exploration of the molecular heterogeneity of this disease, even though some potentially interesting biomarkers such as conjoined genes have not been deeply investigated yet. In the present study, we performed the transcriptome sequencing (RNA-seq) of 10 pediatric B cell precursor (BCP)-ALL cases with different risk (four standard- and six high-risk patients) enrolled in the Italian AIEOP-BFM ALL2000 protocol, in order to characterize the full spectrum of transcriptional events and to identify novel potential genetic mechanisms sustaining their different early response to therapy. Total RNA was extracted from primary leukemic blasts and RNA-seq was performed by Illumina technology. Bioinformatics analysis focused on fusion transcripts, originated from either inter- or intra-chromosomal structural rearrangements. Starting from a raw list of 9001 candidate events, by employing a custom-made bioinformatics pipeline, we obtained a short list of 245 candidate fusions. Among them, 10 events were compatible with chromosomal translocations. Strikingly, 235/245 events were intra-chromosomal fusions, 229 of which involved two contiguous or overlapping genes, resulting in the so-called conjoined genes (CGs). To explore the specificity of these events in leukemia, we performed an extensive bioinformatics meta-analysis and evaluated the presence of the fusions identified in our 10 BCP-ALL cohort in several other publicly available RNA-seq datasets, including leukemic, solid tumor and normal sample collections. Overall, 14/229 (6.1%) CGs were found to be exclusively expressed in leukemic cases, suggesting an association between CGs and leukemia. Moreover, CGs were found to be common events both in standard- and high-risk BCP-ALL patients and it might be suggestive of a novel potential transcriptional regulation mechanism active in leukemic cells. - Identical EP300 variant leading to Rubinstein–Taybi syndrome with different clinical and immunologic phenotype
Francesco Saettini, Grazia Fazio, Maria Teresa Bonati, Daniele Moratto, Valentina Massa, Elisabetta Di Fede, Silvia Castiglioni, Daniela Marchetti, Marco Chiarini, Alessandra Sottini,et al.
Wiley
AbstractThe Rubinstein–Taybi syndrome (RSTS) is a rare developmental disorder characterized by craniofacial dysmorphisms, broad thumbs and toes, intellectual disability, growth deficiency, and recurrent infections. Mutations in the cyclic adenosine monophosphate response element‐binding protein (CREB)‐binding protein (CREBBP) or in the E1A‐associated protein p300 (EP300) genes have been demonstrated in 55% (RSTS1) and up to 8% of the patients (RSTS2), respectively. Dysfunction of immune response has been reported in a subgroup of individuals with RSTS. Here we characterize two patients carrying the same EP300 variant and distinctive RSTS features (including congenital heart abnormalities, short stature, feeding problems, and gastroesophageal reflux). Whole exome sequencing did not support a dual molecular diagnosis hypothesis. Nonetheless, patients showed distinct clinical manifestations and immunological features. The most severe phenotype was associated with reduced T‐cell production and diversity. This latter feature was confirmed in a control group of four RSTS patients. - Potential role of STAG1 mutations in genetic predisposition to childhood hematological malignancies
Claudia Saitta, Stefano Rebellato, Laura Rachele Bettini, Giovanni Giudici, Nicolò Panini, Eugenio Erba, Valentina Massa, Franziska Auer, Ulrike Friedrich, Julia Hauer,et al.
Springer Science and Business Media LLC - Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma
Anne Schedel, Ulrike Anne Friedrich, Mina N. F. Morcos, Rabea Wagener, Juha Mehtonen, Titus Watrin, Claudia Saitta, Triantafyllia Brozou, Pia Michler, Carolin Walter,et al.
MDPI AG
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.