Dottoressa di ricerca

ciclo: XXXIV

Titolo della tesi: New insight into the catalytic -dependent and -independent roles of METTL3 in sustaining aberrant translation in Chronic Myeloid Leukemia.

RNA modifications play a fundamental role in fine-tuning of gene expression. To date, more than 160 RNA modifications have been discovered in coding and non-coding transcripts. N6- methyladenosine (m6A), in particular, has attracted the interest of researchers around the world because it is the most abundant internal chemical modification in mRNAs and controls every aspect of the post-transcriptional regulation of these molecules. Similar to epigenetic modifications in histones and DNA, m6A is a reversible and dynamic modification installed by "writer", removed by "eraser", and recognized by "reader" proteins. Alterations to m6A pattern have a profound impact on cell differentiation, normal development and human diseases. Alteration of m6A level has been found to be closely associated with the onset, the metastasis and drug resistance of various kinds of cancers; in particular, m6A is an important driver of malignant transformation in the hematopoietic compartment. Acute Myeloid Leukemia (AML) is a clear example of how alteration in m6A level can disrupt normal cellular differentiation and contribute to cancer development. Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by the accumulation of myeloid cells at different stages (blasts) in the blood. CML progression is driven by the presence of tyrosine kinase BCR-ABL1 fusion protein, which deregulates transcription and translation of several signaling pathways. Although progress has been made in the understanding of signal transduction in the BCR-ABL1-mediated transformation, the role of m6A in CML remains unknown. We found that METTL3 and METTL14, that form the main writer complex responsible for m6A deposition within mRNAs, are significantly higher in peripheral blood of CML patients than in healthy controls, moreover their expression in CML cell lines is comparable or even higher than in AML cell lines. Therein, we perturbed the catalytic subunit METTL3 level in CML patients and cell lines highlighting that METTL3 is crucial for proliferation and cell cycle progression of CML cells, both sensitive and resistant to TKIs treatment. In particular, we found that METTL3 regulates translation process both indirectly, by sustaining transcription and translation of MYC, the master regulator of ribosome biogenesis and translation, and directly, by regulating PES1 protein level, a ribosome assembly factor that plays an oncogenic role in several tumors. We propose a model in which the nuclear METTL3/METTL14 methyltransferase complex modifies nascent transcripts whose translation is enhanced by cytoplasmic localization of METTL3, independently from its catalytic activity. In conclusion, our work contributed to unveil the novel role of METTL3 in sustaining the aberrant translation that characterized CML. Furthermore, our results point to METTL3 as a novel relevant oncogene in CML and as a promising therapeutic target for TKI resistant CML.

Produzione scientifica

11573/1665942 - 2023 - circPVT1 and PVT1/AKT3 show a role in cell proliferation, apoptosis, and tumor subtype-definition in small cell lung cancer
Tolomeo, Doron; Traversa, Debora; Venuto, Santina; Ebbesen, Karoline K; García Rodríguez, Juan L; Tamma, Grazia; Ranieri, Marianna; Simonetti, Giorgia; Ghetti, Martina; Paganelli, Matteo; Visci, Grazia; Liso, Arcangelo; Kok, Klaas; Muscarella, Lucia Anna; Fabrizio, Federico Pio; Frassanito, Maria Antonia; Lamanuzzi, Aurelia; Saltarella, Ilaria; Solimando, Antonio Giovanni; Fatica, Alessandro; Ianniello, Zaira; Marsano, René Massimiliano; Palazzo, Antonio; Azzariti, Amalia; Longo, Vito; Tommasi, Stefania; Galetta, Domenico; Catino, Annamaria; Zito, Alfredo; Mazza, Tommaso; Napoli, Alessandro; Martinelli, Giovanni; Kjems, Jørgen; Kristensen, Lasse Sommer; Vacca, Angelo; Storlazzi, Clelia Tiziana - 01a Articolo in rivista
rivista: GENES, CHROMOSOMES & CANCER (John Wiley & Sons Incorporated:Customer Service, 111 River Street:Hoboken, NJ 07030:(800)225-5945, (201)748-6000, EMAIL:, INTERNET:, Fax: (212)748-6551) pp. 1-15 - issn: 1045-2257 - wos: WOS:000921351500001 (8) - scopus: 2-s2.0-85146980361 (8)

11573/1610957 - 2022 - METTL3 contribution to cell proliferation in Thymic Epithelial Tumor Cells
Iaiza, Alessia; Tito, Claudia; Ianniello, Zaira; Ganci, Federica; Laquintana, Valentina; Gallo, Enzo; Sacconi, Andrea; Masciarelli, Silvia; De Angelis, Luciana; Aversa, Sara; Diso, Daniele; Anile, Marco; Petrozza, Vincenzo; Facciolo, Francesco; Melis, Enrico; Pescarmona, Edoardo; Venuta, Federico; Marino, Mirella; Blandino, Giovanni; Fontemaggi, Giulia; Fatica, Alessandro; Fazi, Francesco - 04f Poster
congresso: EMBO Workshop: The epitranscriptome (Heidelberg; Germany)
libro: Poster a congresso - ()

11573/1650849 - 2022 - MALAT1-dependent hsa_circ_0076611 regulates translation rate in triple-negative breast cancer
Turco, Chiara; Esposito, Gabriella; Iaiza, Alessia; Goeman, Frauke; Benedetti, Anna; Gallo, Enzo; Daralioti, Theodora; Perracchio, Letizia; Sacconi, Andrea; Pasanisi, Patrizia; Muti, Paola; Pulito, Claudio; Strano, Sabrina; Ianniello, Zaira; Fatica, Alessandro; Forcato, Mattia; Fazi, Francesco; Blandino, Giovanni; Fontemaggi, Giulia - 01a Articolo in rivista
rivista: COMMUNICATIONS BIOLOGY ([London]: Springer Nature) pp. 1-17 - issn: 2399-3642 - wos: WOS:000812308700006 (9) - scopus: 2-s2.0-85132079710 (10)

11573/1571355 - 2021 - Translational control of polyamine metabolism by CNBP is required for Drosophila locomotor function
Coni, Sonia; Falconio, Federica A; Marzullo, Marta; Munafò, Marzia; Zuliani, Benedetta; Mosti, Federica; Fatica, Alessandro; Ianniello, Zaira; Bordone, Rosa; Macone, Alberto; Agostinelli, Enzo; Perna, Alessia; Matkovic, Tanja; Sigrist, Stephan; Silvestri, Gabriella; Canettieri, Gianluca; Ciapponi, Laura - 01a Articolo in rivista
rivista: ELIFE (Cambridge: eLife Sciences Publications) pp. - - issn: 2050-084X - wos: WOS:000696095100001 (7) - scopus: 2-s2.0-85116196697 (8)

11573/1571404 - 2021 - METTL3-dependent MALAT1 delocalization drives c-Myc induction in thymic epithelial tumors
Iaiza, A.; Tito, C.; Ianniello, Z.; Ganci, F.; Laquintana, V.; Gallo, E.; Sacconi, A.; Masciarelli, S.; De Angelis, L.; Aversa, S.; Diso, D.; Anile, M.; Petrozza, V.; Facciolo, F.; Melis, E.; Pescarmona, E.; Venuta, F.; Marino, M.; Blandino, G.; Fontemaggi, G.; Fatica, A.; Fazi, F. - 01a Articolo in rivista
rivista: CLINICAL EPIGENETICS (Berlin : Springer) pp. 173- - issn: 1868-7083 - wos: WOS:000696541400003 (20) - scopus: 2-s2.0-85115179423 (21)

11573/1575650 - 2021 - New insight into the catalytic -dependent and -independent roles of METTL3 in sustaining aberrant translation in chronic myeloid leukemia
Ianniello, Z.; Sorci, M.; Ceci Ginistrelli, L.; Iaiza, A.; Marchioni, M.; Tito, C.; Capuano, E.; Masciarelli, S.; Ottone, T.; Attrotto, C.; Rizzo, M.; Franceschini, L.; De Pretis, S.; Voso, M. T.; Pelizzola, M.; Fazi, F.; Fatica, A. - 01a Articolo in rivista
rivista: CELL DEATH & DISEASE (Nature Group) pp. 1-12 - issn: 2041-4889 - wos: WOS:000698956000001 (21) - scopus: 2-s2.0-85115718682 (24)

11573/1610222 - 2021 - New insight into the catalytic -dependent and -independent roles of METTL3 in sustaining aberrant translation in Chronic Myeloid Leukemia
Ianniello, Zaira; Sorci, Melissa; Ceci Ginistrelli, Lavinia; Iaiza, Alessia; Marcella, Marchioni; Tito, Claudia; Capuano, Ernestina; Masciarelli, Silvia; Tiziana, Ottone; Cristina, Attrotto; Manuela, Rizzo; Luca, Franceschini; Stefano De Pretis, ; Maria Teresa Voso, ; Mattia, Pelizzola; Fazi, Francesco; Fatica, Alessandro - 04f Poster
congresso: 23rd Annual John Goldman E-Conference o​n Chronic Myeloid Leukemia: Biology and Therapy (Online)
libro: European School of Haematology - ()

11573/1486471 - 2021 - ADAR1 is a new target of METTL3 and plays a pro-oncogenic role in glioblastoma by an editing-independent mechanism
Tassinari, Valentina; Cesarini, Valeriana; Tomaselli, Sara; Ianniello, Zaira; Silvestris, Domenico Alessandro; Ginistrelli, Lavinia Ceci; Martini, Maurizio; De Angelis, Biagio; De Luca, Gabriele; Vitiani, Lucia Ricci; Fatica, Alessandro; Locatelli, Franco; Gallo, Angela - 01a Articolo in rivista
rivista: GENOME BIOLOGY (BioMed Central) pp. 1-22 - issn: 1474-760X - wos: WOS:000613239700001 (67) - scopus: 2-s2.0-85100012270 (69)

11573/1471575 - 2020 - Blockade of EIF5A hypusination limits colorectal cancer growth by inhibiting MYC elongation
Coni, S.; Serrao, S. M.; Yurtsever, Z. N.; Di Magno, L.; Bordone, R.; Bertani, C.; Licursi, V.; Ianniello, Z.; Infante, P.; Moretti, M.; Petroni, M.; Guerrieri, F.; Fatica, A.; Macone, A.; De Smaele, E.; Di Marcotullio, L.; Giannini, G.; Maroder, M.; Agostinelli, E.; Canettieri, G. - 01a Articolo in rivista
rivista: CELL DEATH & DISEASE (Nature Group) pp. - - issn: 2041-4889 - wos: WOS:000597627300001 (34) - scopus: 2-s2.0-85097416564 (38)

11573/1263074 - 2019 - N6-Methyladenosine (m6A): A Promising New Molecular Target in Acute Myeloid Leukemia
Ianniello, Zaira; Paiardini, Alessandro; Fatica, Alessandro - 01a Articolo in rivista
rivista: FRONTIERS IN ONCOLOGY (Lausanne : Frontiers Editorial Office, 2011-) pp. - - issn: 2234-943X - wos: WOS:000463924400001 (53) - scopus: 2-s2.0-85067465851 (53)

11573/1347292 - 2019 - The METTL3/METTL14 m6A methylation complex plays a crucial role in Chronic Myeloid Leukemia survival by regulating MYC expression.
Ianniello, Zaira; Sorci, Melissa; Lavinia Ceci Ginistrelli, ; Marcella, Marchioni; Tito, Claudia; Capuano, Ernestina; Masciarelli, Silvia; Mattia, Pelizzola; Fazi, Francesco; Fatica, Alessandro - 04f Poster
congresso: RNA epigenetics in human disease 2019 - STORM Therapeutics Conference (Cambridge - UK)
libro: RNA epigenetics in human disease 2019 – STORM Therapeutics Conference - Abstract Book - ()

11573/1135319 - 2018 - N6-Methyladenosine Role in Acute Myeloid Leukaemia
Ianniello, Zaira; Fatica, Alessandro - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel: MDPI Center) pp. - - issn: 1422-0067 - wos: WOS:000442869800197 (33) - scopus: 2-s2.0-85052133559 (37)

11573/1156943 - 2018 - A positive feed-forward regulatory loop between METTL3 and WTAP sustains the oncogenic role of the m6A methylation complex in myeloid leukemia
Ianniello, Zaira; Sorci, Melissa; Lavinia Ceci Ginistrelli, ; Capuano, Ernestina; Marcella, Marchioni; Fazi, Francesco; Fatica, Alessandro - 04d Abstract in atti di convegno
congresso: XV FISV CONGRESS Sapienza University of Rome, Italy September 18-21, 2018 (Roma)
libro: Programme & Abstracts Book - ()

11573/1131988 - 2018 - METTL3 regulates WTAP protein homeostasis
Sorci, Melissa; Ianniello, Zaira; Cruciani, Sonia; Larivera, Simone; Ginistrelli, Lavinia Ceci; Capuano, Ernestina; Marchioni, Marcella; Fazi, Francesco; Fatica, Alessandro - 01a Articolo in rivista
rivista: CELL DEATH & DISEASE (Nature Group) pp. - - issn: 2041-4889 - wos: WOS:000440240000002 (102) - scopus: 2-s2.0-85050603594 (106)

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