FRANCESCA LICCARDO

Dottoressa di ricerca

ciclo: XXXV


supervisore: Francesco Fazi

Titolo della tesi: Retinoic Acid and proteotoxic stress induce myeloid leukemia progenitors cell death overcoming the protective effects of the bone marrow niche mesenchymal cells.

The biological issue - Acute myeloid leukemia (AML) is a group of diseases due to chromosomal and genetic mutations that impair myeloid progenitor differentiation. Some leukemic blasts express mutant proteins sensitizing them to pharmacologically induced proteotoxic stresses. Indeed, our lab demonstrated that in the presence of the differentiating agent Retinoic acid, the ER stress inducer Tunicamycin and the oxidative stress inducer Arsenic Trioxide trigger cell death of AML cell lines and primary blasts bearing the FLT3-ITD mutation. Whereas Retinoic acid and Arsenic trioxide are the current therapy for acute promyelocytic leukemia (APL), Tunicamycin has never been used in clinical practice. Therefore, in order to develop a new therapeutic strategy, my Ph.D. project investigated the proteasome inhibitor Bortezomib, which induces ER stress and is already clinically approved for multiple myeloma and mantle cell lymphoma. Results - AML cell lines were treated with low doses of Retinoic Acid (R), Bortezomib (B), and Arsenic Trioxide (A). FLT3-ITD+ cell lines and primary blasts are highly sensitive to the triple combination RBA but not to the single agents. The cytotoxic effect is mostly due to the generation of oxidative stress and the suppression of the pro-survival branches of the Unfolded Protein Response (UPR). Additionally, the role of the bone marrow niche was examined. In an in vitro co-culture system, bone marrow stromal cells (BMSCs) protect AML from RBA toxicity by attenuating oxidative stress. However, pharmacological doses of ascorbic acid (Vit C) used as an adjuvant pro-oxidant agent, tamper with this protection. Importantly, combined treatment efficacy was confirmed in vivo. Furthermore, the combination of RBA with some promising targeted therapies also provided encouraging results. Conclusion - FLT3-ITD+ AML cells are sensitive to RBA combination. Notably, the bone marrow niche can protect leukemic blasts from oxidative stress, but additional Vit C hampers this protective effect. These results stress the importance of studying AML in the context of the bone marrow niche and open to possible applications in AML treatment.

Produzione scientifica

11573/1702967 - 2024 - Modulation of cAMP/cGMP signaling as prevention of congenital heart defects in Pde2A deficient embryos: a matter of oxidative stress
Cardarelli, Silvia; Biglietto, Martina; Orsini, Tiziana; Fustaino, Valentina; Monaco, Lucia; De Oliveira Do Rêgo, Ana Gabriela; Liccardo, Francesca; Masciarelli, Silvia; Fazi, Francesco; Naro, Fabio; De Angelis, Luciana; Pellegrini, Manuela - 01a Articolo in rivista
rivista: CELL DEATH & DISEASE (Nature Group) pp. 1-13 - issn: 2041-4889 - wos: (0) - scopus: 2-s2.0-85185933176 (0)

11573/1678432 - 2023 - Retinoic acid and proteotoxic stress induce myeloid leukemia progenitors cell death overcoming the protective effects of the bone marrow niche mesenchymal cells
Liccardo, Francesca; Sniegocka, Martyna; Ottone Mariadomenica Divona, Tiziana; Miglietta, Selenia; Familiari, Giuseppe; Petrozza, Vincenzo; Tamagnone, Luca; Teresa Voso, Maria; Masciarelli, Silvia; Fazi, Francesco - 04f Poster
congresso: ESH 4th Scientific Workshop - THE HAEMATOLOGICAL TUMOUR MICROENVIRONMENT AND ITS THERAPEUTIC TARGETING (Londra)
libro: ESH 4th Scientific Workshop - ()

11573/1686664 - 2023 - Retinoic acid and proteotoxic stress induce AML cell death overcoming stromal cell protection
Liccardo, Francesca; Śniegocka, Martyna; Tito, Claudia; Iaiza, Alessia; Ottone, Tiziana; Divona, Mariadomenica; Travaglini, Serena; Mattei, Maurizio; Cicconi, Rosella; Miglietta, Selenia; Familiari, Giuseppe; Nottola, Stefania Annarita; Petrozza, Vincenzo; Tamagnone, Luca; Teresa Voso, Maria; Masciarelli, Silvia; Fazi, Francesco - 01a Articolo in rivista
rivista: JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH (London : BioMed Central) pp. 1-15 - issn: 1756-9966 - wos: WOS:001058414700001 (1) - scopus: 2-s2.0-85169408665 (1)

11573/1651452 - 2022 - Circular RNAs activity in the leukemic bone marrow microenvironment
Liccardo, F.; Iaiza, A.; Sniegocka, M.; Masciarelli, S.; Fazi, F. - 01g Articolo di rassegna (Review)
rivista: NON-CODING RNA (Basel : MDPI) pp. 1-14 - issn: 2311-553X - wos: WOS:000845800400001 (2) - scopus: 2-s2.0-85133651335 (3)

11573/1678352 - 2022 - Bone marrow stromal cells support acute myeloid leukemia stem cells enhancing antioxidant defenses
Masciarelli, Silvia; Liccardo, Francesca; Sniegocka, Martyna; Romano, Viviana; Ottone, Tiziana; Travaglini, Serena; Miglietta, Selenia; Nottola, Stefania Annarita; Familiari, Giuseppe; Petrozza, Vincenzo; Tamagnone, Luca; Teresa Voso, Maria; Fazi, Francesco - 04f Poster
congresso: 75° Congresso Nazionale SIAI (Padova)
libro: 75° Congresso Nazionale SIAI - ()

11573/1651765 - 2022 - Understanding ER homeostasis and the UPR to enhance treatment efficacy of acute myeloid leukemia
Sniegocka, M.; Liccardo, F.; Fazi, F.; Masciarelli, S. - 01g Articolo di rassegna (Review)
rivista: DRUG RESISTANCE UPDATES (W B Saunders Company:Fulfillment Department, The Curtis Center, Independence Square West:Philadelphia, PA 19106:(800)654-2452, (215)238-7800, EMAIL: wbspcs@harcourt.com, INTERNET: http://elsevierhealth.com, Fax: (215)238-6445) pp. 1-12 - issn: 1368-7646 - wos: WOS:000837975000001 (7) - scopus: 2-s2.0-85134847995 (7)

11573/1554362 - 2021 - Self-assembling ferritin-dendrimer nanoparticles for targeted delivery of nucleic acids to myeloid leukemia cells
Palombarini, F.; Masciarelli, S.; Incocciati, A.; Liccardo, F.; Di Fabio, E.; Iazzetti, A.; Fabrizi, G.; Fazi, F.; Macone, A.; Bonamore, A.; Boffi, A. - 01a Articolo in rivista
rivista: JOURNAL OF NANOBIOTECHNOLOGY (London : BioMed Central.) pp. 1-12 - issn: 1477-3155 - wos: WOS:000660095400001 (27) - scopus: 2-s2.0-85107462102 (27)

11573/1390401 - 2019 - Development of a combination strategy based on ER and oxidative stress in Acute Myeloid Leukemia
Masciarelli, Silvia; Capuano, Ernestina; Liccardo, Francesca; Ottone, Tiziana; Lo-Coco, Francesco; Fazi, Francesco - 04d Abstract in atti di convegno
congresso: Gordon Research Conference on Stress Proteins in Growth, Development and Disease 2019 (Lucca (Barga), Italy)
libro: Gordon Research Conference - 2019 Meeting - Stress Proteins in Growth, Development and Disease - Programme & Abstracts Book - ()

11573/1389043 - 2019 - Retinoic acid synergizes with the unfolded protein response and oxidative stress to induce AML cell death
Masciarelli, Silvia; Capuano, Ernestina; Liccardo, Francesca; Sniegocka, Martyna; Ottone, Tiziana; Lo-Coco, Francesco; Fazi, Francesco - 04d Abstract in atti di convegno
congresso: 5th INTERNATIONAL CONFERENCE ACUTE MYELOID LEUKEMIA “MOLECULAR AND TRANSLATIONAL”: ADVANCES IN BIOLOGY AND TREATMENT (Estoril, Portugal October 24-26, 2019)
libro: 5th INTERNATIONAL CONFERENCE ACUTE MYELOID LEUKEMIA “MOLECULAR AND TRANSLATIONAL”: ADVANCES IN BIOLOGY AND TREATMENT, Programme & Abstracts Book - ()

11573/1389610 - 2019 - Retinoic acid synergizes with the unfolded protein response and oxidative stress to induce AML cell death
Masciarelli, Silvia; Capuano, Ernestina; Liccardo, Francesca; Sniegocka, Martyna; Ottone, Tiziana; Lo-Coco, Francesco; Fazi, Francesco - 04d Abstract in atti di convegno
congresso: ABCD Congress 2019 (Bologna)
libro: ABCD Congress 2019 - Programme & Abstracts Book - ()

11573/1348145 - 2019 - Retinoic acid synergizes with the unfolded protein response and oxidative stress to induce cell death in FLT3-ITD+ AML
Masciarelli, Silvia; Capuano, Ernestina; Ottone, Tiziana; Divona, Mariadomenica; Lavorgna, Serena; Liccardo, Francesca; Śniegocka, Martyna; Travaglini, Serena; Noguera, Nelida I; Picardi, Alessandra; Petrozza, Vincenzo; Fatica, Alessandro; Tamagnone, Luca; Voso, Maria Teresa; Lo Coco, Francesco; Fazi, Francesco - 01a Articolo in rivista
rivista: BLOOD ADVANCES (Washington DC: American Society of Hematology) pp. 4155-4160 - issn: 2473-9529 - wos: WOS:000504042200002 (18) - scopus: 2-s2.0-85077915937 (19)

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