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16 results on '"Divona, M."'

1. Risk-adapted MRD-directed therapy for young adults with acute myeloid leukemia: 6-year update of the GIMEMA AML1310 trial

Author

Venditti, A, Piciocchi, A, Candoni, A, Arena, V, Palmieri, R, Fili, C, Carella, A, Calafiore, V, Cairoli, R, De Fabritiis, P, Storti, G, Salutari, P, Lanza, F, Martinelli, G, Curti, A, Luppi, M, Ingrosso, C, Martelli, M, Cuneo, A, Albano, F, Mule, A, Tafuri, A, Cudillo, L, Tieghi, A, Fracchiolla, N, Capelli, D, Trisolini, S, Alati, C, La Sala, E, Maurillo, L, Del Principe, M, Consalvo, M, Divona, M, Ottone, T, Cerretti, R, Sconocchia, G, Voso, M, Fazi, P, Vignetti, M, Buccisano, F, Venditti A., Piciocchi A., Candoni A., Arena V., Palmieri R., Fili C., Carella A. M., Calafiore V., Cairoli R., De Fabritiis P., Storti G., Salutari P., Lanza F., Martinelli G., Curti A., Luppi M., Ingrosso C., Martelli M. P., Cuneo A., Albano F., Mule A., Tafuri A., Cudillo L., Tieghi A., Fracchiolla N. S., Capelli D., Trisolini S. M., Alati C., La Sala E., Maurillo L., Del Principe M. I., Consalvo M. A. I., Divona M. D., Ottone T., Cerretti R., Sconocchia G., Voso M. T., Fazi P., Vignetti M., Buccisano F., Venditti, A, Piciocchi, A, Candoni, A, Arena, V, Palmieri, R, Fili, C, Carella, A, Calafiore, V, Cairoli, R, De Fabritiis, P, Storti, G, Salutari, P, Lanza, F, Martinelli, G, Curti, A, Luppi, M, Ingrosso, C, Martelli, M, Cuneo, A, Albano, F, Mule, A, Tafuri, A, Cudillo, L, Tieghi, A, Fracchiolla, N, Capelli, D, Trisolini, S, Alati, C, La Sala, E, Maurillo, L, Del Principe, M, Consalvo, M, Divona, M, Ottone, T, Cerretti, R, Sconocchia, G, Voso, M, Fazi, P, Vignetti, M, Buccisano, F, Venditti A., Piciocchi A., Candoni A., Arena V., Palmieri R., Fili C., Carella A. M., Calafiore V., Cairoli R., De Fabritiis P., Storti G., Salutari P., Lanza F., Martinelli G., Curti A., Luppi M., Ingrosso C., Martelli M. P., Cuneo A., Albano F., Mule A., Tafuri A., Cudillo L., Tieghi A., Fracchiolla N. S., Capelli D., Trisolini S. M., Alati C., La Sala E., Maurillo L., Del Principe M. I., Consalvo M. A. I., Divona M. D., Ottone T., Cerretti R., Sconocchia G., Voso M. T., Fazi P., Vignetti M., and Buccisano F.

Published
2024

2. Expression profiling of extramedullary acute myeloid leukemia suggests involvement of epithelial–mesenchymal transition pathways

Author

Ottone, T, Silvestrini, G, Piazza, R, Travaglini, S, Gurnari, C, Marchesi, F, Nardozza, A, Fabiani, E, Attardi, E, Guarnera, L, Divona, M, Ricci, P, Irno Consalvo, M, Ienzi, S, Arcese, R, Biagi, A, Fiori, L, Novello, M, Mauriello, A, Venditti, A, Anemona, L, Voso, M, Ottone T., Silvestrini G., Piazza R., Travaglini S., Gurnari C., Marchesi F., Nardozza A. M., Fabiani E., Attardi E., Guarnera L., Divona M., Ricci P., Irno Consalvo M. A., Ienzi S., Arcese R., Biagi A., Fiori L., Novello M., Mauriello A., Venditti A., Anemona L., Voso M. T., Ottone, T, Silvestrini, G, Piazza, R, Travaglini, S, Gurnari, C, Marchesi, F, Nardozza, A, Fabiani, E, Attardi, E, Guarnera, L, Divona, M, Ricci, P, Irno Consalvo, M, Ienzi, S, Arcese, R, Biagi, A, Fiori, L, Novello, M, Mauriello, A, Venditti, A, Anemona, L, Voso, M, Ottone T., Silvestrini G., Piazza R., Travaglini S., Gurnari C., Marchesi F., Nardozza A. M., Fabiani E., Attardi E., Guarnera L., Divona M., Ricci P., Irno Consalvo M. A., Ienzi S., Arcese R., Biagi A., Fiori L., Novello M., Mauriello A., Venditti A., Anemona L., and Voso M. T.

Abstract

Extramedullary (EM) colonization is a rare complication of acute myeloid leukemia (AML), occurring in about 10% of patients, but the processes underlying tissue invasion are not entirely characterized. Through the application of RNAseq technology, we examined the transcriptome profile of 13 AMLs, 9 of whom presented an EM localization. Our analysis revealed significant deregulation within the extracellular matrix (ECM)-receptor interaction and focal-adhesion pathways, specifically in the EM sites. The transcription factor TWIST1, which is known to impact on cancer invasion by dysregulating epithelial–mesenchymal-transition (EMT) processes, was significantly upregulated in EM-AML. To test the functional impact of TWIST1 overexpression, we treated OCI-AML3s with TWIST1-siRNA or metformin, a drug known to inhibit tumor progression in cancer models. After 48 h, we showed downregulation of TWIST1, and of the EMT-related genes FN1 and SNAI2. This was associated with significant impairment of migration and invasion processes by Boyden chamber assays. Our study shed light on the molecular mechanisms associated with EM tissue invasion in AML, and on the ability of metformin to interfere with key players of this process. TWIST1 may configure as candidate marker of EM-AML progression, and inhibition of EMT-pathways may represent an innovative therapeutic intervention to prevent or treat this complication. [Figure not available: see fulltext.]

Published
2023

3. LABNET AML: AN EFFICIENT NETWORK THAT CONNECTS HEMATOLOGY CENTERS AND LABORATORIES FOR A HIGH-LEVEL DIAGNOSTIC/PROGNOSTIC WORKUP OF AML

Author

Voso, M, Cucci, R, Messina, M, Santoro, A, Divona, M, Albano, F, Ottaviani, E, Bertorelle, R, Guerrasio, A, Gottardi, E, Izzo, B, Tarantini, G, Scardocci, A, Siragusa, S, Forghieri, F, Cairoli, R, Cambo, B, Vallisa, D, Venditti, A, Ferrara, F, Mannina, D, Cilloni, D, La, S, Piciocchi, A, Falini, B, Pane, F, Saglio, G, Vignetti, M, Amadori, S, Voso MT, Cucci R, Messina M, Santoro A, Divona M, Albano F, Ottaviani E, Bertorelle R, Guerrasio A, Gottardi E, Izzo B, Tarantini G, Scardocci A, Siragusa S, Forghieri F, Cairoli R, Cambo B, Vallisa D, Venditti A, Ferrara F, Mannina D, Cilloni D, La SalaE, Piciocchi A, Falini B, Pane F, Saglio G, Vignetti M, Amadori S, Voso, M, Cucci, R, Messina, M, Santoro, A, Divona, M, Albano, F, Ottaviani, E, Bertorelle, R, Guerrasio, A, Gottardi, E, Izzo, B, Tarantini, G, Scardocci, A, Siragusa, S, Forghieri, F, Cairoli, R, Cambo, B, Vallisa, D, Venditti, A, Ferrara, F, Mannina, D, Cilloni, D, La, S, Piciocchi, A, Falini, B, Pane, F, Saglio, G, Vignetti, M, Amadori, S, Voso MT, Cucci R, Messina M, Santoro A, Divona M, Albano F, Ottaviani E, Bertorelle R, Guerrasio A, Gottardi E, Izzo B, Tarantini G, Scardocci A, Siragusa S, Forghieri F, Cairoli R, Cambo B, Vallisa D, Venditti A, Ferrara F, Mannina D, Cilloni D, La SalaE, Piciocchi A, Falini B, Pane F, Saglio G, Vignetti M, and Amadori S

Published
2021

4. CD99 as a novel therapeutic target on leukemic progenitor cells in FLT3-ITDmut AML

Author

Travaglini, S., Ottone, T., Angelini, D. F., Fiori, V., Dominici, S., Noguera, N. I., Sniegocka, M., Antonelli, S., Irno Consalvo, M. A., De Bardi, M., Banella, C., Divona, M., Marchesi, F., Masciarelli, Silvia, Fazi, F., Pieraccioli, M., Palmieri, R., De Angelis, G., Buccisano, F., Venditti, A., Battistini, L., Magnani, M., Voso, M. T., Masciarelli S., Travaglini, S., Ottone, T., Angelini, D. F., Fiori, V., Dominici, S., Noguera, N. I., Sniegocka, M., Antonelli, S., Irno Consalvo, M. A., De Bardi, M., Banella, C., Divona, M., Marchesi, F., Masciarelli, Silvia, Fazi, F., Pieraccioli, M., Palmieri, R., De Angelis, G., Buccisano, F., Venditti, A., Battistini, L., Magnani, M., Voso, M. T., and Masciarelli S.

Abstract

Acute Myeloid Leukemia with FLT3 internal tandem duplication mutations (FLT3-ITDmut AML) is an aggressive leukemia character- ized by heterogeneous genetic landscape [1]. Despite significant advances in AML therapy, the relapse rate remains high, due to the emergence of resistant clones, possibly involving leukemic stem cells (LSCs) [2]. This highlights the unmet need for deeper understanding of the molecular and immunophenotypic land- scape of LSCs in FLT3-ITDmut AML. We previously identified a population of leukemic precursor cells (LPCs), present at the time of initial AML diagnosis, characterized by the CD34/CD123/CD25/ CD99+ immunophenotype, and predictive for FLT3-ITDmut positivity [3]. In particular, these cells overexpress CD99 antigen, which may represent a target for monoclonal antibody (mAb) treatment [4]

Published
2022

5. Long-term results of all-trans retinoic acid and arsenic trioxide in non-high-risk acute promyelocytic leukemia: update of the APL0406 Italian-German randomized trial

Author

Cicconi, L, Platzbecker, U, Avvisati, G, Paoloni, F, Thiede, C, Vignetti, M, Fazi, P, Ferrara, F, Divona, M, Albano, F, Efficace, F, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Annibali, O, Wattad, M, Lubbert, M, Brandts, C, Hanel, M, Rollig, C, Schmitz, N, Lin, H, Frairia, C, Fozza, C, Maria D’Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Dohner, K, Ganser, A, Dohner, H, Amadori, S, Mandelli, F, Teresa Voso, M, Ehninger, G, Schlenk, R, Lo-Coco, F, Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts C, Hanel M, Rollig C, Schmitz N, Lin H, Frairia C, Fozza C, Maria D’Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Teresa Voso M, Ehninger G, Schlenk RF, Lo-Coco F., Cicconi, L, Platzbecker, U, Avvisati, G, Paoloni, F, Thiede, C, Vignetti, M, Fazi, P, Ferrara, F, Divona, M, Albano, F, Efficace, F, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Annibali, O, Wattad, M, Lubbert, M, Brandts, C, Hanel, M, Rollig, C, Schmitz, N, Lin, H, Frairia, C, Fozza, C, Maria D’Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Dohner, K, Ganser, A, Dohner, H, Amadori, S, Mandelli, F, Teresa Voso, M, Ehninger, G, Schlenk, R, Lo-Coco, F, Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts C, Hanel M, Rollig C, Schmitz N, Lin H, Frairia C, Fozza C, Maria D’Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Teresa Voso M, Ehninger G, Schlenk RF, and Lo-Coco F.

Published
2020

6. Early and sensitive detection of PML-A216V mutation by droplet digital PCR in ATO-resistant acute promyelocytic leukemia

Author

Alfonso, V, Iaccarino, L, Ottone, T, Cicconi, L, Lavorgna, S, Divona, M, Cairoli, R, Cristiano, A, Ciardi, C, Travaglini, S, Falconi, G, Hasan, S, Venditti, A, Arcese, W, Voso, M, Lo-Coco, F, Alfonso V, Iaccarino L, Ottone T, Cicconi L, Lavorgna S, Divona M, Cairoli R, Cristiano A, Ciardi C, Travaglini S, Falconi G, Hasan SK, Venditti A, Arcese W, Voso MT, Lo-Coco F., Alfonso, V, Iaccarino, L, Ottone, T, Cicconi, L, Lavorgna, S, Divona, M, Cairoli, R, Cristiano, A, Ciardi, C, Travaglini, S, Falconi, G, Hasan, S, Venditti, A, Arcese, W, Voso, M, Lo-Coco, F, Alfonso V, Iaccarino L, Ottone T, Cicconi L, Lavorgna S, Divona M, Cairoli R, Cristiano A, Ciardi C, Travaglini S, Falconi G, Hasan SK, Venditti A, Arcese W, Voso MT, and Lo-Coco F.

Published
2019

7. VERY LONG-TERM RESULTS OF ALL-TRANS RETINOIC ACID AND ARSENIC TRIOXIDE IN NON-HIGH RISK ACUTE PROMYELOCYTIC LEUKEMIA: LATEST UPDATE OF THE ITALIAN-GERMAN APL0406 RANDOMIZED TRIAL

Author

Cicconi, L, Platzbecker, U, Avvisati, G, Paoloni, F, Thiede, C, Vignetti, M, Fazi, P, Ferrara, F, Divona, M, Albano, F, Efficace, F, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Annibali, O, Wattad, M, Lubbert, M, Brandts, C, Hanel, M, Rollig, C, Schmitz, N, Lin, H, Frairia, C, Fozza, C, Maria D’Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Dohner, K, Ganser, A, Dohner, H, Amadori, S, Mandelli, F, Teresa Voso, M, Ehninger, G, Schlenk, R, Lo-Coco, F, Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts C, Hanel M, Rollig C, Schmitz N, Lin H, Frairia C, Fozza C, Maria D’Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Teresa Voso M, Ehninger G, Schlenk RF, Lo-Coco F., Cicconi, L, Platzbecker, U, Avvisati, G, Paoloni, F, Thiede, C, Vignetti, M, Fazi, P, Ferrara, F, Divona, M, Albano, F, Efficace, F, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Annibali, O, Wattad, M, Lubbert, M, Brandts, C, Hanel, M, Rollig, C, Schmitz, N, Lin, H, Frairia, C, Fozza, C, Maria D’Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Dohner, K, Ganser, A, Dohner, H, Amadori, S, Mandelli, F, Teresa Voso, M, Ehninger, G, Schlenk, R, Lo-Coco, F, Cicconi L, Platzbecker U, Avvisati G, Paoloni F, Thiede C, Vignetti M, Fazi P, Ferrara F, Divona M, Albano F, Efficace F, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Annibali O, Wattad M, Lubbert M, Brandts C, Hanel M, Rollig C, Schmitz N, Lin H, Frairia C, Fozza C, Maria D’Arco A, Di Renzo N, Cortelezzi A, Fabbiano F, Dohner K, Ganser A, Dohner H, Amadori S, Mandelli F, Teresa Voso M, Ehninger G, Schlenk RF, and Lo-Coco F.

Published
2019

8. SENSITIVE AND EARLY DETECTION OF THE PML-A216V MUTATION BY DROPLET DIGITAL PCR IN ARSENIC TRIOXIDE RESISTANT ACUTE PROMYELOCYTIC LEUKEMIA

Author

Alfonso, V, Iaccarino, L, Ottone, T, Cicconi, L, Lavorgna, S, Divona, M, Cairoli, R, Cristiano, A, Ciardi, C, Chiusolo, P, Venditti, A, Arcese, W, Voso, M, Lo Coco, F, Alfonso V, Iaccarino L, Ottone T, Cicconi L, Lavorgna S, Divona M, Cairoli R, Cristiano A, Ciardi C, Chiusolo P, Venditti A, Arcese W, Voso MT, Lo Coco F, Alfonso, V, Iaccarino, L, Ottone, T, Cicconi, L, Lavorgna, S, Divona, M, Cairoli, R, Cristiano, A, Ciardi, C, Chiusolo, P, Venditti, A, Arcese, W, Voso, M, Lo Coco, F, Alfonso V, Iaccarino L, Ottone T, Cicconi L, Lavorgna S, Divona M, Cairoli R, Cristiano A, Ciardi C, Chiusolo P, Venditti A, Arcese W, Voso MT, and Lo Coco F

Published
2018

10. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: Final results of the randomized Italian-German APL0406 trial

Author

Platzbecker, U, Avvisati, G, Cicconi, L, Thiede, C, Paoloni, F, Vignetti, M, Ferrara, F, Divona, M, Albano, F, Efficace, F, Fazi, P, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Wattad, M, Lübbert, M, Brandts, C, Hänel, M, Röllig, C, Schmitz, N, Link, H, Frairia, C, Pogliani, E, Fozza, C, D'Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Döhner, K, Ganser, A, Döhner, H, Amadori, S, Mandelli, F, Ehninger, G, Schlenk, R, Lo-Coco, F, Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F., Platzbecker, U, Avvisati, G, Cicconi, L, Thiede, C, Paoloni, F, Vignetti, M, Ferrara, F, Divona, M, Albano, F, Efficace, F, Fazi, P, Sborgia, M, Di Bona, E, Breccia, M, Borlenghi, E, Cairoli, R, Rambaldi, A, Melillo, L, La Nasa, G, Fiedler, W, Brossart, P, Hertenstein, B, Salih, H, Wattad, M, Lübbert, M, Brandts, C, Hänel, M, Röllig, C, Schmitz, N, Link, H, Frairia, C, Pogliani, E, Fozza, C, D'Arco, A, Di Renzo, N, Cortelezzi, A, Fabbiano, F, Döhner, K, Ganser, A, Döhner, H, Amadori, S, Mandelli, F, Ehninger, G, Schlenk, R, Lo-Coco, F, Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D'Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, and Lo-Coco F.

Abstract

Purpose: The initial results of the APL0406 trial showed that the combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to standard ATRA and chemotherapy (CHT) in first-line therapy of low- or intermediate-risk acute promyelocytic leukemia (APL). We herein report the final analysis on the complete series of patients enrolled onto this trial. Patients and Methods: The APL0406 study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis ≤ 10 × 109/L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Results: Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively (P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3% v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively (P < .001, P = .0013, and P = .0073, respectively). Postinduction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm. Conclusion: These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low- and intermediate-risk APL.

Published
2017

11. Retinoic acid synergizes with the unfolded protein response and oxidative stress to induce cell death in FLT3-ITD+ AML.

Author

Masciarelli, Silvia, Capuano, E, Ottone, T, Divona, M, Lavorgna, S, Liccardo, F, Śniegocka, M, Travaglini, S, Noguera, Ni, Picardi, A, Petrozza, V, Fatica, A, Tamagnone, Luca, Voso, M, Lo Coco, F, Fazi, F1., Masciarelli S, Tamagnone L (ORCID:0000-0002-2884-7946), Masciarelli, Silvia, Capuano, E, Ottone, T, Divona, M, Lavorgna, S, Liccardo, F, Śniegocka, M, Travaglini, S, Noguera, Ni, Picardi, A, Petrozza, V, Fatica, A, Tamagnone, Luca, Voso, M, Lo Coco, F, Fazi, F1., Masciarelli S, and Tamagnone L (ORCID:0000-0002-2884-7946)

Abstract

Acute myeloid leukemia (AML) is often characterized by the expression of fusion or mutant proteins that cause impaired differentiation and enhanced proliferation and survival. The presence of mutant proteins prone to misfolding can render the cells sensitive to endoplasmic reticulum (ER) stress and oxidative stress that could otherwise be overcome. Here, we show that the triple combination of the differentiating agent retinoic acid (RA), the ER stress-inducing drug tunicamycin (Tm), and arsenic trioxide (ATO), able to generate oxidative stress, leads to the death of AML cell lines expressing fusion proteins involving the gene MLL and the internal tandem duplication (ITD) in the FLT3 tyrosine kinase receptor. Importantly, the combination of RA, Tm, and ATO decreased the colony-forming capacity of primary leukemic blasts bearing the FLT-ITD mutation without affecting healthy hematopoietic progenitor cells. We demonstrate in cell lines that combination of these drugs generates ER and oxidative stresses and impairs maturation and causes accumulation of FLT3 protein in the ER. Our data provide a proof of concept that low amounts of drugs that generate ER and oxidative stresses combined with RA could be an effective targeted therapy to hit AML cells characterized by MLL fusion proteins and FLT3-ITD mutation.

Published
2019

12. Retinoic acid and arsenic trioxide sensitize acute promyelocytic leukemia cells to ER stress

Author

Masciarelli, Silvia, Capuano, E., Ottone, T., Divona, M., De Panfilis, S., Banella, C., Noguera, N. I., Picardi, A., Fontemaggi, G., Blandino, G., Lo-Coco, F., Fazi, Francesco, Masciarelli S., Masciarelli, Silvia, Capuano, E., Ottone, T., Divona, M., De Panfilis, S., Banella, C., Noguera, N. I., Picardi, A., Fontemaggi, G., Blandino, G., Lo-Coco, F., Fazi, Francesco, and Masciarelli S.

Abstract

Retinoic acid (RA) in association with chemotherapy or with arsenic trioxide (ATO) results in high cure rates of acute promyelocytic leukemia (APL). We show that RA-induced differentiation of human leukemic cell lines and primary blasts dramatically increases their sensitivity to endoplasmic reticulum (ER) stress-inducing drugs at doses that are not toxic in the absence of RA. In addition, we demonstrate that the PERK pathway, triggered in response to ER stress, has a major protective role. Moreover, low amounts of pharmacologically induced ER stress are sufficient to strongly increase ATO toxicity. Indeed, in the presence of ER stress, ATO efficiently induced apoptosis in RA-sensitive and RA-resistant APL cell lines, at doses ineffective in the absence of ER stress. Our findings identify the ER stress-related pathways as potential targets in the search for novel therapeutic strategies in AML.

Published
2018

13. PML-RAR alpha kinetics and impact of FLT3-ITD mutations in newly diagnosed acute promyelocytic leukaemia treated with ATRA and ATO or ATRA and chemotherapy

Author

Cicconi, L, Divona, M, Ciardi, C, Ottone, T, Ferrantini, A, Lavorgna, S, Alfonso, V, Paoloni, F, Piciocchi, A, Avvisati, G, Ferrara, F, Di Bona, E, Albano, F, Breccia, M, Cerqui, E, Sborgia, M, Kropp, Mg, Santoro, A, Levis, A, Sica, Simona, Amadori, S, Voso, Mt, Mandelli, F, Lo-Coco, F, Sica, S (ORCID:0000-0003-2426-3465), Cicconi, L, Divona, M, Ciardi, C, Ottone, T, Ferrantini, A, Lavorgna, S, Alfonso, V, Paoloni, F, Piciocchi, A, Avvisati, G, Ferrara, F, Di Bona, E, Albano, F, Breccia, M, Cerqui, E, Sborgia, M, Kropp, Mg, Santoro, A, Levis, A, Sica, Simona, Amadori, S, Voso, Mt, Mandelli, F, Lo-Coco, F, and Sica, S (ORCID:0000-0003-2426-3465)

Abstract

The APL0406 study showed that arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are not inferior to standard ATRA and chemotherapy (CHT) in newly diagnosed, low-intermediaterisk acute promyelocytic leukaemia (APL). We analysed the kinetics of promyelocytic leukaemia-retinoic acid receptor-alpha (PML-RAR alpha) transcripts by real-time quantitative PCR (RQ-PCR) in bone marrow samples from 184 patients and assessed the prognostic impact of fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) in 159 patients enrolled in this trial in Italy. After induction therapy, the reduction of PML-RARa transcripts was significantly greater in patients receiving ATRA-CHT as compared with those treated with ATRA-ATO (3.4 vs 2.9 logs; P = 0.0182). Conversely, at the end of consolidation, a greater log reduction of PML-RAR alpha transcripts was detected in the ATRA-ATO as compared with the ATRA-CHT group (6.3 vs 5.3 logs; P = 0.0024). FLT3-ITD mutations had no significant impact on either event-free survival (EFS) or cumulative incidence of relapse in patients receiving ATRA-ATO, whereas a trend for inferior EFS was observed in FLT3-ITD-positive patients receiving ATRA-CHT. Our study shows at the molecular level that ATRA-ATO exerts at least equal and probably superior antileukaemic efficacy compared with ATRA-CHT in low-intermediaterisk APL. The data also suggest that ATRA-ATO may abrogate the negative prognostic impact of FLT3-ITD.

Published
2016

14. Argonaute 2 sustains the gene expression program driving human monocytic differentiation of acute myeloid leukemia cells

Author

Iosue, I., Quaranta, R., Masciarelli, Silvia, Fontemaggi, G., Batassa, E. M., Bertolami, C., Ottone, T., Divona, M., Salvatori, B., Padula, F., Fatica, A., Lo-Coco, F., Nervi, C., Fazi, F., Masciarelli S., Iosue, I., Quaranta, R., Masciarelli, Silvia, Fontemaggi, G., Batassa, E. M., Bertolami, C., Ottone, T., Divona, M., Salvatori, B., Padula, F., Fatica, A., Lo-Coco, F., Nervi, C., Fazi, F., and Masciarelli S.

Abstract

MicroRNAs are key regulators of many biological processes, including cell differentiation. These small RNAs exert their function assembled in the RNA-induced silencing complexes (RISCs), where members of Argonaute (Ago) family of proteins provide a unique platform for target recognition and gene silencing. Here, by using myeloid cell lines and primary blasts, we show that Ago2 has a key role in human monocytic cell fate determination and in LPS-induced inflammatory response of 1,25-dihydroxyvitamin D3 (D3)-treated myeloid cells. The silencing of Ago2 impairs the D3-dependent miR-17-5p/20a/106a, miR-125b and miR-155 downregulation, the accumulation of their translational targets AML1, VDR and C/EBPb and monocytic cell differentiation. Moreover, we show that Ago2 is recruited on miR-155 host gene promoter and on the upstream region of an overlapping antisense lncRNA, determining their epigenetic silencing, and miR-155 downregulation. These findings highlight Ago2 as a new factor in myeloid cell fate determination in acute myeloid leukemia cells. © 2013 Macmillan Publishers Limited All rights reserved.

Published
2013

15. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia

Author

Lo Coco, F, Avvisati, G, Vignetti, M, Thiede, C, Orlando, Sm, Iacobelli, S, Ferrara, F, Fazi, P, Cicconi, L, Di Bona, E, Specchia, G, Sica, Simona, Divona, M, Levis, A, Fiedler, W, Cerqui, E, Breccia, M, Fioritoni, G, Salih, Hr, Cazzola, M, Melillo, L, Carella, Am, Brandts, Ch, Morra, E, Von Lilienfeld Toal, M, Hertenstein, B, Wattad, M, Lübbert, M, Hänel, M, Schmitz, N, Link, H, Kropp, Mg, Rambaldi, A, La Nasa, G, Luppi, M, Ciceri, F, Finizio, O, Venditti, A, Fabbiano, F, Döhner, K, Sauer, M, Ganser, A, Amadori, S, Mandelli, F, Döhner, H, Ehninger, G, Schlenk, Rf, Platzbecker, U., Sica, Simona (ORCID:0000-0003-2426-3465), Lo Coco, F, Avvisati, G, Vignetti, M, Thiede, C, Orlando, Sm, Iacobelli, S, Ferrara, F, Fazi, P, Cicconi, L, Di Bona, E, Specchia, G, Sica, Simona, Divona, M, Levis, A, Fiedler, W, Cerqui, E, Breccia, M, Fioritoni, G, Salih, Hr, Cazzola, M, Melillo, L, Carella, Am, Brandts, Ch, Morra, E, Von Lilienfeld Toal, M, Hertenstein, B, Wattad, M, Lübbert, M, Hänel, M, Schmitz, N, Link, H, Kropp, Mg, Rambaldi, A, La Nasa, G, Luppi, M, Ciceri, F, Finizio, O, Venditti, A, Fabbiano, F, Döhner, K, Sauer, M, Ganser, A, Amadori, S, Mandelli, F, Döhner, H, Ehninger, G, Schlenk, Rf, Platzbecker, U., and Sica, Simona (ORCID:0000-0003-2426-3465)

Abstract

All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity.

Published
2013

16. Comparative molecular analysis of therapy-related and de novo acute promyelocytic leukemia

Author

Ottone, T, Cicconi, L, Hasan, Sk, Lavorgna, S, Divona, M, Voso, Maria Teresa, Montefusco, E, Melillo, L, Barragán, E, Platzbecker, U, Giannì, L, Hubmann, M, Pagoni, M, Amadori, S, Lo Coco, F., Ottone, T, Cicconi, L, Hasan, Sk, Lavorgna, S, Divona, M, Voso, Maria Teresa, Montefusco, E, Melillo, L, Barragán, E, Platzbecker, U, Giannì, L, Hubmann, M, Pagoni, M, Amadori, S, and Lo Coco, F.

Abstract

Therapy-related acute promyelocytic leukemia (t-APL) has been reported as a late complication of exposure to radiotherapy and/or chemotherapeutic agents targeting DNA topoisomerase II. We have analyzed in t-APL novel gene mutations recently associated with myeloid disorders. Unlike previous reports in acute myeloid leukemia (AML), our results showed neither IDHs nor TET2 mutations in t-APL. However we found an R882H mutation in the DNMT3A gene in a patient with t-APL suggesting a possible role of this alteration in the pathogenesis of t-APL., Therapy-related acute promyelocytic leukemia (t-APL) has been reported as a late complication of exposure to radiotherapy and/or chemotherapeutic agents targeting DNA topoisomerase II. We have analyzed in t-APL novel gene mutations recently associated with myeloid disorders. Unlike previous reports in acute myeloid leukemia (AML), our results showed neither IDHs nor TET2 mutations in t-APL. However we found an R882H mutation in the DNMT3A gene in a patient with t-APL suggesting a possible role of this alteration in the pathogenesis of t-APL.

Published
2012

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