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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

5. 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

6. 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

7. P434: MITOCONDRIAL MCL1 REGULATES LEUKEMIC CELLS METABOLISM VIA DIRECT INTERACTION WITH HEXOKINASE II. METABOLIC SIGNATURE AT ONSET PREDICTS OVERALL SURVIVAL IN AMLS’ PATIENTS

Author

Noguera, N. I., primary, Catalano, G., additional, Zaza, A., additional, Banella, C., additional, Ottone, T., additional, Pelosi, E., additional, Travaglini, S., additional, Divona, M., additional, Del Principe, M. I., additional, Buccisano, F., additional, Maurillo, L., additional, Amatuna, E., additional, Testa, U., additional, Venditti, A., additional, and Voso, M. T., additional

Published
2022
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8. Clinical relevance of an objective - limit of detection - limit of quantification - based flow cytometry approach for measurable residual disease assessment in acute myeloid leukemia. A post-hoc analysis of the GIMEMA AML1310 trial

Author

Buccisano, F, Palmieri, R, Piciocchi, A, Arena, V, Maurillo, L, Del Principe, M, Paterno, G, Irno-Consalvo, M, Ottone, T, Divona, M, Conti, C, Fraboni, D, Lavorgna, S, Arcese, W, Voso, Mt, and Venditti, A

Subjects
measurable residual disease, Acute myeloid leukemia, immunophenotyping, minimal residual disease, Acute myeloid leukemia, minimal residual disease, measurable residual disease, immunophenotyping, Settore MED/15
Published
2022

9. 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

12. 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

13. 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

19. 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

20. Characterization ofFLT3-ITD(mut)acute myeloid leukemia: molecular profiling of leukemic precursor cells

Author

Travaglini, S, Angelini, DF, Alfonso, V, Guerrera, G, Lavorgna, S, Divona, M, Nardozza, AM, Consalvo, MI, Fabiani, E, De Bardi, M, Neri, B, Forghieri, F, Marchesi, F, Paterno, G, Cerretti, R, Barragan, E, Fiori, V, Dominici, S, Del Principe, MI, Venditti, A, Battistini, L, Arcese, W, Lo-Coco, F, Voso, MT, and Ottone, T

Subjects
body regions, psychological phenomena and processes
Abstract

Acute myeloid leukemia (AML) withFLT3-ITD mutations (FLT3-ITDmut) remains a therapeutic challenge, with a still high relapse rate, despite targeted treatment with tyrosine kinase inhibitors. In this disease, the CD34/CD123/CD25/CD99+ leukemic precursor cells (LPCs) phenotype predicts forFLT3-ITD-positivity. The aim of this study was to characterize the distribution ofFLT3-ITD mutation in different progenitor cell subsets to shed light on the subclonal architecture ofFLT3-ITD(mut)AML. Using high-speed cell sorting, we sequentially purified LPCs and CD34+ progenitors in samples from patients withFLT3-ITD(mut)AML (n = 12). A higherFLT3-ITD(mut)load was observed within CD34/CD123/CD25/CD99+ LPCs, as compared to CD34+ progenitors (CD123+/-,CD25-,CD99low/-) (p = 0.0005) and mononuclear cells (MNCs) (p < 0.0001). This was associated with significantly increased CD99 mean fluorescence intensity in LPCs. Significantly higherFLT3-ITD(mut)burden was also observed in LPCs of AML patients with a smallFLT3-ITD(mut)clones at diagnosis. On the contrary, the mutation burden of other myeloid genes was similar in MNCs, highly purified LPCs and/or CD34+ progenitors. Treatment with an anti-CD99 mAb was cytotoxic on LPCs in two patients, whereas there was no effect on CD34+ cells from healthy donors. Our study shows thatFLT3-ITD mutations occur early in LPCs, which represent the leukemic reservoir. CD99 may represent a new therapeutic target inFLT3-ITD(mut)AML.

Published
2020

22. 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

24. PS1011 MEASURABLE RESIDUAL DISEASE BY MULTIPARAMETRIC FLOW-CYTOMETRY IS A RELIABLE TOOL FOR RISK-STRATIFICATION OF FLT3-MUTATED AML PATIENTS

Author

Palmieri, R., primary, Maurillo, L., additional, Principe, M.I. Del, additional, Veroli, A. Di, additional, Paterno, G., additional, Bellis, E. De, additional, Cerretti, R., additional, Angelis, G. De, additional, Mariotti, B., additional, Ottone, T., additional, Divona, M., additional, Lavorgna, S., additional, Consalvo, M.A. Irno, additional, Conti, C., additional, Attrotto, C., additional, Fraboni, D., additional, Voso, M.T., additional, Amadori, S., additional, Coco, F. Lo, additional, Arcese, W., additional, Venditti, A., additional, and Buccisano, F., additional

Published
2019
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25. 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

27. Retinoic acid sensitizes acute myeloid leukemia cells to ER stress

Author

Masciarelli, Silvia, Capuano, Ernestina, Bellissimo, Teresa, Ottone, T., Divona, M. D., Lo Coco, F., and Fazi, Francesco

Subjects
AML, ER stress, RA, ATO, neoplasms
Abstract

Acute myeloid leukemia (AML) is caused by the blockade of hematopoietic myeloid precursors at different stages of differentiation. A subtype of AML, acute promyelocytic leukemia (APL), is a paradigm of differentiation therapy since retinoic acid (RA) is able to induce leukemic blast terminal differentiation leading to cure rates exceeding 80% when administered in combination with chemotherapy. Although APL patients refractory to RA or who relapsed are very effectively treated with arsenic trioxide (ATO) in combination with RA, the elevated costs limit its use in developing countries and in first line therapy so that RA plus chemotherapy currently remain the standard of care (1, 2). Most importantly non-APL acute myeloid leukemia do not respond to RA indicating the need for novel strategies to sensitize AML cells to RA. Here we show that RA-triggered differentiation of APL cells induces endoplasmic reticulum (ER) stress slightly activating the unfolded protein response (UPR). This is sufficient to render leukemic cell lines and human primary blasts very sensitive to doses of ER stress inducing drugs, like tunicamycin (Tm), that are not toxic for the same cells in the absence of RA or for most cell types. Furthermore we observed that low doses of Tm, even in the absence of RA, are sufficient to strongly increase ATO toxicity. Indeed both RA-sensitive and RA-resistant APL cell lines resulted sensitive to Tm-ATO combined treatment at low doses of ATO that are ineffective in the absence of ER stress. The use of inhibitors targeting specific UPR branches indicate that the Protein Kinase RNA-like Endoplasmic Reticulum kinase (PERK) pathway protects differentiating APL cells from ER stress rendering it an interesting therapeutic molecular target. Finally, we extended our observations in a non-APL model, assessing that RA sensitize the non-APL cell line HL60 to ER stress. Altogether our data indicate ER stress as a possible target for designing novel combination therapeutic strategies in AML. Contribution of AIRC (StG 4841) and FILAS-RU-2014-1020 to FF was greatly appreciated., Italian Journal of Anatomy and Embryology, Vol. 121, No. 1 (Supplement) 2016

Published
2017
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28. 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

30. The E3 ubiquitin ligase WWP1 sustains the growth of acute myeloid leukaemia

Author

Sanarico, A G, primary, Ronchini, C, additional, Croce, A, additional, Memmi, E M, additional, Cammarata, U A, additional, De Antoni, A, additional, Lavorgna, S, additional, Divona, M, additional, Giacò, L, additional, Melloni, G E M, additional, Brendolan, A, additional, Simonetti, G, additional, Martinelli, G, additional, Mancuso, P, additional, Bertolini, F, additional, Coco, F Lo, additional, Melino, G, additional, Pelicci, P G, additional, and Bernassola, F, additional

Published
2017
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33. 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

34. Identification of emerging FLT3 ITD-positive clones during clinical remission and kinetics of disease relapse in acute myeloid leukaemia with mutated nucleophosmin

Author

Ottone, Zaza, T, S, Divona, M, Hasan, S, Lavorgna, S, Laterza, S, Cicconi, L, Panetta, P, Di Giandomenico, J, Cittadini, M, Ciardi, C, Montefusco, E, Franchi, A, Annino, L, Venditti, A, Amadori, S, and LO COCO, F

Subjects
Oncology, FLT3 Internal Tandem Duplication, Adult, Male, NPM1, medicine.medical_specialty, Myeloid, Gene Dosage, Somatic evolution in cancer, law.invention, law, Recurrence, hemic and lymphatic diseases, Internal medicine, Gene Duplication, Gene duplication, medicine, Humans, Polymerase chain reaction, Retrospective Studies, business.industry, Induction chemotherapy, Nuclear Proteins, hemic and immune systems, Hematology, Induction Chemotherapy, Middle Aged, medicine.disease, body regions, Leukemia, Leukemia, Myeloid, Acute, medicine.anatomical_structure, fms-Like Tyrosine Kinase 3, embryonic structures, Immunology, Mutation, Female, business, Settore MED/15 - Malattie del Sangue, Nucleophosmin, psychological phenomena and processes
Abstract

FLT3 internal tandem duplication (ITD) mutations are frequently detected at diagnosis in cytogenetically normal acute myeloid leukaemia (CN-AML) and predict unfavourable outcome. FLT3 ITD is an unstable aberration and may be lost or acquired at relapse. Recent whole genome sequencing studies have suggested that FLT3 ITD(+)ve AML relapse may evolve from small subclones undetectable at diagnosis by routine polymerase chain reaction (PCR). We developed a patient-specific real-time quantitative-PCR (RQ-PCR) to implement FLT3 ITD detection in six AML patients whose blasts carried wild-type FLT3 at diagnosis and who relapsed with FLT3 ITD by routine PCR. Patient-specific forward primers were designed after cloning and sequencing the FLT3 ITD in each case. The assay allowed retrospective detection of FLT3 ITD in diagnostic samples of 4/6 cases and to establish the kinetics of clonal evolution preceding relapse. After conventional chemotherapy, all patients had early relapse despite having been classified as NPM1(+)ve/FLT3 ITD(-)ve at presentation, with shorter remissions being observed in four patients re-classified as FLT3 ITD(+)ve by the new assay. Notably, FLT3 ITD clone became detectable by conventional PCR in three patients tested during remission after initial treatment. Our data underscore the need of identifying low FLT3 ITD levels, which are probably associated with relapse in otherwise good prognosis CN-AML.

Published
2012

36. The E3 ubiquitin ligase WWP1 sustains the growth of acute myeloid leukaemia

Author

Sanarico, A G, Ronchini, C, Croce, A, Memmi, E M, Cammarata, U A, De Antoni, A, Lavorgna, S, Divona, M, Giacò, L, Melloni, G E M, Brendolan, A, Simonetti, G, Martinelli, G, Mancuso, P, Bertolini, F, Coco, F Lo, Melino, G, Pelicci, P G, and Bernassola, F

Abstract

The E3 ubiquitin ligase (E3) WWP1 is an oncogenic factor implicated in the maintenance of different types of epithelial cancers. The role of WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) in haematological neoplasms remains unknown. Acute myeloid leukaemia (AML) is characterized by the expansion of malignant myeloid cells blocked at different stages of differentiation. Here we report that the expression of WWP1 is significantly augmented in a large cohort of primary AML patients and in AML cell lines, compared with haematopoietic cells from healthy donors. We show that WWP1 inactivation severely impairs the growth of primary AML blasts and cell lines in vitro. In vivo, we observed a reduced leukaemogenic potential of WWP1-depleted AML cells upon transplantation into immunocompromised mice. Mechanistically, WWP1 inactivation induces the accumulation of its protein substrate p27Kip1, which ultimately contributes to G0/G1cell cycle arrest of AML blasts. In addition, WWP1 depletion triggers the autophagy signalling and reduces survival of leukaemic cells. Collectively, our findings provide molecular insights into the anti-cancer potential of WWP1 inhibition, suggesting that this E3 is a promising biomarker and druggable target in AML.

Published
2018
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37. 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

38. 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

39. 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

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

Author

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

Published
2013
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42. Retinoic acid and arsenic trioxide sensitize acute promyelocytic leukemia cells to ER stress

Author

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

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
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44. Simultaneous detection of NPM1 and FLT3-ITD mutations by capillary electrophoresis in acute myeloid leukemia.

Author

Noguera, N I, Ammatuna, E, Zangrilli, D, Lavorgna, S, Divona, M, Buccisano, F, Amadori, S, Mecucci, C, Falini, B, and Lo-Coco, F

Subjects
ACUTE myeloid leukemia
Abstract

A correction to the article "Simultaneous detection of NPM1 and FLT3-ITD mutations by capillary electrophoresis in acute myeloid leukemia" that was published in a previous issue of the periodical is presented.

Published
2007
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45. MICROBIAL ELECTROLYSIS CELL: HYDROGEN PRODUCTION USING MICROBIAL CONSORTIA FROM ROMANIAN WATERS.

Author

CUCU, A., COSTACHE, T. A., DIVONA, M., TILIAKOS, A., STAMATIN, I., and CIOCANEA, A.

Subjects
*ELECTROLYSIS, *BIOELECTROCHEMISTRY, *AQUEOUS electrolytes, *MARINE ecology, *AQUATIC microbiology, *WASTEWATER treatment
Abstract

The present study aims to provide additional insight into the bioelectrochemical processes that drive biohydrogen production by microorganisms living in aqueous ecosystems. To this end, we have obtained water samples from three locations in Romania (the Black Sea, Lake Siutghiol and the River Sabar), and employed them in the cathodic chamber of a Microbial Electrolysis Cell (MEC) run at a negative polarization of 1,100mV vs. Ag∣AgCl. The microbial species present in the water samples employed in the MEC proved capable of driving biohydrogen production through electrolysis without the need of mediators, reaching a maximum efficiency of 57% in biohydrogen production using the marine waters sample. Microbial activity also led to the reduction of nitrates present in the wastewater substrate; this may spell promising developments in wastewater treatment coupled with biohydrogen production. [ABSTRACT FROM AUTHOR]

Published
2013

46. Novel Multiplex Droplet Digital PCR Assays to Monitor Minimal Residual Disease in Chronic Myeloid Leukemia Patients Showing Atypical BCR-ABL1 Transcripts

Author

Carmen Fava, Jessica Petiti, Marco Lo Iacono, Maria Cristina Rapanotti, Giuseppe Saglio, Mariadomenica Divona, Enrico Gottardi, Lucrezia Pironi, Cristina Fantino, Giovanna Rege-Cambrin, Daniela Cilloni, Barbara Izzo, Matteo Dragani, Fabrizio Quarantelli, Petiti, J., Iacono, M. L., Dragani, M., Pironi, L., Fantino, C., Rapanotti, M. C., Quarantelli, F., Izzo, B., Divona, M., Rege-Cambrin, G., Saglio, G., Gottardi, E. M., Cilloni, D., and Fava, C.

Subjects
Oncology, BCR–ABL1, medicine.medical_specialty, atypical transcripts, lcsh:Medicine, 03 medical and health sciences, 0302 clinical medicine, chronic myeloid leukemia, Internal medicine, hemic and lymphatic diseases, medicine, Multiplex, Digital polymerase chain reaction, 030304 developmental biology, 0303 health sciences, treatment-free remission, ABL, business.industry, digital PCR, lcsh:R, Myeloid leukemia, General Medicine, BCR, Minimal residual disease, Atypical transcript, Fusion transcript, 030220 oncology & carcinogenesis, Molecular Response, MRD monitoring, business, Nested polymerase chain reaction, ABL1
Abstract

BCR-ABL1 fusion transcript is the minimal residual disease marker in chronic myeloid leukemia, 2% of patients show unusual breakpoints generating atypical transcripts, not quantifiable by standardized real-time PCR (RT&ndash, PCR). Response monitoring is performed by non-quantitative NESTED PCR, useless for evaluating patients&rsquo, molecular remission, excluding them from treatment-free-remission protocols. Droplet digital PCR (ddPCR) is highly sensitive technology, allowing an absolute quantification independent of standard curves. Based on this, we have developed assays able to evaluate the molecular response in atypical patients. We designed new ddPCR-based molecular assays able to quantify atypical BCR-ABL1 transcripts, with a detection limit of 0.001%, validated in a cohort of 65 RNA from 11 patients. Fifty samples were identified congruently by ddPCR and NESTED PCR (40 positives and 10 negatives for atypical BCR&ndash, ABL1 transcript), while 11 positive samples were detected only by ddPCR. Our results highlight ddPCR usefulness, primarily when the BCR&ndash, ABL1/ABL1 level is less than 1.5% and NESTED PCR results are often inaccurate. Furthermore, we identified 3 patients who maintained a deep molecular response for at least one year, who could be considered good candidates for treatment-free remission approaches. Here, we describe a new promising molecular approach, highly sensitive, to monitor atypical BCR&ndash, ABL1 patients, paving the foundation to include them in treatment-free remission protocols.

Published
2020
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47. 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

Erika Borlenghi, Arnold Ganser, Christian Thiede, Hartmut Döhner, Roberto Cairoli, Mohammed Wattad, Norbert Schmitz, Agostino Cortelezzi, Alfonso Maria D'Arco, Massimo Breccia, Franco Mandelli, Richard F. Schlenk, Mariadomenica Divona, Marco Sborgia, Francesco Albano, Laura Cicconi, Enrico Maria Pogliani, Konstanze Döhner, Claudio Fozza, Giuseppe Avvisati, Francesco Lo-Coco, Michael Lübbert, Felicetto Ferrara, Sergio Amadori, Walter Fiedler, Francesco Fabbiano, Bernd Hertenstein, Helmut R. Salih, Lorella Melillo, Uwe Platzbecker, Alessandro Rambaldi, Giorgio La Nasa, Christian Brandts, Nicola Di Renzo, Christoph Röllig, Hartmut Link, Marco Vignetti, Francesca Paoloni, Eros Di Bona, Fabio Efficace, Peter Brossart, Chiara Frairia, Paola Fazi, Gerhard Ehninger, Mathias Hänel, 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, and Lo-Coco, F

Subjects
Male, 0301 basic medicine, Cancer Research, Phases of clinical research, Gastroenterology, Arsenicals, law.invention, 0302 clinical medicine, Arsenic Trioxide, Leukemia, Promyelocytic, Acute, Randomized controlled trial, Maintenance therapy, Risk Factors, law, Antineoplastic Combined Chemotherapy Protocols, Arsenical, Cumulative incidence, Prospective Studies, Oxides, Middle Aged, Leukemia, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Female, Human, medicine.drug, Adult, Acute promyelocytic leukemia, medicine.medical_specialty, Adolescent, Tretinoin, Young Adult, 03 medical and health sciences, Internal medicine, medicine, Humans, neoplasms, Aged, Antineoplastic Combined Chemotherapy Protocol, business.industry, Risk Factor, organic chemicals, Oxide, Induction chemotherapy, medicine.disease, biological factors, Surgery, Prospective Studie, 030104 developmental biology, Commentary, business, Settore MED/15 - Malattie del Sangue
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
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48. Acute Promyelocytic Leukemia-like AML: Genetic Perspective and Clinical Implications.

Author

Guarnera L, Fabiani E, Falconi G, Silvestrini G, Catanoso ML, Divona M, and Voso MT

Abstract

Acute promyelocytic leukemia (APL) is a rare type of AML, characterized by the t(15;17) translocation and accounting for 8-15% of cases. The introduction of target therapies, such as all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), radically changed the management of APL, making it the most curable AML subtype. However, a small percentage (estimated to be 2%) of AML presenting with APL-like morphology and/or immunophenotype lacks t(15;17). This rare APL-like AML group, whose first case was described in the early 1990s, now includes over 40 entities. These diseases present great heterogeneity in terms of genetic lesions, clinical presentation, sensitivity to targeted agents and chemotherapy, and prognosis. Furthermore, the diagnosis is very challenging. Thus, in this paper, we aim to comprehensively review the literature reports and studies addressing APL-like entities, investigate the biological mechanisms of leukemogenesis, evaluate the clinical characteristics, and discuss future lines of research and possible clinical approaches.

Published
2024
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49. Acute myeloid leukemia with paraneoplastic pemphigus successfully treated with a personalized antileukemic and immunosuppressive strategy.

Author

Iovene FR, Santinelli E, Armiento D, Sarlo C, Bancone C, Silvestri L, Erculei S, Sanhust MG, Cristiano A, Fabiani E, Divona M, Page C, Di Zenzo G, Cantonetti M, and Rigacci L

Subjects
Humans, Male, Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Pemphigoid, Bullous therapy, Pemphigoid, Bullous drug therapy, Cytarabine administration & dosage, Cytarabine therapeutic use, Immunosuppressive Agents therapeutic use, Pemphigus therapy, Pemphigus complications, Vidarabine analogs & derivatives, Vidarabine therapeutic use, Vidarabine administration & dosage, Immunoglobulins, Intravenous therapeutic use, Plasmapheresis, Precision Medicine, Leukemia, Myeloid, Acute therapy, Leukemia, Myeloid, Acute complications, Paraneoplastic Syndromes etiology, Paraneoplastic Syndromes therapy
Abstract

Bullous pemphigoid (BP) is a rare blistering disease often considered a primary sign of a paraneoplastic syndrome. Retrospective studies have established its link with hematological malignancies, particularly lymphoproliferative disorders. Here, we present what we believe to be the inaugural case of successful simultaneous management of BP and de novo acute myeloid leukemia (AML) in a 28-year-old male patient. Given the rarity and severity of both conditions, our treatment strategy aimed to maximize efficacy by combining immunosuppressive therapy (initially plasmapheresis with high-dose corticosteroids, followed by anti-CD20 monoclonal antibody and intravenous immunoglobulins 2 g/m 2 ) with lymphodepleting antileukemic chemotherapy utilizing Fludarabine (FLAG-IDA induction regimen). Following diagnosis, considering the patient's youth and the concurrent presence of two rare and potentially life-threatening diseases, we opted for an aggressive treatment. Upon achieving complete morphological remission of AML with measurable residual disease (MRD) negativity, despite incomplete resolution of BP, we proceeded with high-dose cytarabine consolidation followed by peripheral stem cell harvest and autologous stem cell transplantation (ASCT). Our conditioning regimen for ASCT involved Bu-Cy with the addition of anti-thymocyte globulins. At day + 100 post-ASCT, bone marrow evaluation confirmed morphological remission and MRD negativity. Meanwhile, BP had completely resolved with normalization of BP180 antibody levels., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Published
2024
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50. Applicability of 2022 classifications of acute myeloid leukemia in the real-world setting.

Author

Attardi E, Savi A, Borsellino B, Piciocchi A, Cipriani M, Ottone T, Fabiani E, Divona M, Travaglini S, Pascale MR, Awada H, Durmaz A, Visconte V, Della Porta MG, Venditti A, Maciejewski JP, Gurnari C, and Voso MT

Subjects
Humans, Prognosis, Cytogenetics, World Health Organization, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute complications, Myelodysplastic Syndromes diagnosis
Abstract

The increasing knowledge of molecular genetics of acute myeloid leukemia (AML) necessitated the update of previous diagnostic and prognostic schemes, which resulted in the development of the World Health Organization (WHO), the International Consensus Classification (ICC), and the new European LeukemiaNet (ELN) recommendations in 2022. We aimed to provide a real-world application of the new models, unravel differences and similarities, and test their implementation in clinical AML diagnosis. A total of 1001 patients diagnosed with AML were reclassified based on the new schemes. The overall diagnostic changes between the WHO 2016 and the WHO 2022 and ICC classifications were 22.8% and 23.7%, respectively, with a 13.1% difference in patients' distribution between ICC and WHO 2022. The 2022 ICC "not otherwise specified" and WHO "defined by differentiation" AML category sizes shrank when compared with that in WHO 2016 (24.1% and 26.8% respectively, vs 38.7%), particularly because of an expansion of the myelodysplasia (MDS)-related group. Of 397 patients with a MDS-related AML according to the ICC, 55.9% were defined by the presence of a MDS-related karyotype. The overall restratification between ELN 2017 and ELN 2022 was 12.9%. The 2022 AML classifications led to a significant improvement of diagnostic schemes. In the real-world setting, conventional cytogenetics, usually rapidly available and less expensive than molecular characterization, stratified 56% of secondary AML, still maintaining a powerful diagnostic role. Considering the similarities between WHO and ICC diagnostic schemes, a tentative scheme to generate a unified model is desirable., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Published
2023
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