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6. Pre-transplant persistence of minimal residual disease does not contraindicate allogeneic stem cell transplantation for adult patients with acute myeloid leukemia

Author

Buccisano, F, Maurillo, L, Piciocchi, A, Del Principe, M I, Picardi, A, Cerretti, R, Cudillo, L, De Angelis, G, Sarlo, C, Cefalo, M, Ditto, C, Di Veroli, A, Mariotti, B, Nasso, D, De Bellis, E, Del Poeta, G, Voso, M T, Sconocchia, G, Lo Coco, F, Arcese, W, Amadori, S, and Venditti, A

Published
2017
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8. 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. Alterations of the BCL-6 Gene in Diffuse Large-Cell Lymphoma

Author

Ye, B. H., Lo Coco, F., Chang, C.-C., Zhang, J., Migliazza, A., Cechova, K., Knowles, D. M., Offit, K., Chaganti, R. S. K., Dalla-Favera, R., Capron, A., editor, Compans, R. W., editor, Cooper, M., editor, Koprowski, H., editor, McConnell, I., editor, Melchers, F., editor, Oldstone, M., editor, Olsnes, S., editor, Potter, Michael, editor, Saedler, H., editor, Vogt, P. K., editor, Wagner, H., editor, Wilson, I., editor, and Melchers, Fritz, editor

Published
1995
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15. 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

16. 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

17. IN ADULT ACUTE MYELOID LEUKEMIA (AML) PERIPHERAL BLOOD MEASURABLE RESIDUAL DISEASE (MRD) BY FLOW CYTOMETRY (FC) IS FEASIBLE AND IS PROGNOSTICALLY RELEVANT

Author

Maurillo, L, Buccisano, F, Piciocchi, A, Del Principe, M, Candoni, A, Melillo, L, Calafiore, V, Cairoli, R, De Fabritiis, P, Storti, G, Salutari, P, Lanza, F, Martinelli, G, Luppi, M, Mazza, P, Martelli, M, Cuneo, A, Albano, F, Fabbiano, F, Tafuri, A, Chierichini, A, Tieghi, A, Fracchiolla, N, Capelli, D, Foa, R, Alati, C, La Sala, E, Voso, M, Fazi, P, Vignetti, M, Consalvo, M, Ottone, T, Lavorgna, S, Arcese, W, Lo Coco, F, Amadori, S, Venditti, A, Maurillo L, Buccisano F, Piciocchi A, Del Principe MI, Candoni A, Melillo L, Calafiore V, Cairoli R, De Fabritiis P, Storti G, Salutari P, Lanza F, Martinelli G, Luppi M, Mazza P, Martelli MP, Cuneo A, Albano F, Fabbiano F, Tafuri A, Chierichini A, Tieghi A, Fracchiolla NS, Capelli D, Foa R, Alati C, La Sala E, Voso MT, Fazi P, Vignetti M, Consalvo MI, Ottone T, Lavorgna S, Arcese W, Lo Coco F, Amadori S, Venditti a., Maurillo, L, Buccisano, F, Piciocchi, A, Del Principe, M, Candoni, A, Melillo, L, Calafiore, V, Cairoli, R, De Fabritiis, P, Storti, G, Salutari, P, Lanza, F, Martinelli, G, Luppi, M, Mazza, P, Martelli, M, Cuneo, A, Albano, F, Fabbiano, F, Tafuri, A, Chierichini, A, Tieghi, A, Fracchiolla, N, Capelli, D, Foa, R, Alati, C, La Sala, E, Voso, M, Fazi, P, Vignetti, M, Consalvo, M, Ottone, T, Lavorgna, S, Arcese, W, Lo Coco, F, Amadori, S, Venditti, A, Maurillo L, Buccisano F, Piciocchi A, Del Principe MI, Candoni A, Melillo L, Calafiore V, Cairoli R, De Fabritiis P, Storti G, Salutari P, Lanza F, Martinelli G, Luppi M, Mazza P, Martelli MP, Cuneo A, Albano F, Fabbiano F, Tafuri A, Chierichini A, Tieghi A, Fracchiolla NS, Capelli D, Foa R, Alati C, La Sala E, Voso MT, Fazi P, Vignetti M, Consalvo MI, Ottone T, Lavorgna S, Arcese W, Lo Coco F, Amadori S, and Venditti a.

Published
2019

21. Genome-wide association study identifies susceptibility loci for acute myeloid leukemia

Author

Lin WY, Fordham SE, Hungate E, Sunter NJ, Elstob C, Xu Y, Park C, Quante A, Strauch K, Gieger C, Skol A, Rahman T, Sucheston-Campbell L, Wang J, Hahn T, Clay-Gilmour AI, Jones GL, Marr HJ, Jackson GH, Menne T, Collin M, Ivey A, Hills RK, Burnett AK, Russell NH, Fitzgibbon J, Larson RA, Le Beau MM, Stock W, Heidenreich O, Alharbi A, Allsup DJ, Houlston RS, Norden J, Dickinson AM, Douglas E, Lendrem C, Daly AK, Palm L, Piechocki K, Jeffries S, Bornhäuser M, Röllig C, Altmann H, Ruhnke L, Kunadt D, Wagenführ L, Cordell HJ, Darlay R, Andersen MK, Fontana MC, Martinelli G, Marconi G, Sanz MA, Cervera J, Gómez-Seguí I, Cluzeau T, Moreilhon C, Raynaud S, Sill H, Voso MT, Lo-Coco F, Dombret H, Cheok M, Preudhomme C, Gale RE, Linch D, Gaal-Wesinger J, Masszi A, Nowak D, Hofmann WK, Gilkes A, Porkka K, Milosevic Feenstra JD, Kralovics R, Grimwade D, Meggendorfer M, Haferlach T, Krizsán S, Bödör C, Stölzel F, Onel K, and Allan JM

Subjects
RISK, HLA, OLDER PATIENTS, AML, hemic and lymphatic diseases, HUMAN-LEUKOCYTE ANTIGEN, HIF-1-ALPHA, IMMUNE ESCAPE, CLONAL EVOLUTION, CANCER, GENE-MUTATIONS
Abstract

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10 -8 ; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10 -10 ; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).

Published
2021

22. Characteristics and outcome of acute myeloid leukemia with uncommon retinoic acid receptor-alpha (RARA) fusion variants

Author

Cicconi, L., Testi, A. M., Montesinos, P., Rego, E., Zhu, H. H., Takahashi, H., Dworzak, M., Estey, E., Schwarer, A., Esteve, J., Annibali, O., Castelli, R., Mirabile, M., Angelini, M., Lazarevic, V., Kumar, J., Avvisati, G., Gurnari, C., Locatelli, Franco, Voso, M. T., Sanz, M. A., Lo-Coco, F., Abla, O., Locatelli F. (ORCID:0000-0002-7976-3654), Cicconi, L., Testi, A. M., Montesinos, P., Rego, E., Zhu, H. H., Takahashi, H., Dworzak, M., Estey, E., Schwarer, A., Esteve, J., Annibali, O., Castelli, R., Mirabile, M., Angelini, M., Lazarevic, V., Kumar, J., Avvisati, G., Gurnari, C., Locatelli, Franco, Voso, M. T., Sanz, M. A., Lo-Coco, F., Abla, O., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

NO ABSTRACT

Published
2021

24. 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 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, and Lo-Coco, F

Subjects
Hematology
Published
2019

25. 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

28. 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

29. Obesity is a risk factor for acute promyelocytic leukemia: evidence from population and cross-sectional studies studies and correlation with flt3 mutations and polyunsaturated fatty acid metabolism

Author

Mazzarella L, Botteri E, Matthews A, Gatti E, Di Salvatore D, Bagnardi V, Breccia M, Montesinos P, Bernal T, Gil C, Ley TJ, Sanz M, Bhaskaran K, Lo Coco F, and Pelicci PG

Subjects
Acute Myeloid Leukemia, Acute Promyelocytic Leukemia, Clinical and Molecular Epidemiology, Cytogenetics and Molecular Genetics, hemic and lymphatic diseases
Abstract

Obesity correlates with hematological malignances including leukemias, but risk of specific leukemia subtypes like Acute Promyelocytic Leukemia and underlying molecular mechanisms are poorly understood. We explored multiple datasets for correlation between leukemia, Body Mass Index and molecular features. In a population-based study (n=5.2 million), we correlated Body Mass Index with promyelocytic, other acute myeloid, lymphoid or other leukemias. In cross-sectional studies, we tested body mass index deviation in promyelocytic leukemia trial cohorts from what expected based on national surveys. We interrogated The Cancer Genome Atlas for transcriptional signatures and mutations enriched in promyelocytic leukemia and/or obesity and confirmed correlation between body mass and FLT3 mutations in promyelocytic leukemia cohorts by logistic regression. In the population-based study, Hazard Ratio per 5 kg/m2 increase was: promyelocytic leukemia 1.44 (95% CI 1.0-2.08); non-promyelocytic acute myeloid leukemias 1.17 (1.10-1.26); lymphoid leukemias 1.04 (1.0-1.09); other 1.10 (1.04-1.15). In cross-sectional studies, body mass deviated significantly from expected (Italy p

Published
2020

32. NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia

Author

Thomé, C. (Carolina), Ferreira, G.A. (Germano Aguiar), Pereira-Martins, D.A. (Diego Antonio), dos Santos, G.A. (Guilherme Augusto), Ortiz, C.A. (César Alexander), de Souza, L.E.B. (Lucas Eduardo Botelho), Sobral, L.M. (Lays Martins), Silva, C.L.A. (Cleide Lúcia Araújo), Scheucher, P.S. (Priscila Santos), Gil, C.D. (Cristiane Damas), Leopoldino, A.M. (Andréia Machado), Silveira, D.R.A. (Douglas R. A.), Coelho-Silva, J.L. (Juan L.), Traina, F. (Fabíola), Koury, L.C. (Luisa C.), Melo, R.A. (Raul), Bittencourt, H.N.S. (Henrique), Pagnano, K. (Katia), Pasquini, R. (Ricardo), Nunes, E.C. (Elenaide C.), Fagundes, E.M. (Evandro), Gloria, A.B.F. (Ana Beatriz F.), Kerbauy, F.R. (Fábio Rodrigues), Chauffaille, M.d.L. (Maria de Lourdes), Keating, A. (Armand), Tallman, M.S. (Martin), Ribeiro, R.C. (Raul), Dillon, R. (Richard), Ganser, A. (Arnold), Löwenberg, B. (Bob), Valk, P.J.M. (Peter), Lo-Coco, F. (Francesco), Sanz, M.A. (Miguel Angel), Berliner, N. (Nancy), Faça, V.M. (Vitor Marcel), Rego, E.M. (Eduardo), Thomé, C. (Carolina), Ferreira, G.A. (Germano Aguiar), Pereira-Martins, D.A. (Diego Antonio), dos Santos, G.A. (Guilherme Augusto), Ortiz, C.A. (César Alexander), de Souza, L.E.B. (Lucas Eduardo Botelho), Sobral, L.M. (Lays Martins), Silva, C.L.A. (Cleide Lúcia Araújo), Scheucher, P.S. (Priscila Santos), Gil, C.D. (Cristiane Damas), Leopoldino, A.M. (Andréia Machado), Silveira, D.R.A. (Douglas R. A.), Coelho-Silva, J.L. (Juan L.), Traina, F. (Fabíola), Koury, L.C. (Luisa C.), Melo, R.A. (Raul), Bittencourt, H.N.S. (Henrique), Pagnano, K. (Katia), Pasquini, R. (Ricardo), Nunes, E.C. (Elenaide C.), Fagundes, E.M. (Evandro), Gloria, A.B.F. (Ana Beatriz F.), Kerbauy, F.R. (Fábio Rodrigues), Chauffaille, M.d.L. (Maria de Lourdes), Keating, A. (Armand), Tallman, M.S. (Martin), Ribeiro, R.C. (Raul), Dillon, R. (Richard), Ganser, A. (Arnold), Löwenberg, B. (Bob), Valk, P.J.M. (Peter), Lo-Coco, F. (Francesco), Sanz, M.A. (Miguel Angel), Berliner, N. (Nancy), Faça, V.M. (Vitor Marcel), and Rego, E.M. (Eduardo)

Abstract

Non-T cell activation linker (NTAL) is a lipid raft-membrane protein expressed by normal and leukemic cells and involved in cell signaling. In acute promyelocytic leukemia (APL), NTAL depletion from lipid rafts decreases cell viability through regulation of the Akt/PI3K pathway. The role of NTAL in APL cell processes, and its association with clinical outcome, has not, however, been established. Here, we show that reduced levels of NTAL were associated with increased all-trans retinoic acid (ATRA)-induced differentiation, generation of reactive oxygen species, and mitochondrial dysfunction. Additionally, NTAL-knockdown (NTAL-KD) in APL cell lines led to activation of Ras, inhibition of Akt/mTOR pathways, and increased expression of autophagy markers, leading to an increased apoptosis rate following arsenic trioxide treatment. Furthermore, NTAL-KD in NB4 cells decreased the tumor burden

Published
2020
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33. Reduced SLIT2 is associated with increased cell proliferation and arsenic trioxide resistance in acute promyelocytic Leukemia

Author

Weinhäuser, I., Pereira-Martins, D.A., Ortiz, C., Silveira, D.R., Simões, L.A.A., Bianco, T.M., Araujo, C.L., Koury, L.C.D., Melo, R.A. (Raul), Bittencourt, R.I., Pagnano, K. (Katia), Pasquini, R. (Ricardo), Nunes, E.C., Fagundes, E.M. (Evandro), Gloria, ABF, Kerbauy, F., De Lourdes Chauffaille, M., Keating, A, Tallman, M.S. (Martin), Ribeiro, R.C. (Raul), Dillon, R, Ganser, A. (Arnold), Löwenberg, B., Valk, P.J.M. (Peter), Lo-Coco, F. (Francesco), Sanz, M.A. (Miguel Angel), Berliner, N. (Nancy), Ammatuna, E., Lucena-Araujo, A.R. (Antonio), Schuringa, J.J. (Jan Jacob), Rego, E.M. (Eduardo), Weinhäuser, I., Pereira-Martins, D.A., Ortiz, C., Silveira, D.R., Simões, L.A.A., Bianco, T.M., Araujo, C.L., Koury, L.C.D., Melo, R.A. (Raul), Bittencourt, R.I., Pagnano, K. (Katia), Pasquini, R. (Ricardo), Nunes, E.C., Fagundes, E.M. (Evandro), Gloria, ABF, Kerbauy, F., De Lourdes Chauffaille, M., Keating, A, Tallman, M.S. (Martin), Ribeiro, R.C. (Raul), Dillon, R, Ganser, A. (Arnold), Löwenberg, B., Valk, P.J.M. (Peter), Lo-Coco, F. (Francesco), Sanz, M.A. (Miguel Angel), Berliner, N. (Nancy), Ammatuna, E., Lucena-Araujo, A.R. (Antonio), Schuringa, J.J. (Jan Jacob), and Rego, E.M. (Eduardo)

Abstract

The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate SLIT2 expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemia. Hence, we aimed to investigate the levels of SLIT2 in acute promyelocytic leukemia (APL) and assess its biological activity in vitro and in vivo. Our analysis indicated that blasts with SLIT2high transcript levels were associated with cell cycle arrest, while SLIT2low APL blasts displayed a more stem-cell like phenotype. In a retrospective analysis using a cohort of patients treated with all-trans retinoic acid (ATRA) and anthracyclines, high SLIT2 expression was correlated with reduced leukocyte count (p = 0.024), and independently associated with improved overall survival (hazard ratio: 0.94; 95% confidence interval: 0.92–0.97; p < 0.001). Functionally, SLIT2-knockdown in primary APL blasts and cell lines led to increased cell proliferation and resistance to arsenic trioxide induced apoptosis. Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count (p = 0.001) and decreased overall survival (p = 0.002) compared with the control. In summary, our data highlight the tumor suppressive function of SLIT2 in APL and its deteriorating effects on disease progression when downregulated.

Published
2020
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34. Obesity is a risk factor for acute promyelocytic leukemia: evidence from population and cross-sectional studies studies and correlation with flt3 mutations and polyunsaturated fatty acid metabolism

Author

Mazzarella, L, Botteri, E, Matthews, A, Gatti, E, Di Salvatore, D, Bagnardi, V, Breccia, M, Montesinos, P, Bernal, T, Gil, C, Ley, T, Sanz, M, Bhaskaran, K, Lo Coco, F, Pelicci, P, Mazzarella, Luca, Botteri, Edoardo, Matthews, Anthony, Gatti, Elena, Di Salvatore, Davide, Bagnardi, Vincenzo, Breccia, Massimo, Montesinos, Pau, Bernal, Teresa, Gil, Cristina, Ley, Timothy J, Sanz, Miguel, Bhaskaran, Krishnan, Lo Coco, Francesco, Pelicci, Pier Giuseppe, Mazzarella, L, Botteri, E, Matthews, A, Gatti, E, Di Salvatore, D, Bagnardi, V, Breccia, M, Montesinos, P, Bernal, T, Gil, C, Ley, T, Sanz, M, Bhaskaran, K, Lo Coco, F, Pelicci, P, Mazzarella, Luca, Botteri, Edoardo, Matthews, Anthony, Gatti, Elena, Di Salvatore, Davide, Bagnardi, Vincenzo, Breccia, Massimo, Montesinos, Pau, Bernal, Teresa, Gil, Cristina, Ley, Timothy J, Sanz, Miguel, Bhaskaran, Krishnan, Lo Coco, Francesco, and Pelicci, Pier Giuseppe

Abstract

Obesity correlates with hematologic malignancies including leukemias, but risk of specific leukemia subtypes like acute promyelocytic leukemia and underlying molecular mechanisms are poorly understood. We explored multiple datasets for correlation between leukemia, body mass index (BMI) and molecular features. In a population-based study (n=5.2 million), we correlated BMI with promyelocytic leukemia, and other acute myeloid, lymphoid or other leukemias. In cross-sectional studies, we tested BMI deviation in promyelocytic leukemia trial cohorts from that expected based on national surveys. We explored The Cancer Genome Atlas for transcriptional signatures and mutations enriched in promyelocytic leukemia and/or obesity, and confirmed a correlation between body mass and FLT3 mutations in promyelocytic leukemia cohorts by logistic regression. In the population-based study, hazard ratio per 5 kg/m2 increase was: promyelocytic leukemia 1.44 (95%CI: 1.0-2.08), non-promyelocytic acute myeloid leukemias 1.17 (95%CI: 1.10-1.26), lymphoid leukemias 1.04 (95%CI: 1.0-1.09), other 1.10 (95%CI: 1.04-1.15). In cross-sectional studies, body mass deviated significantly from that expected (Italy: P<0.001; Spain: P=0.011; USA: P<0.001). Promyelocytic leukemia showed upregulation of polyunsaturated fatty acid metabolism genes. Odds of FLT3 mutations were higher in obese acute myeloid leukemias (odds ratio=2.4, P=0.007), whether promyelocytic or not, a correlation confirmed in the pooled promyelocytic leukemia cohorts (OR=1.22, 1.05-1.43 per 5 kg/m2). These results strengthen the evidence for obesity as a bona fide risk factor for myeloid leukemias, and in particular APL. FLT3 mutations and polyunsaturated fatty acid metabolism may play a previously under-appreciated role in obesity-associated leukemogenesis.

Published
2020

36. NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia

Author

Thome, CH, Ferreira, GA, Pereira-Martins, DA, dos Santos, GA, Ortiz, CA, de Souza, LEB, Sobral, LM, Silva, CLA, Scheucher, PS, Gil, CD, Leopoldino, AM, Silveira, DR, Coelho-Silva, JL, Traina, F, Koury, LCD, Melo, RA, Bittencourt, R, Pagnano, K, Pasquini, R, Nunes, EC, Fagundes, EM, Gloria, ABF, Kerbauy, FR, Chauffaille, MD, Keating, A, Tallman, MS, Ribeiro, RC, Dillon, R, Ganser, A, Löwenberg, Bob, van der Valk, P, Lo-Coco, F, Sanz, MA, Berliner, N, Faca, VM, Rego, EM, Thome, CH, Ferreira, GA, Pereira-Martins, DA, dos Santos, GA, Ortiz, CA, de Souza, LEB, Sobral, LM, Silva, CLA, Scheucher, PS, Gil, CD, Leopoldino, AM, Silveira, DR, Coelho-Silva, JL, Traina, F, Koury, LCD, Melo, RA, Bittencourt, R, Pagnano, K, Pasquini, R, Nunes, EC, Fagundes, EM, Gloria, ABF, Kerbauy, FR, Chauffaille, MD, Keating, A, Tallman, MS, Ribeiro, RC, Dillon, R, Ganser, A, Löwenberg, Bob, van der Valk, P, Lo-Coco, F, Sanz, MA, Berliner, N, Faca, VM, and Rego, EM

Published
2020

37. Reduced SLIT2 is associated with increased cell proliferation and arsenic trioxide resistance in acute promyelocytic Leukemia

Author

Weinhäuser, I, Pereira-Martins, DA, Ortiz, C, Silveira, DR, Simões, LAA, Bianco, TM, Araujo, CL, Koury, LCD, Melo, RA, Bittencourt, RI, Pagnano, K, Pasquini, R, Nunes, EC, Fagundes, EM, Gloria, ABF, Kerbauy, F, De Lourdes Chauffaille, M, Keating, A, Tallman, MS, Ribeiro, RC, Dillon, R, Ganser, A, Löwenberg, Bob, Valk, Peter, Lo-Coco, F, Sanz, MA, Berliner, N, Ammatuna, E, Lucena-Araujo, AR, Schuringa, JJ, Rego, EM, Weinhäuser, I, Pereira-Martins, DA, Ortiz, C, Silveira, DR, Simões, LAA, Bianco, TM, Araujo, CL, Koury, LCD, Melo, RA, Bittencourt, RI, Pagnano, K, Pasquini, R, Nunes, EC, Fagundes, EM, Gloria, ABF, Kerbauy, F, De Lourdes Chauffaille, M, Keating, A, Tallman, MS, Ribeiro, RC, Dillon, R, Ganser, A, Löwenberg, Bob, Valk, Peter, Lo-Coco, F, Sanz, MA, Berliner, N, Ammatuna, E, Lucena-Araujo, AR, Schuringa, JJ, and Rego, EM

Published
2020

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