Cancers (Oct 2020)
Reduced SLIT2 is Associated with Increased Cell Proliferation and Arsenic Trioxide Resistance in Acute Promyelocytic Leukemia
- Isabel Weinhäuser,
- Diego A. Pereira-Martins,
- Cesar Ortiz,
- Douglas R. Silveira,
- Luíse A. A. Simões,
- Thiago M. Bianco,
- Cleide L. Araujo,
- Luisa C. Koury,
- Raul A. M. Melo,
- Rosane I. Bittencourt,
- Katia Pagnano,
- Ricardo Pasquini,
- Elenaide C. Nunes,
- Evandro M. Fagundes,
- Ana B. Gloria,
- Fábio Kerbauy,
- Maria de Lourdes Chauffaille,
- Armand Keating,
- Martin S. Tallman,
- Raul C. Ribeiro,
- Richard Dillon,
- Arnold Ganser,
- Bob Löwenberg,
- Peter Valk,
- Francesco Lo-Coco,
- Miguel A. Sanz,
- Nancy Berliner,
- Emanuele Ammatuna,
- Antonio R. Lucena-Araujo,
- Jan Jacob Schuringa,
- Eduardo M. Rego
Affiliations
- Isabel Weinhäuser
- Department of Internal Medicine, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto 14048-900, Brazil
- Diego A. Pereira-Martins
- Department of Internal Medicine, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto 14048-900, Brazil
- Cesar Ortiz
- Department of Internal Medicine, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto 14048-900, Brazil
- Douglas R. Silveira
- Hematology Division, LIM31, Faculdade de Medicina, University of Sao Paulo, Sao Paulo 05403-000, Brazil
- Luíse A. A. Simões
- Center for Cell Based Therapy, University of São Paulo, Ribeirao Preto 14051-060, Brazil
- Thiago M. Bianco
- Department of Internal Medicine, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto 14048-900, Brazil
- Cleide L. Araujo
- Center for Cell Based Therapy, University of São Paulo, Ribeirao Preto 14051-060, Brazil
- Luisa C. Koury
- Department of Internal Medicine, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto 14048-900, Brazil
- Raul A. M. Melo
- Department of Internal Medicine, University of Pernambuco, Recife 50100-130, Brazil
- Rosane I. Bittencourt
- Hematology Division, Federal University of Rio Grande do Sul, Porto Alegre 96.200-190, Brazil
- Katia Pagnano
- Hematology and Hemotherapy Center, University of Campinas, Campinas 13083-878, Brazil
- Ricardo Pasquini
- Hematology Division, Federal University of Parana, Curitiba 13083-878, Brazil
- Elenaide C. Nunes
- Hematology Division, Federal University of Parana, Curitiba 13083-878, Brazil
- Evandro M. Fagundes
- Hematology Division, Federal University of Minas Gerais, Belo Horizonte 30130-100, Brazil
- Ana B. Gloria
- Hematology Division, Federal University of Minas Gerais, Belo Horizonte 30130-100, Brazil
- Fábio Kerbauy
- Hematology Division, Federal University of Sao Paulo, Sao Paulo 04023-062, Brazil
- Maria de Lourdes Chauffaille
- Hematology Division, Federal University of Sao Paulo, Sao Paulo 04023-062, Brazil
- Armand Keating
- Princess Margaret Cancer Centre, Toronto, ON M5G 2C1, Canada
- Martin S. Tallman
- Leukemia Service, Memorial Sloan-Kettering Cancer Center/Weill Cornell Medical College, New York, NY 10065, USA
- Raul C. Ribeiro
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
- Richard Dillon
- Department of Medical and Molecular Genetics, King’s College London School of Medicine, London WC2R 2LS, UK
- Arnold Ganser
- Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany
- Bob Löwenberg
- Department of Hematology, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
- Peter Valk
- Department of Hematology, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
- Francesco Lo-Coco
- Department of Biopathology, University Tor Vergata, 00133 Rome, Italy
- Miguel A. Sanz
- Department of Hematology, Hospital Universitari I Politècnic La Fe, 46-009 Valencia, Spain
- Nancy Berliner
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Emanuele Ammatuna
- Department of Experimental Hematology, Cancer Research Centre Groningen, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
- Antonio R. Lucena-Araujo
- Department of Genetics, Federal University of Pernambuco, Recife 50670-901, Brazil
- Jan Jacob Schuringa
- Department of Experimental Hematology, Cancer Research Centre Groningen, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
- Eduardo M. Rego
- Center for Cell Based Therapy, University of São Paulo, Ribeirao Preto 14051-060, Brazil
- DOI
- https://doi.org/10.3390/cancers12113134
- Journal volume & issue
-
Vol. 12,
no. 11
p. 3134
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 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.
Keywords