Reduced SLIT2 is Associated with Increased Cell Proliferation and Arsenic Trioxide Resistance in Acute Promyelocytic Leukemia.

Data de publicació: 27/10/2020 Data Ahead of Print: 27/10/2020

Autors de IIS La Fe

Miguel Ángel Sanz Alonso

Autor

Autors aliens a IIS La Fe

Weinhäuser I
Pereira-Martins DA
Ortiz C
Silveira DR
Simões LAA
Bianco TM
Araujo CL
Koury LC
Melo RAM
Bittencourt RI
Pagnano K
Pasquini R
Nunes EC
Fagundes EM
Gloria AB
Kerbauy F
Chauffaille ML
Keating A
Tallman MS
Ribeiro RC
Dillon R
Ganser A
Löwenberg B
Valk P
Lo-Coco F
Berliner N
Ammatuna E
Lucena-Araujo AR
Schuringa JJ
Rego EM

Grups d'Investigació

Hematología y Hemoterapia

Investigador Principal

Javier De La Rubia Comos

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 SLIT2 high transcript levels were associated with cell cycle arrest, while SLIT2 low 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.

Dades de la publicació

ISSN/ISSNe:: 2072-6694, 2072-6694
Tipus:: Article
Pàgines:: -
DOI:: 10.3390/cancers12113134
PubMed:: 33120864
Factor d'Impacte:: 1,818 SCImago ℠
Quartil:: Q1 SCImago ℠

Documents

No hi ha documents

Mètriques

Filiacions

Weinhäuser I:: Department of Internal Medicine, Department of Medical Images, Hematology, and Clinical Oncology, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto 14048-900, Brazil

Center for Cell Based Therapy, University of São Paulo, Ribeirao Preto 14051-060, Brazil
Pereira-Martins DA:: Department of Internal Medicine, Department of Medical Images, Hematology, and Clinical Oncology, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto 14048-900, Brazil

Center for Cell Based Therapy, University of São Paulo, Ribeirao Preto 14051-060, Brazil
Ortiz C:: Department of Internal Medicine, Department of Medical Images, Hematology, and Clinical Oncology, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto 14048-900, Brazil

Center for Cell Based Therapy, University of São Paulo, Ribeirao Preto 14051-060, Brazil
Silveira DR:: Hematology Division, LIM31, Faculdade de Medicina, University of Sao Paulo, Sao Paulo 05403-000, Brazil

Department of Hematology, AC Camargo Cancer Center, Sao Paulo 01525-001, Brazil
Simões LAA:: Center for Cell Based Therapy, University of São Paulo, Ribeirao Preto 14051-060, Brazil

Hematology Division, LIM31, Faculdade de Medicina, University of Sao Paulo, Sao Paulo 05403-000, Brazil
Bianco TM:: Department of Internal Medicine, Department of Medical Images, Hematology, and Clinical Oncology, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto 14048-900, Brazil
Araujo CL:: Center for Cell Based Therapy, University of São Paulo, Ribeirao Preto 14051-060, Brazil
Koury LC:: Department of Internal Medicine, Department of Medical Images, Hematology, and Clinical Oncology, Medical School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto 14048-900, Brazil
Melo RAM:: Department of Internal Medicine, University of Pernambuco, Recife 50100-130, Brazil
Bittencourt RI:: Hematology Division, Federal University of Rio Grande do Sul, Porto Alegre 96.200-190, Brazil
Pagnano K:: Hematology and Hemotherapy Center, University of Campinas, Campinas 13083-878, Brazil
Pasquini R:: Hematology Division, Federal University of Parana, Curitiba 13083-878, Brazil
Nunes EC:: Hematology Division, Federal University of Parana, Curitiba 13083-878, Brazil
Fagundes EM:: Hematology Division, Federal University of Minas Gerais, Belo Horizonte 30130-100, Brazil
Gloria AB:: Hematology Division, Federal University of Minas Gerais, Belo Horizonte 30130-100, Brazil
Kerbauy F:: Hematology Division, Federal University of Sao Paulo, Sao Paulo 04023-062, Brazil
Chauffaille ML:: Hematology Division, Federal University of Sao Paulo, Sao Paulo 04023-062, Brazil
Keating A:: Princess Margaret Cancer Centre, Toronto, ON M5G 2C1, Canada
Tallman MS:: Leukemia Service, Memorial Sloan-Kettering Cancer Center/Weill Cornell Medical College, New York, NY 10065, USA
Ribeiro RC:: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
Dillon R:: Department of Medical and Molecular Genetics, King's College London School of Medicine, London WC2R 2LS, UK
Ganser A:: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany
Lo-Coco F:: Department of Biopathology, University Tor Vergata, 00133 Rome, Italy

Santa Lucia Foundation, 00179 Rome, Italy
Sanz MA:: Department of Hematology, Hospital Universitari I Politècnic La Fe, 46-009 Valencia, Spain

CIBERONC, Instituto Carlos III, 28029 Madrid, Spain
Berliner N:: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Lucena-Araujo AR:: Department of Genetics, Federal University of Pernambuco, Recife 50670-901, Brazil
Rego EM:: Center for Cell Based Therapy, University of São Paulo, Ribeirao Preto 14051-060, Brazil

Hematology Division, LIM31, Faculdade de Medicina, University of Sao Paulo, Sao Paulo 05403-000, Brazil

Keywords

ATRA, SLIT2, acute promyelocytic leukemia, treatment outcomes

Campos d'Estudi

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