TY - JOUR
T1 - Reduced SLIT2 is associated with increased cell proliferation and arsenic trioxide resistance in acute promyelocytic Leukemia
AU - Weinhäuser, Isabel
AU - Pereira-Martins, Diego A.
AU - Ortiz, Cesar
AU - Silveira, Douglas R.
AU - Simões, Luíse A.A.
AU - Bianco, Thiago M.
AU - Araujo, Cleide L.
AU - Koury, Luisa C.
AU - Melo, Raul A.M.
AU - Bittencourt, Rosane I.
AU - Pagnano, Katia
AU - Pasquini, Ricardo
AU - Nunes, Elenaide C.
AU - Fagundes, Evandro M.
AU - Gloria, Ana B.
AU - Kerbauy, Fábio
AU - De Lourdes Chauffaille, Maria
AU - Keating, Armand
AU - Tallman, Martin S.
AU - Ribeiro, Raul C.
AU - Dillon, Richard
AU - Ganser, Arnold
AU - Löwenberg, Bob
AU - Valk, Peter
AU - Lo-Coco, Francesco
AU - Sanz, Miguel A.
AU - Berliner, Nancy
AU - Ammatuna, Emanuele
AU - Lucena-Araujo, Antonio R.
AU - Schuringa, Jan Jacob
AU - Rego, Eduardo M.
N1 - Funding Information:
Funding: This investigation was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Grant #2013/08135-2). D.A.P.-M. received a fellowship from FAPESP (Grant #2017/23117-1). I.W. received a fellowship from FAPESP (Grant #2015/09228-0).
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/11
Y1 - 2020/11
N2 - 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.
AB - 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.
KW - ATRA
KW - Acute promyelocytic leukemia
KW - SLIT2
KW - Treatment outcomes
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UR - http://www.scopus.com/inward/citedby.url?scp=85094889696&partnerID=8YFLogxK
U2 - 10.3390/cancers12113134
DO - 10.3390/cancers12113134
M3 - Article
C2 - 33120864
AN - SCOPUS:85094889696
SN - 2072-6694
VL - 12
SP - 1
EP - 16
JO - Cancers
JF - Cancers
IS - 11
M1 - 3134
ER -
