Reduced SLIT2 is associated with increased cell proliferation and arsenic trioxide resistance in acute promyelocytic leukemia Journal Article
| Authors: | Weinhäuser, I.; Pereira-Martins, D. A.; Ortiz, C.; Silveira, D. R.; Simões, L. A. A.; Bianco, T. M.; Araujo, C. L.; Koury, L. C.; Melo, R. A. M.; Bittencourt, R. I.; Pagnano, K.; Pasquini, R.; Nunes, E. C.; Fagundes, E. M.; Gloria, A. B.; Kerbauy, F.; De Lourdes Chauffaille, M.; Keating, A.; Tallman, M. S.; Ribeiro, R. C.; Dillon, R.; Ganser, A.; Löwenberg, B.; Valk, P.; Lo-Coco, F.; Sanz, M. A.; Berliner, N.; Ammatuna, E.; Lucena-Araujo, A. R.; Schuringa, J. J.; Rego, E. M. |
| Article Title: | Reduced SLIT2 is associated with increased cell proliferation and arsenic trioxide resistance in acute promyelocytic leukemia |
| 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. © 2020 by the authors. Licensee MDPI, Basel, Switzerland. |
| Keywords: | adult; controlled study; protein expression; aged; human cell; major clinical study; overall survival; cancer growth; nonhuman; cytarabine; follow up; protein function; cell proliferation; animal cell; mouse; phenotype; apoptosis; animal experiment; animal model; cohort analysis; in vivo study; in vitro study; drug resistance; retrospective study; arsenic trioxide; biological activity; promyelocytic leukemia; cell cycle arrest; down regulation; hematopoietic stem cell; leukocyte count; anthracycline; retinoic acid; acute promyelocytic leukemia; promyelocyte; treatment outcomes; clinical outcome; atra; survival prediction; human; male; female; article; slit2 protein; slit2 |
| Journal Title: | Cancers |
| Volume: | 12 |
| Issue: | 11 |
| ISSN: | 2072-6694 |
| Publisher: | MDPI |
| Date Published: | 2020-11-01 |
| Start Page: | 3134 |
| Language: | English |
| DOI: | 10.3390/cancers12113134 |
| PROVIDER: | scopus |
| PMCID: | PMC7693375 |
| PUBMED: | 33120864 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2020 -- Source: Scopus |
