Reduced SLIT2 is Associated with Increased Cell Proliferation and Arsenic Trioxide Resistance in Acute Promyelocytic Leukemia
Open Access
- 27 October 2020
- Vol. 12 (11), 3134
- https://doi.org/10.3390/cancers12113134
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.Keywords
This publication has 41 references indexed in Scilit:
- Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid LeukemiaNew England Journal of Medicine, 2013
- Is the T1/2N1 (≤3 nodes) category actually stage IIIA (TNM)/IIIa (Japanese classification) in patients with primary colorectal cancer?Oncology Reports, 2011
- miR-218 Suppresses Nasopharyngeal Cancer Progression through Downregulation of Survivin and the SLIT2-ROBO1 PathwayCancer Research, 2011
- Identification and Characterization of Bmi-1-responding Element within the Human p16 Promoter*Journal of Biological Chemistry, 2010
- Tumour-initiating cells: challenges and opportunities for anticancer drug discoveryNature Reviews Drug Discovery, 2009
- Prediction of molecular subtypes in acute myeloid leukemia based on gene expression profilingHaematologica, 2009
- Slit-2 Induces a Tumor-suppressive Effect by Regulating β-Catenin in Breast Cancer CellsJournal of Biological Chemistry, 2008
- Genome-scale loss-of-function screening with a lentiviral RNAi libraryNature Methods, 2006
- Leukemia with distinct phenotypes in transgenic mice expressing PML/RARα, PLZF/RARα or NPM/RARαOncogene, 2005
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005