1 research outputs found
Reduced SLIT2 is associated with increased cell proliferation and arsenic trioxide resistance in acute promyelocytic Leukemia
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