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.

M2-polarized macrophages control LSC fate by enhancing stemness, homing, immune evasion and metabolic reprogramming

“…These data were further validated in our murine PML-RARA model (28), whereby the injection of murine BM-derived M0 and M2d macrophage significantly increased the absolute number of murine APL blast cells retrieved from the BM compared to control mice 10 days after the transplant (Figure 2F). These data indicate that alterations in the BM niche can impact on the progression of leukemia and suggest that the presence of an immunosuppressive environment can facilitate the engraftment of favorable AML samples.…”

Bcl‐2 hijacks the arsenic trioxide resistance in SH‐SY5Y cells

“… 21 However, more and more different genetic mutations were predicted to have the relation with ATO resistance and disease recurrence. 22 In comparison with the genetic variants, we characterized at the Bcl‐2 protein level to demonstrate the cancer cells can acquire resistance ability by increasing the Bcl‐2 expression. Novel agents target Bcl‐2 and combinatorial treatment based on these findings are needed to solve the issue of ATO resistance in patients with relapsed APL.…”

“…Most clinical researches focused on the PML B2 domain mutations in patients who acquired ATO resistance 21 . However, more and more different genetic mutations were predicted to have the relation with ATO resistance and disease recurrence 22 . In comparison with the genetic variants, we characterized at the Bcl‐2 protein level to demonstrate the cancer cells can acquire resistance ability by increasing the Bcl‐2 expression.…”

Acute Promyelocytic Leukemia

“…An integrative score in APL, combining gene mutations with expression analysis, has therefore been proposed, categorizing patients in different sets with differences in terms of response rate, relapse, and survival [ 1 ]. The clinical relevance of the SLIT2 gene, an embryonic gene from the SLIT-ROBO family, was reported in an international study [ 3 ]. Reduced SLIT2 expression was associated with high leukocyte counts and reduced overall survival.…”

“…Reduced SLIT2 expression was associated with high leukocyte counts and reduced overall survival. Blasts with SLIT2 high transcript levels were associated with cell cycle arrest, while SLIT2 low blasts displayed a more stem-cell like phenotype [ 3 ]. This study suggests that the tumor suppressive function of SLIT2 could be considered as a prognostic marker in APL.…”