NTAL is associated with treatment outcome, cell proliferation and differentiation in acute promyelocytic leukemia

Abstract

non-t cell activation linker (ntAL) is a lipid raft-membrane protein expressed by normal and leukemic cells and involved in cell signaling. in acute promyelocytic leukemia (ApL), ntAL depletion from lipid rafts decreases cell viability through regulation of the Akt/PI3K pathway. The role of NTAL in APL cell processes, and its association with clinical outcome, has not, however, been established. Here, we show that reduced levels of ntAL were associated with increased all-trans retinoic acid (AtRA)induced differentiation, generation of reactive oxygen species, and mitochondrial dysfunction. Additionally, ntAL-knockdown (ntAL-KD) in ApL cell lines led to activation of Ras, inhibition of Akt/ mtoR pathways, and increased expression of autophagy markers, leading to an increased apoptosis rate following arsenic trioxide treatment. Furthermore, NTAL-KD in NB4 cells decreased the tumor burden in (noD scid gamma) nSG mice, suggesting its implication in tumor growth. A retrospective analysis of NTAL expression in a cohort of patients treated with AtRA and anthracyclines, revealed that

Reduced SLIT2 is Associated with Increased Cell Proliferation and Arsenic Trioxide Resistance in Acute Promyelocytic Leukemia

“…Interestingly, a more discrete anti-tumorigenic effect was observed in NB4-R2 cells (ATRA-resistant). This could be explained by the more aggressive phenotype observed on this cell line in comparison with the parental counterpart (NB4 cells) [30] Intriguingly, the knock-down of SLIT2 appeared to execute a more prominent effect than the peptide treatment, arguing that SLIT2 carries out not solely receptor mediated functions, but also important intracrine signaling worth further exploration.…”

The Expression of NTAL and Its Protein Interactors Is Associated With Clinical Outcomes in Acute Myeloid Leukemia

“…We have demonstrated that NTAL downregulation is associated with reduced cell viability and proliferation in APL and also leading to decreased tumor burden in vivo xenograft models of mantle cell lymphoma and leukemia (9,30). Here, we further extended our study of NTAL in AML, initially evaluating NTAL gene expression between several neoplastic cell lines using the Cancer Cell Line Encyclopedia.…”

“…A, sections of U937 (CT and NTAL-KD) tumors stained with hematoxylin and eosin or immunostained for NTAL. B, tumor masses derived after 2 weeks: U937: CT (1.073 g ± 0.1486) and NTAL-KD (0.5975 g ± 0.1506) (n = 4, p = 0.0287, 95% confidence interval) and NB4: CT (1.286 g ± 0.3137) and NTAL-KD (0.8540 g ± 0.3402) (n = 5, p = 0.0143, 95% confidence interval) ( * data published) (9). C, Western blotting analysis of total tumor protein extracts from engrafted tumors for NTAL, procaspase-3, p-Akt (Ser-473), Akt, Ras, p-p44/42 MAPK, and p44/42 MAPK (animals A1 = 1, A2 = 2, and A3 = 3).…”

“…However, NTAL-KD tumors presented a lower growth rate, and the mean tumor weight was reduced by 1.8fold for U973 NTAL-KD and 1.5-fold for NTAL-KD NB4 (Fig. 2B) (9). Also, the evaluation of proliferation and apoptotic markers in NTAL-KD xenograft tumors showed decreased levels of procaspase-3, p-Akt (Ser-473), Akt, Ras, p-p44/42 mitogen-activated protein kinase (MAPK), and total p44/42 MAPK proteins.…”

“…Recently, we extended the analysis about the functional role of NTAL in APL, showing that reduced NTAL levels were associated with increased alltrans retinoic acid (ATRA)-induced cell differentiation, reactive oxygen species generation, Ras activation, and Akt/mammalian target of rapamycin (mTOR) pathway inhibition. Furthermore, a retrospective analysis of NTAL expression in a cohort of patients with APL treated with ATRA plus anthracyclinebased chemotherapy revealed that high NTAL expression was associated with high leukocyte counts and decreased overall survival (OS) (9).…”