Down regulation of membrane‐bound Neu3 constitutes a new potential marker for childhood acute lymphoblastic leukemia and induces apoptosis suppression of neoplastic cells

Abstract

Membrane-linked sialidase Neu3 is a key enzyme for the extralysosomal catabolism of gangliosides. In this respect, it regulates pivotal cell surface events, including trans-membrane signaling, and plays an essential role in carcinogenesis. In this report, we demonstrated that acute lymphoblastic leukemia (ALL), lymphoblasts (primary cells from patients and cell lines) are characterized by a marked down-regulation of Neu3 in terms of both gene expression (230 to 40%) and enzymatic activity toward ganglioside GD1a (225.6 to 30.6%), when compared with cells from healthy controls. Induced overexpression of Neu3 in the ALL-cell line, MOLT-4, led to a significant increase of ceramide (166%) and to a parallel decrease of lactosylceramide (255%). These events strongly guided lymphoblasts to apoptosis, as we assessed by the decrease in Bcl2/ Bax ratio, the accumulation of Neu3 transfected cells in the sub G0-G1 phase of the cell cycle, the enhanced annexin-V positivity, the higher cleavage of procaspase-3. Therefore, the reduced expression of Neu3 in ALL could help lymphoblasts to survive, maintaining the cellular content of ceramide below a critical level. Interestingly, we found that Neu3 activity varied in relation to disease progression, increasing in clinical remission after chemotherapy, and decreasing again in patients that relapsed. In addition, a negative correlation was observed between Neu3 expression and the percentage of the ALL marker 9-OAcGD3 positive cells. Consequently, Neu3 could represent a new potent biomarker in childhood ALL, to assess the efficacy of therapeutic protocols and to rapidly identify an eventual relapse.

RETRACTED ARTICLE: 9-O-acetylated sialic acids differentiating normal haematopoietic precursors from leukemic stem cells with high aldehyde dehydrogenase activity in children with acute lymphoblastic leukaemia

“…Moreover, the high expression of Neu5,9Ac 2 -GPs on the lymphoblasts plays a role in their survival [39,40] and that of O-acetylated sialoglycoconjugates in maturation of erythrocytes [41]. These expressions are orchestrated by a series of enzymes [42][43][44][45]. Therefore, modulating one or more of these enzymes and/or targeting them for drugtargeted immunotherapy might be of help in managing this disease.…”

Bak Compensated for Bax in p53-null Cells to Release Cytochrome c for the Initiation of Mitochondrial Signaling during Withanolide D-Induced Apoptosis

“…Phosphatidyl-serine externalization was analyzed by double staining the cells with FITC-annexin V and PI (5 µg/ml) [38]. Alternatively, treated cells were stained with 7-AAD for 30 minutes.…”

Bioactive Sphingolipids in Response to Chemotherapy: A Scope on Leukemias

“…However some genetic changes altering the expressions of hematopoietic transcription factors are suspected to be responsible for the malignant transformation [164] (for more detailed information about characteristics of ALL, please see reviews [165] and [166]). A recent report showed that membrane-bound sialidase, an enzyme responsible for the degradation of gangliosides, was downregulated in ALL; and when sialidase was overexpressed, apoptotic induction was obtained with the concomitant increase in ceramide levels and decrease in lactosylceramide [167]. By another report, ganglioside GD3 was found to be upregulated [168] and O-acetylated in ALL cells rendering it unable to induce apoptosis suggesting that it is a survival trick adopted by leukemic cells [169].…”