Activation of Wnt/β‐catenin pathway mediates growth and survival in B‐cell progenitor acute lymphoblastic leukaemia

Abstract

SummaryThis study investigated the response of acute lymphoblastic leukaemia (ALL) cells to Wnt proteins. Accumulation of b-catenin was measured by Western blotting and immunofluorescence microscopy. Reverse transcription polymerase chain reaction (RT-PCR) analysis of B-cell progenitor acute lymphoblastic leukaemia (ALL) cells revealed expression of Wnt genes, including WNT2B in 33%, WNT5A in 42%, WNT10B in 58% and WNT16B in 25% of cases. The Wnt receptors, (Frizzled) FZD7 and FZD8 were also expressed in most cases while FZD3, FZD4 and FZD9 were occasionally detected. Stimulation of ALL cells with Wnt-3a activated canonical Wnt signalling with increased expression and nuclear translocation of b-catenin. This resulted in a 1AE7-to 5AE3-fold increase in cell proliferation, which was associated with enhanced cell cycle entry. A significant increase in the survival of ALL cells under conditions of serum deprivation was also observed. Microarray analysis and quantitative RT-PCR revealed that activation of the Wnt/b-catenin pathway led to altered expression of genes involved in cell cycle regulation and apoptosis in normal and leukaemic B-cell progenitors. Our results demonstrate that Wnt-3a provides proliferative and survival cues in ALL cells. This data suggests that targeting the Wnt signalling pathway may be a useful therapeutic strategy in ALL.

In vitro study of the effects of ELF electric fields on gene expression in human epidermal cells

“…The most frequent leukemia in the child is acute lymphoblastic leukemia (ALL). Several papers concerning this subject indicate an activation of the Wnt signaling pathway in ALL [Khan et al, 2007] and an increase in the concentration of β-catenin [Chung et al, 2002]. Other articles showed inhibition of the Wnt signaling pathway as "an attractive target for the use of more specific therapies…" [Román-Gómez, 2007].…”

The EMT activator ZEB1 promotes tumor growth and determines differential response to chemotherapy in mantle cell lymphoma

“…[45][46][47] In several hematological malignancies, including MCLs, Wnt signaling enhances cell viability, whereas its inhibition reduces it. 5,15,17,18,20 We therefore questioned whether ZEB1 determines enhanced cell viability in MCL cells. As shown in Figure 4a, knockdown of ZEB1 resulted in a partial decrease of MCL basal cell viability that was similar to that obtained by interference of b-catenin.…”

“…1,[3][4][5][6][7][8][9][10][11] Of particular interest is the canonical Wnt pathway that has a crucial role in normal hematopoiesis and whose aberrant activation, long known to drive tumorigenesis in solid tumors, has also been involved in a number of hematological malignancies, including MCLs. 3,5,6,[12][13][14][15][16][17][18][19]20 In addition to gain-of-function mutations of intracellular components of the Wnt pathway, overexpression of Wnt receptors and ligands or downregulation of Wnt inhibitors through nongenetic modifications are also common. 3,[5][6][7]21 Short-lived response and development of resistance to first-line immunochemotherapy are major challenges in MCL and new therapeutic strategies are being developed.…”

“…1,22,23 Constitutive Wnt signaling associates to increased cellular proliferation and higher resistance to apoptosis and chemotherapy in subsets of leukemias and lymphomas and established cell lines derived from them, including MCLs. 3,5,6,13,[15][16][17][18][19][20] In turn, inhibitors of Wnt pathway induce cytotoxicity in leukemia and lymphoma cells. 5,16,17 The characterization in MCLs of a subpopulation of stem-like cells retaining the capacity for tumor initiation could help explaining relapses and also offers new avenues in MCL treatment.…”

Microenvironment and its role in acquire drug resistance of leukemia treatment

“…WNT/ β-catenin signaling pathway regulates variety of development function in different tissue including the hematopoietic tissue [19]. In leukemia, WNT signaling is expressed in B-cell and BM-MSCs in higher level than the normal status [20]. Activated WNT by BM microenvironment protects B-ALL from death to chemotherapy [20].…”