The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells

Reduced expression of the tumor suppressor PHLPP1 enhances the antiapoptotic B-cell receptor signal in chronic lymphocytic leukemia B-cells

“…3 This antiapoptotic BCR signal was shown to depend on induction of the Bcl-2 family protein Mcl-1, which is post-transcriptionally regulated by the Akt kinase. 4 To determine whether expression of PHLPP1 will affect the propagation of this antiapoptotic signal, CLL B-cells from 13 patients were nucleofected with PHLPP1a mRNA, placed in culture for 3 h to allow for maximal expression of PHLPP1 protein and then stimulated for additional 20 h with immobilized anti-IgM. Annexin V/propidium iodide staining showed that the viability of anti-IgM-stimulated CLL cells transfected with PHLPP1a mRNA was significantly reduced with respect to cells transfected with control mRNA, demonstrating that PHLPP1 expression inhibits the antiapoptotic BCR signal (Figure 5a).…”

“…1,2 A key signaling molecule downstream of the BCR in CLL B-cells is the Akt kinase, sustained activation of which induces changes in the expression of several cell cycle and apoptosisregulatory proteins, including cyclin D3, Mcl-1, Bcl-xL and XIAP. [3][4][5] This kinase is also activated in response to many other microenvironmental stimuli that increase leukemic cell survival or induce proliferation, including CXCL12, CD40 ligand, IL-4, CpG oligonucleotides, lysophosphatidic acid, high-density lipoprotein particles and contact with bone marrow stromal cells. [6][7][8][9][10][11][12][13] In addition, increased basal Akt activity has been reported in some studies, suggesting that constitutive Akt signaling may contribute to the increased survival of the malignant lymphocytes.…”

Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis

“…34 Briefly, 2 Â 10 6 per ml of CLL cells were stimulated using 100 U of IL2 (R&D Systems, Minneapolis, MN, USA) and 1 mM CpG oligonucleotides (ODN2006FInvivogen, San Diego, CA, USA). They were then incubated with or without 1 mM VPA for 48 h. Proliferation was measured using a WST1 (2-(4-lodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium) assay (Roche Diagnostics, Mannheim, Germany): 10 ml of WST1 reagent was directly added to the cultured cells, incubated for 4 h (at 37 1C, 5% CO 2 ) and quantified spectrophotometrically at 450 nm.…”

N-(4-hydroxyphenyl)retinamide promotes apoptosis of resting and proliferating B-cell chronic lymphocytic leukemia cells and potentiates fludarabine and ABT-737 cytotoxicity

“…CLL cells display increased levels of antiapoptotic Bcl-2 family members, particularly CLL cells from lymph nodes, 4 from patients resistant to chemotherapy 5 or subjected in vitro to microenvironment stimuli. 6 Especially relevant is Mcl-1, for which elevated levels are associated with poor treatment response and high risk of CLL disease progression. 7,8 Mcl-1 reduction strategies were able to restore in vitro chemotherapic cytotoxicity.…”

“…7,8 Mcl-1 reduction strategies were able to restore in vitro chemotherapic cytotoxicity. 6,9 CLL cells are sensitive to oxidative stress. They lose viability when incubated with H 2 O 2 -generating systems 10 and display compromised antioxidant defense.…”