RRC ID 65506
Author Balakrishnan K, Burger JA, Fu M, Doifode T, Wierda WG, Gandhi V.
Title Regulation of Mcl-1 expression in context to bone marrow stromal microenvironment in chronic lymphocytic leukemia.
Journal Neoplasia
Abstract A growing body of evidence suggests that the resistance of CLL cells to apoptosis is partly mediated through the interactions between leukemia cells and adjacent stromal cells residing in the lymphatic tissue or bone marrow microenvironment. Mcl-1, an anti-apoptotic protein that is associated with failure to treatment is up-regulated in CLL lymphocytes after interaction with microenvironment. However, the regulation of its expression in context to microenvironment is unclear. We evaluated and compared changes in Mcl-1 in CLL B-cells in suspension culture and when co-cultured on stromal cells. The blockade of apoptosis in co-cultured CLL cells is associated with diminution in caspase-3 and PARP cleavage and is not dependent on cytogenetic profile or prognostic factors of the disease. Stroma-derived resistance to apoptosis is associated with a cascade of transcriptional events such as increase in levels of total RNA Pol II and its phosphorylation at Ser2 and Ser5, increase in the rate of global RNA synthesis, and amplification of Mcl-1 transcript levels. The latter is associated with increase in Mcl-1 protein level without an impact on the levels of Bcl-2 and Bcl-xL. Post-translational modifications of protein kinases show increased phosphorylation of Akt at Ser473, Erk at Thr202/Tyr204 and Gsk-3β at Ser9 and augmentation of total Mcl-1 accumulation along with phosphorylation at Ser159/Thr163 sites. Collectively, stroma-induced apoptosis resistance is mediated through signaling proteins that regulate transcriptional and translational expression and post-translational modification of Mcl-1 in CLL cells in context to bone marrow stromal microenvironment.
Volume 16(12)
Pages 1036-46
Published 2014-12-1
DOI 10.1016/j.neo.2014.10.002
PII S1476-5586(14)00150-X
PMID 25499217
PMC PMC4309260
MeSH Adult Aged Bone Marrow Cells / metabolism* Cell Proliferation Cell Survival Female Flow Cytometry Gene Expression Regulation, Leukemic / physiology* Humans Leukemia, Lymphocytic, Chronic, B-Cell / blood Leukemia, Lymphocytic, Chronic, B-Cell / genetics* Leukemia, Lymphocytic, Chronic, B-Cell / pathology Male Middle Aged Myeloid Cell Leukemia Sequence 1 Protein / genetics* Proto-Oncogene Proteins c-bcl-2 / genetics RNA, Messenger / genetics Real-Time Polymerase Chain Reaction Stromal Cells / metabolism Tumor Cells, Cultured
IF 5.696
Human and Animal Cells StromaNKtert(RCB2350)