title: Regulation of Mcl-1 expression in context to bone marrow stromal microenvironment in chronic lymphocytic leukemia.
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.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX; Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
authors.forename: Kumudha
authors.initials: K
authors.lastname: Balakrishnan
authors.affiliation: Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
authors.forename: Min
authors.initials: M
authors.lastname: Fu
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
authors.forename: Tejaswini
authors.initials: T
authors.lastname: Doifode
authors.affiliation: Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX; Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX. Electronic address: vgandhi@mdanderson.org.
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
mesh_terms: D000328:Adult; D000368:Aged; D001854:Bone Marrow Cells / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger