title: Interaction with vascular endothelium enhances survival in primary chronic lymphocytic leukemia cells via NF-kappaB activation and de novo gene transcription.
abstract: Chronic lymphocytic leukemia (CLL) cells rapidly undergo apoptosis in vitro, suggesting that the in vivo microenvironment provides crucial antiapoptotic signals. Overexpression of the antiapoptotic proteins Bcl-2 and Mcl-1 is a hallmark of CLL, and their expression is further enhanced in the lymphoid tissues. However, the high levels of Mcl-1 found in peripheral blood samples, coupled with its short half-life, led us to hypothesize that it must be actively maintained in the peripheral circulation. Coculture of CLL cells with human vascular endothelial cells significantly enhanced tumor cell survival, an effect that was not observed with normal B cells. This was associated with elevated levels of the antiapoptotic proteins Bcl-2, Mcl-1, and Bcl-X(L) and marked increased expression of CD38 and CD49d, both of which are associated with clinically aggressive disease. Because CD38, CD49d, and some Bcl-2 family genes are transcriptional targets for NF-κB, we assessed NF-κB activation following coculture with endothelial cells. DNA binding of the NF-κB subunit Rel A was significantly increased and strongly correlated with changes in transcription of CD38, CD49d, BCL2, MCL1, and BCLXL, effects that were reversed by a peptide inhibitor of Rel A. These effects were not observed following coculture with nonendothelial cell lines. Therefore, CLL cells receive specific survival signals following interaction with endothelial cells mediated through the activation of NF-κB and the induction of downstream target genes. This type of interaction in the peripheral vasculature may explain the constitutive NF-κB activation and the overexpression of Bcl-2 family proteins commonly seen in this disease.
authors.affiliation: Department of Haematological Medicine, King's College London, London, United Kingdom.
authors.forename: Andrea G S
authors.initials: AG
authors.lastname: Buggins
authors.forename: Chris
authors.initials: C
authors.lastname: Pepper
authors.forename: Piers E M
authors.initials: PE
authors.lastname: Patten
authors.forename: Saman
authors.initials: S
authors.lastname: Hewamana
authors.forename: Satyen
authors.initials: S
authors.lastname: Gohil
authors.forename: Jane
authors.initials: J
authors.lastname: Moorhead
authors.forename: Najeem'deen
authors.initials: N
authors.lastname: Folarin
authors.forename: Deborah
authors.initials: D
authors.lastname: Yallop
authors.forename: N Shaun B
authors.initials: NS
authors.lastname: Thomas
authors.forename: Ghulam J
authors.initials: GJ
authors.lastname: Mufti
authors.forename: Chris
authors.initials: C
authors.lastname: Fegan
authors.forename: Stephen
authors.initials: S
authors.lastname: Devereux
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D018920:Coculture Techniques; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D039441:Integrin alpha4 / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D004273:DNA, Neoplasm; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D051996:Transcription Factor RelA; D039441:Integrin alpha4; D051997:ADP-ribosyl Cyclase 1