title: Stromal endothelial cells establish a bidirectional crosstalk with chronic lymphocytic leukemia cells through the TNF-related factors BAFF, APRIL, and CD40L.
abstract: Chronic lymphocytic leukemia (CLL) is a clonal B cell disorder of unknown origin. Accessory signals from the microenvironment are critical for the survival, expansion, and progression of malignant B cells. We found that the CLL stroma included microvascular endothelial cells (MVECs) expressing BAFF and APRIL, two TNF family members related to the T cell-associated B cell-stimulating molecule CD40L. Constitutive release of soluble BAFF and APRIL increased upon engagement of CD40 on MVECs by CD40L aberrantly expressed on CLL cells. In addition to enhancing MVEC expression of CD40, leukemic CD40L induced cleavases that elicited intracellular processing of pro-BAFF and pro-APRIL proteins in MVECs. The resulting soluble BAFF and APRIL proteins delivered survival, activation, Ig gene remodeling, and differentiation signals by stimulating CLL cells through TACI, BAFF-R, and BCMA receptors. BAFF and APRIL further amplified CLL cell survival by upregulating the expression of leukemic CD40L. Inhibition of TACI, BCMA, and BAFF-R expression on CLL cells; abrogation of CD40 expression in MVECs; or suppression of BAFF and APRIL cleavases in MVECs reduced the survival and diversification of malignant B cells. These data indicate that BAFF, APRIL, and CD40L form a CLL-enhancing bidirectional signaling network linking neoplastic B cells with the microvascular stroma.
authors.affiliation: Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Cols
authors.forename: Carolina M
authors.initials: CM
authors.lastname: Barra
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.forename: Irene
authors.initials: I
authors.lastname: Puga
authors.forename: Weifeng
authors.initials: W
authors.lastname: Xu
authors.forename: April
authors.initials: A
authors.lastname: Chiu
authors.forename: Wayne
authors.initials: W
authors.lastname: Tam
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Knowles
authors.forename: Stacey R
authors.initials: SR
authors.lastname: Dillon
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.forename: Richard R
authors.initials: RR
authors.lastname: Furman
authors.forename: Kang
authors.initials: K
authors.lastname: Chen
authors.forename: Andrea
authors.initials: A
authors.lastname: Cerutti
mesh_terms: D053264:B-Cell Activating Factor / Q000378:metabolism*; D015139:Blotting, Southern; D023201:CD40 Ligand / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D020239:Receptor Cross-Talk / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000378:metabolism*
chemical_list: D053264:B-Cell Activating Factor; C505719:TNFSF13B protein, human; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D023201:CD40 Ligand