title: Aberrant expression of functional BAFF-system receptors by malignant B-cell precursors impacts leukemia cell survival.
abstract: Despite exhibiting oncogenic events, patient's leukemia cells are responsive and dependent on signals from their malignant bone marrow (BM) microenvironment, which modulate their survival, cell cycle progression, trafficking and resistance to chemotherapy. Identification of the signaling pathways mediating this leukemia/microenvironment interplay is critical for the development of novel molecular targeted therapies.We observed that primary leukemia B-cell precursors aberrantly express receptors of the BAFF-system, BAFF-R, BCMA, and TACI. These receptors are functional as their ligation triggers activation of NF-κB, MAPK/JNK, and Akt signaling. Leukemia cells express surface BAFF and APRIL ligands, and soluble BAFF is significantly higher in leukemia patients in comparison to age-matched controls. Interestingly, leukemia cells also express surface APRIL, which seems to be encoded by APRIL-δ, a novel isoform that lacks the furin convertase domain. Importantly, we observed BM microenvironmental cells express the ligands BAFF and APRIL, including surface and secreted BAFF by BM endothelial cells. Functional studies showed that signals through BAFF-system receptors impact the survival and basal proliferation of leukemia B-cell precursors, and support the involvement of both homotypic and heterotypic mechanisms.This study shows an unforeseen role for the BAFF-system in the biology of precursor B-cell leukemia, and suggests that the target disruption of BAFF signals may constitute a valid strategy for the treatment of this cancer.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Sara
authors.initials: S
authors.lastname: Maia
authors.forename: Marc
authors.initials: M
authors.lastname: Pelletier
authors.forename: Jixin
authors.initials: J
authors.lastname: Ding
authors.forename: Yen-Ming
authors.initials: YM
authors.lastname: Hsu
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.forename: Sambasiva P
authors.initials: SP
authors.lastname: Rao
authors.forename: Lee M
authors.initials: LM
authors.lastname: Nadler
authors.forename: Angelo A
authors.initials: AA
authors.lastname: Cardoso
mesh_terms: D000595:Amino Acid Sequence; D053264:B-Cell Activating Factor / Q000235:genetics; D053265:B-Cell Activation Factor Receptor / Q000235:genetics*; D053301:B-Cell Maturation Antigen / Q000235:genetics*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000737:chemistry / Q000235:genetics
chemical_list: D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; D016328:NF-kappa B; C505719:TNFSF13B protein, human; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases