title: Constitutive activation of distinct BCR-signaling pathways in a subset of CLL patients: a molecular signature of anergy.
abstract: Stimulation through the B-cell antigen receptor (BCR) is believed to be involved in the natural history of chronic lymphocytic leukemia (CLL). Some cases respond to the in vitro cross-linking of surface immunoglobulin (sIg) with effective activation. In contrast, the remaining cases do not respond to such stimulation, thereby resembling B cells anergized after antigen encounter in vivo. However the biochemical differences between the 2 groups are ill defined, and in humans the term B-cell anergy lacks a molecular definition. We examined the expression and activation of key molecules involved in signaling pathways originating from the BCR, and we report that a proportion of CLL patients (a) expresses constitutively phosphorylated extracellular signal-regulated kinase (ERK)1/2 in the absence of AKT activation; (b) displays constitutive phosphorylation of MEK1/2 and increased nuclear factor of activated T cells (NF-AT) transactivation; and (c) is characterized by cellular unresponsiveness to sIg ligation. This molecular profile recapitulates the signaling pattern of anergic murine B cells. Our data indicate that constitutive activation of mitogen activated protein (MAP) kinase signaling pathway along with NF-AT transactivation in the absence of AKT activation may also represent the molecular signature of anergic human B lymphocytes. CLL cases with this signature may be taken as a human model of anergic B cells aberrantly expanded.
authors.affiliation: Department of Oncology, Unit and Laboratory of Lymphoid Malignancies, Università Vita-Salute San Raffaele and Istituto Scientifico San Raffaele, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Muzio
authors.forename: Benedetta
authors.initials: B
authors.lastname: Apollonio
authors.forename: Cristina
authors.initials: C
authors.lastname: Scielzo
authors.forename: Michela
authors.initials: M
authors.lastname: Frenquelli
authors.forename: Irene
authors.initials: I
authors.lastname: Vandoni
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Boussiotis
authors.forename: Federico
authors.initials: F
authors.lastname: Caligaris-Cappio
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
mesh_terms: D002460:Cell Line; D017635:Clonal Anergy; D006801:Humans; D066298:In Vitro Techniques; D019169:Jurkat Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000145:classification / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D050778:NFATC Transcription Factors / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D050778:NFATC Transcription Factors; D011947:Receptors, Antigen, B-Cell; D051057:Proto-Oncogene Proteins c-akt