Submitted September 6, 2007
Accepted February 16, 2008
Constitutive activation of distinct BCR-signaling pathways in a subset of CLL patients: a molecular signature of anergy
Marta Muzio, Benedetta Apollonio, Cristina Scielzo, Michela Frenquelli, Irene Vandoni, Vassiliki Boussiotis, Federico Caligaris-Cappio*, and Paolo Ghia
Department of Oncology, Unit and Laboratory of Lymphoid Malignancies, Universita Vita-Salute San Raffaele and Istituto Scientifico San Raffaele, Milano, Italy
Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
* Corresponding author; email: caligaris.federico{at}hsr.it.
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 crosslinking 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 two 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) a proportion of CLL patients express constitutively phosphorylated ERK1/2 in the absence of AKT activation; b) these cases display constitutive phosphorylation of MEK1/2 and increased NF-AT transactivation; and c) are 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 MAP kinase signaling pathway along with NFAT 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.
