title: Targeting B-cell anergy in chronic lymphocytic leukemia.
abstract: B-cell receptor (BCR) triggering and responsiveness have a crucial role in the survival and expansion of chronic lymphocytic leukemia (CLL) clones. Analysis of in vitro response of CLL cells to BCR triggering allowed the definition of 2 main subsets of patients and lack of signaling capacity was associated with constitutive activation of extracellular-regulated kinases 1/2 (ERK1/2) and nuclear factor of activated T cells c1 (NF-ATc1), consistent with the idea that at least one group of CLL patients derives from the abnormal expansion of anergic B cells. In the present work, we further investigated the anergic subset of CLL (defined as the one with constitutive ERK1/2 phosphorylation) and found that it is characterized by low levels of surface immunoglobulin M and impairment of calcium mobilization after BCR engagement in vitro. Chronic BCR triggering promoted CLL cell survival selectively in phosphorylated ERK1/2 samples and the use of mitogen-activated protein kinase and NF-AT signaling inhibitors specifically induced apoptosis in this group of patients. Apoptosis induction was preceded by an initial phase of anergy reversal consisting in the loss of ERK phosphorylation and NF-AT nuclear translocation and by the restoration of BCR responsiveness, reinforcing the idea that the anergic program favors the survival of leukemic lymphocytes.
authors: Division of Molecular Oncology, San Raffaele Scientific Institute, Milano, Italy.
authors: Benedetta
authors: B
authors: Apollonio
authors: Cristina
authors: C
authors: Scielzo
authors: Maria Teresa Sabrina
authors: MT
authors: Bertilaccio
authors: Elisa
authors: E
authors: Ten Hacken
authors: Lydia
authors: L
authors: Scarfò
authors: Pamela
authors: P
authors: Ranghetti
authors: Freda
authors: F
authors: Stevenson
authors: Graham
authors: G
authors: Packham
authors: Paolo
authors: P
authors: Ghia
authors: Marta
authors: M
authors: Muzio
authors: Federico
authors: F
authors: Caligaris-Cappio
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D017635:Clonal Anergy / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D007142:Immunoglobulin gamma-Chains / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000276:immunology / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy / Q000379:methods*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D007142:Immunoglobulin gamma-Chains; C499308:Rag2 protein, mouse; D011947:Receptors, Antigen, B-Cell