Targeting B-cell anergy in chronic lymphocytic leukemia.

Benedetta Apollonio, Cristina Scielzo, Maria Teresa Sabrina Bertilaccio, Elisa Ten Hacken, Lydia Scarfò, Pamela Ranghetti, Freda Stevenson, Graham Packham, Paolo Ghia, Marta Muzio, Federico Caligaris-Cappio

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalBlood
Volume121
Issue number19
DOIs
Publication statusPublished - May 9 2013

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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  • Cite this

    Apollonio, B., Scielzo, C., Bertilaccio, M. T. S., Ten Hacken, E., Scarfò, L., Ranghetti, P., Stevenson, F., Packham, G., Ghia, P., Muzio, M., & Caligaris-Cappio, F. (2013). Targeting B-cell anergy in chronic lymphocytic leukemia. Blood, 121(19). https://doi.org/10.1182/blood-2012-12-474718