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Chronic Lymphocytic Leukemia
In vitro and in vivo evidence for uncoupling of B-cell receptor internalization and signaling in chronic lymphocytic leukemia
Eve M. Coulter,1 Andrea Pepper,2 Silvia Mele,3 Najeem’deen Folarin,4
William Townsend,1 Kirsty Cuthill,4 Elizabeth H. Phillips,1 Piers E. M. Patten1,4 and Stephen Devereux4
1School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King’s College London; 2Brighton and Sussex Medical School, Medical research Building, University of Sussex, Brighton; 3St John’s Institute of Dermatology, Department of Genetics and Molecular Medicine, King's College London and 4Department of Haematological Medicine, Kings College Hospital, London, UK
ABSTRACT
B-cell receptor activation, occurring within lymph nodes, plays a key role in the pathogenesis of chronic lymphocytic leukemia and is linked to prognosis. As well as activation of downstream signaling, receptor ligation triggers internalization, transit to acidified endosomes and degradation of ligand-receptor complexes. Herein, we investigated the relationship between these two processes in normal and leukemic B cells. We found that leukemic B cells, particularly anergic cases lacking the capacity to initiate downstream signaling, internalize and accumu- late ligand in acidified endosomes more efficiently than normal B cells. Furthermore, ligation of either surface CD79B, a B-cell receptor compo- nent required for downstream signaling, or surface Immunoglobulin M (IgM) by cognate agonistic antibody, showed that the two molecules internalize independently of each other in leukemic but not normal B cells. Since association with surface CD79B is required for surface reten- tion of IgM, this suggests that uncoupling of B-cell receptor internaliza- tion from signaling may be due to the dissociation of these two mole- cules in leukemic cells. A comparison of lymph node with peripheral blood cells from chronic lymphocytic leukemia patients showed that, despite recent B-cell receptor activation, lymph node B cells expressed higher levels of surface IgM. This surprising finding suggests that the B- cell receptors of lymph node- and peripheral blood-derived leukemic cells might be functionally distinct. Finally, long-term therapy with the Bruton’s tyrosine kinase inhibitors ibrutinib or acalabrutinib resulted in a switch to an anergic pattern of B-cell receptor function with reduced sig- naling capacity, surface IgM expression and more efficient internaliza- tion.
Introduction
It is now clear that signaling through the B-cell receptor (BCR) plays a key role in the pathogenesis of chronic lymphocytic leukemia (CLL) and other lymphomas. Several components of this pathway, including Syk,1 Erk,2 Akt,3 NFAT4 and NFκB5 can be constitutively activated and drugs that target BCR signaling, such as the Bruton’s tyrosine kinase inhibitors (BTKi), ibrutinib and acalabrutinib, are proving extremely effective in the clinic.6,7 BCR responsiveness varies markedly between patients with CLL and is linked to prognosis.8 Some cases show features of anergy,4,9 a pattern that is associated with lack of ability to transduce a down- stream signal in response to BCR ligation and the presence of markers of good prognosis, including low levels of CD38 and mutated immunoglobulin heavy- chain variable (IGHV) genes. In contrast, cases with responsive or signaling com- petent BCRs usually express high levels of CD38, have unmutated IGHV genes and a more unfavorable clinical course;10 interestingly, these patients tend to respond more rapidly to BCR antagonists than those with anergic BCRs. Although BTKi therapy is very successful in controlling CLL, it is not curative and many
Ferrata Storti Foundation
Haematologica 2018 Volume 103(3):497-505
Correspondence:
eve.coulter@kcl.ac.uk
Received: July 21, 2017.
Accepted: December 12, 2017. Pre-published: December 14, 2017.
doi:10.3324/haematol.2017.176164
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/3/497
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haematologica | 2018; 103(3)
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