Investigating the role of the B-cell receptor in mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is a mature B-cell lymphoma typically characterised by the expression of cluster of differentiation 5 (CD5) and a t(11;14) translocation resulting in overexpression of cyclins. MCL displays significant morphological and clinical heterogeneity. Like chronic lymphocytic leukaemia (CLL), MCL can be divided into two subsets based upon immunoglobulin heavy chain variable (IGHV) region status: the more common unmutated (U-) IGHV and less common mutated (M-) IGHV subset. It has been suggested that, like in CLL, IGHV status informs different origin and clinical behaviour, with U-MCL being of pre-germinal centre (pre-GC) origin and aggressive clinical behaviour and M-MCL of post-GC origin and indolent course.
In CLL, B-cell receptor (BCR) levels and signalling capacity have also helped to define subgroups with important clinical and biological significance. This thesis aimed to extend investigations to the BCR of MCLs and understand if BCR expression and signalling variation in MCL could affect variation in clinical behaviour.
A cohort of thirty-six MCL cases were assessed for immunogenetic, phenotypic and functional characteristics including signalling capacity. IGHV3-21 and 4-34 were equally identified in U-MCL whilst IGHV4-34 was most common in M-MCL. Fifty percent (%) had an U-IGHV (>98% homology to germline). Surface immunoglobulin (sIg) M was expressed variably but significantly higher in conventional, nodal MCL (p=0.01) and non-aggressive U-MCL (p=0.03) than in leukaemic non-nodal (LNN) or M-MCL.
Surface IgM (sIgM) expression was higher in MCL than in CLL (p<0.01). Mean signalling capacity was significantly higher in MCL than CLL (p<0.01), and correlated positively with sIgM expression. A subgroup of MCL had low signalling capacity similar to CLL. This ‘CLL-like’ signalling group was composed predominantly of LNN MCL and IGHV3-21 U-MCL with low sIgM expression. In contrast to high signalling MCL cases, this group had a CLL-like BCR engaged functional phenotype: recoverable sIgM expression in vitro, high basal proximal signalling kinases and an ‘activated’ glycosylation profile on the constant Ig region.
MCL tissue and matched lymph node and peripheral blood samples were assessed. The lymph node compartment was identified as the likely site of engagement in non-aggressive MCL; sIgM levels were significantly lower in the lymph node than in the peripheral blood in all tissue and paired samples (p=0.03). Signalling capacity was also significantly lower in lymph node tissue samples (p<0.01). Lower sIgM levels in the lymph node may be indicative of site occurred antigen-induced endocytosis. M-MCL with low sIgM was associated with improved event-free survival (p=0.04).
This study reveals that a proportion of MCL have a BCR engaged signature with low sIgM and low signalling capacity. This likely occurs in the lymph node compartment as a result of the influence of putative (super)antigen, with down-modulation of sIgM. This is particularly prominent in LNN M-MCL and may affect the balance between proliferation and anergy. This mirrors other mature B-cell malignancies, particularly CLL, where this interaction influences clinical outcomes.

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ORCID for Francesco Forconi: orcid.org/0000-0002-2211-1831

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