Surface IgM of CLL cells displays unusual glycans indicative of engagement of antigen in vivo

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BlankBlood, 27 May 2010, Vol. 115, No. 21, pp. 4198-4205.

Surface IgM of CLL cells displays unusual glycans indicative of engagement of

antigen in vivo

Sergey Krysov1, Kathleen N. Potter1, C. Ian Mockridge1, Vania Coelho1, Isla

Wheatley1, Graham Packham1, and Freda K. son1

1 Molecular Immunology Group, Cancer Sciences Division, University of

Southampton School of Medicine, Southampton, United Kingdom

Surface IgM (sIgM) has a key influence on the clinical behavior of chronic

lymphocytic leukemia (CLL). We now report that it exists in 2 forms with

different N-glycosylation patterns in the µ-constant region. One glycoform is

similar to normal B cells in bearing mature complex glycans common to most

cell-surface glycoproteins. The other is an immature mannosylated form more

characteristic of µ chains in the endoplasmic reticulum. Unmutated CLL (U-CLL)

expresses a higher proportion of mannosylated surface µ chains than mutated CLL.

Normal B cells express only the mature glycoform but can express the immature

form after persistent engagement of sIgM, suggesting that glycan modification is

a consequence of antigen exposure. CLL cells express variable proportions of the

mannosylated form and can revert to the mature form after incubation in vitro.

Both glycoforms are able to signal after sIgM engagement in vitro, leading to

enhanced tyrosine phosphorylation. These findings support the concept that CLL

cells are continuously exposed to antigen in vivo, driving the N-glycosylation

pattern of expressed sIgM toward a mannosylated form, especially in U-CLL.

Strikingly, this is reminiscent of follicular lymphoma, where mannosylated Ig is

expressed constitutively via N-glycosylation sites in the variable region,

suggesting a functional asset for this glycoform.