Enhanced levels of both the membrane-bound and soluble forms of IgM Fc receptor (FcμR) in patients with chronic lymphocytic leukemia

Abstract

The association of an IgM-Fc receptor (FcR) with chronic lymphocytic leukemia (CLL) was suggested more than 30 years ago, but its authenticity has never been formally addressed. We exam IntroductionChronic lymphocytic leukemia (CLL) is the most common leukemia of adults in Western countries and accounts for ϳ 30% of all cases of leukemia in the United States. It is a heterogeneous leukemia that is thought to originate from antigen-stimulated B cells that escape from normal cell death mechanisms. 1,2 Survival of CLL patients ranges from a few years to several decades. The most reliable marker thus far for predicting the prognosis of CLL is the mutation status in the immunoglobulin heavy chain variable region (IGHV). Unmutated (UM)-CLL is aggressive and mutated (MT)-CLL is more indolent. [3][4][5] Because DNA sequencing is not practical for most clinical laboratories, various cell surface and intracellular proteins have been explored as potential surrogate markers. ZAP-70, a Syk family tyrosine kinase normally expressed in T cells, has proved to be a very good indicator for UM-CLL, but the required intracellular staining is technically challenging and results in diagnostic inconsistency among clinical laboratories. [6][7][8][9][10][11] Other markers, including membrane proteins (eg, CD38, Fc receptor-like protein 2) and serum proteins (eg, thymidine kinase, soluble CD23, and ␤2-microglobulin), also have been studied as surrogate prognostic indicators. 3,4,[12][13][14][15][16][17] The association of the IgM Fc receptor (FcR) with CLL has long been suggested based on the ability of CLL cells to form rosettes with IgM-coated erythrocytes. [18][19][20][21][22] Unfortunately, this early intriguing suggestion was not pursued thereafter, probably because of uncertainties with such a crude detection procedure. During the course of analysis of B-cell activation antigens with the BAC-1 mouse IgM monoclonal antibody (mAb), we serendipitously found an IgM-binding protein of ϳ 60 kDa that was expressed on CLL B cells and activated normal B cells by immunofluorescence and biochemical analyses using various IgM ligands. 23,24 The gene encoding an authentic FcR has defied identification until our recent discovery of a bona fide FcR cDNA in the B-lineage libraries, including one library derived from CLL B cells. 25 Surprisingly, the corresponding FCMR gene had been already reported as TOSO or Fas apoptosis inhibitory molecule 3 (FAIM3). 26 Notably, the reported inhibition of apoptosis was based on an assay in which apoptosis was induced by ligation of Fas on the Jurkat T-cell line with a mouse IgM mAb (CH11). Our results indicated that FcR per se had no inhibitory activity in Fas-mediated apoptosis and that such inhibition was only achieved when anti-Fas mAb of an IgM but not IgG isotype was used for inducing apoptosis. 25 This incorrect designation has led to the misconception that enhanced FAIM3/TOSO expression by CLL cells may be linked to their resistance to cell death mechanisms. [27][28][29] Here, we examined the expression...

FcμR Interacts and Cooperates with the B Cell Receptor To Promote B Cell Survival

“…Malignant B cells from patients with chronic lymphocytic leukemia (B-CLL) express much higher levels of FcmR than normal B cells from healthy donors (30,31). Antigenic stimulation through the BCR is thought to promote the outgrowth of B-CLL (32,33), and our results suggest that elevated FcmR expression may enhance a BCR-triggered survival signal and contribute to the pathogenesis of B-CLL.…”

Altered Ig levels and antibody responses in mice deficient for the Fc receptor for IgM (FcμR)

“…Because the half-life of the injected IgM is the same in Fcmr KO and WT control mice, FcμR does not appear to be involved in IgM catabolism likely mediated by LSECs, but rather is involved in the production and/or secretion of IgM by B and/or plasma cells. In humans, chronic lymphocytic leukemia (CLL) B cells overexpress cell surface FcμR and rapidly ingest IgM ligands through this receptor (20,21). Curiously, as many CLL patients have reduced serum Ig levels including IgM, it would be worthwhile to determine whether this reduction is related to the enhanced expression of FcμR on the leukemic B cells.…”

Critical role of the IgM Fc receptor in IgM homeostasis, B-cell survival, and humoral immune responses

“…It remains to be elucidated how FcμR-mediated signals cooperate with BCRderived signals to promote B-cell survival. Interestingly, it was recently reported that the malignant B cells from patients with chronic lymphocytic leukemia (CLL) express much higher levels of FcμR than normal B cells from healthy donors (33). It is widely believed that the initial expansion and prolonged survival of the CLL B-cell clone are driven by self-antigen (34).…”