In:
Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 4959-4959
Abstract:
Introduction. Hairy cell leukemia (HCL) is a rare chronic B cell lymphoproliferative disorder characterized by massive infiltration of the spleen by cells displaying a unique “hairy” morphology and surface phenotype. The ontogeny of hairy cells (HCs) and the mechanism underlying their accumulation in the spleen remain elusive. Growing evidence indicates that B cell-activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) play important roles in malignant B cells. BAFF and APRIL are usually produced by myeloid cells and engage three receptors on B cells known as transmembrane activator and calcium modulator and cyclophylin ligand interactor (TACI), B cell maturation antigen (BCMA), and BAFF receptor (BAFF-R). APRIL binding to TACI and BCMA is reinforced by cell-anchored and matrix-associated heparan-sulphate proteoglycans (HSPGs). In this study we verified the role of BAFF and APRIL in HCL. Methods. Splenic tissue sections and B cells from 5 healthy donors and 5 HCL patients were analyzed for expression of BAFF, APRIL, TACI, BCMA, BAFF-R and other molecules through immunohistochemistry, immunofluorescence, flow cytometry, immunoblotting and quantitative real-time RT-PCR. HCs were also cultured with umbilical vein or splenic endothelial cells in the presence or absence of BAFF and APRIL inhibitors, including soluble TACI-Ig decoy receptor, small interfering RNAs (siRNAs) and HSPG-modifying agents, such as heparinitase. HC proliferation, survival and signaling as induced by recombinant BAFF or APRIL were evaluated through standard assays. Results. We found that splenic sinusoids surrounding HCs were comprised of endothelial cells expressing APRIL and, to a lesser extent, BAFF. Endothelial cells up-regulated BAFF and APRIL upon exposure to HC-derived cytokines, including TNF-α. Unlike naïve, germinal center, memory and plasmacytoid B cells but similar to splenic marginal zone B cells, HCs expressed high levels of TACI, BCMA, BAFF-R and HSPGs together with CD1c, CD11c, CD27, CD83, CD123, endocytic receptors, and carbohydrate receptors. Preliminary data indicated that endothelial cells stimulated HCs through a mechanism involving BAFF, APRIL and HSPGs as pretreatment of endothelial cells with BAFF and APRIL small interfering RNAs or heparinitase attenuated the growth and survival of HCs in co-cultures. TACI-Ig, which binds to and neutralizes BAFF and APRIL, had a similar inhibitory effect. Conversely, BAFF, APRIL as well as TACI, BCMA or BAFF-R cross-linking stimulated HC growth. This stimulation was associated with NF-κB activation as well as up-regulation of various pro-survival and growth-inducing intracellular proteins. Conclusions. The present findings suggest that HCs may derive from a splenic marginal zone B cell precursor. In addition, our studies indicate that splenic sinusoids form a BAFF-APRIL-HSPG-rich niche that promotes HC expansion via TACI, BCMA and BAFF-R. Finally, our data suggest that blocking BAFF and APRIL through TACI-Ig, siRNAs and HSPG-modifying agents could have therapeutic value in HCL.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V108.11.4959.4959
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2006
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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