Expression of genes encoding for proteins involved in heparan sulphate and chondroitin sulphate chain synthesis and modification in normal and malignant plasma cells

Abstract

Summary Syndecan‐1 is a proteoglycan that concentrates heparin‐binding factors on the surface of multiple myeloma cells, and probably plays a major role in multiple myeloma biology. As heparan sulphate and chondroitin sulphate are the bioactive components of syndecan‐1, we analysed the signature of genes encoding 100 proteins involved in synthesis of these chains, i.e. from precursor uptake to post‐translational modifications, using Affymetrix microarrays. The expression of enzymes required for heparan sulphate and chondroitin sulphate biosynthesis was shown to increase in parallel with syndecan‐1 expression, throughout the differentiation of memory B cells into plasmablasts and normal bone marrow plasma cells. Sixteen genes were significantly different between normal and malignant plasma cells, nine of these genes –EXT2, CHSY3, CSGALNACT1, HS3ST2, HS2ST1, CHST11, CSGALNACT2, HPSE, SULF2 – encode proteins involved in glycosaminoglycan chain synthesis or modifications. Kaplan–Meier analysis was performed in two independent series of patients: B4GALT7, CSGALNACT1, HS2ST1 were associated with a good prognosis whereas EXT1 was linked to a bad prognosis. This study provides an overall picture of the major genes encoding for proteins involved in heparan sulphate and chondroitin sulphate synthesis and modifications that can be implicated in normal and malignant plasma cells.

Myelopoiesis dysregulation associated to sustained APRIL production in multiple myeloma-infiltrated bone marrow

“…In addition to HS, CD138 also bears another sulfated glycan structure in the form of chondroitin sulfate chains. 30,31 Inhibition by heparitinase but not chondroitinase confirmed that APRIL binding was dependent on HS, and showed that chondroitin sulfate structures were not involved. The complete inhibition seen with sodium chlorate and heparitinase further shows that HS on CD138 mediated the primary binding of soluble APRIL on MM cells without involvement of the signaling receptors TACI and BCMA.…”

Intra-Golgi Formation of IgM–Glycosaminoglycan Complexes Promotes Ig Deposition

“…Heparin is the exclusive product of mast cells (36). In contrast, B cells express the enzymes to produce highly sulfated heparan sulfate (37), and splenocytes indeed synthesize the most highly sulfated heparan of any tissue except the heart (38). The preference of VH56R/Vk38c IgM for heparin over poorly sulfated heparan sulfate strongly suggested that VH56R/Vk38c IgM can bind highly sulfated heparan sulfate in the Golgi of B cells.…”

Insulin is a potent myeloma cell growth factor through insulin/IGF-1 hybrid receptor activation

“…Plasma cell differentiation is also associated with the expression of a high density of syndecan-1, with the necessity to continuously synthesize large levels of heparan sulfate chains and to import glucose. 29 In mammalian Table 3 Primary myeloma cells are stimulated by insulin or IGF-1, and the anti-INSR mAb or the anti-IGF-1 inhibits their survival were cultured for 5 days at 5 Â 10 5 cells/ml in serum-medium free without cytokine or with either insulin (100 ng/ml) or IGF-1 (100 ng/ml). To study the role of human serum insulin or IGF-1, primary myeloma cells were cultured in RPMI-1640 medium and 5% AB serum with either the anti-INSR mAb (1 mg/ml) or IGFBP-3 (2 mg/ml).…”