Bone morphogenic protein 6: a member of a novel class of prognostic factors expressed by normal and malignant plasma cells inhibiting proliferation and angiogenesis

Abstract

Pathogenesis of multiple myeloma is associated with an aberrant expression of pro-proliferative, pro-angiogenic and bone-metabolism-modifying factors by malignant plasma cells. Given the frequently long time span from diagnosis of early-stage plasma cell dyscrasias to overt myeloma and the mostly low proliferation rate of malignant plasma cells, we hypothesize these to similarly express a novel class of inhibitory factors of potential prognostic relevance. Bone morphogenic proteins (BMPs) represent possible candidates as they inhibit proliferation, stimulate bone formation and have an effect on the survival of cancer patients. We assessed the expression of BMPs and their receptors by Affymetrix DNA microarrays (n ¼ 779) including CD138-purified primary myeloma cell samples (n ¼ 635) of previously untreated patients. BMP6 is the only BMP expressed by malignant and normal plasma cells. Its expression is significantly lower in proliferating myeloma cells, myeloma cell lines or plasmablasts. BMP6 significantly inhibits the proliferation of myeloma cell lines, survival of primary myeloma cells and in vitro angiogenesis. A high BMP6 expression in primary myeloma cell samples delineates significantly superior overall survival for patients undergoing high-dose chemotherapy independent of conventional prognostic factors (International Staging System (ISS) stage, b 2 microglobulin).

The role of bone morphogenetic proteins in myeloma cell survival

“…[36,37] In supernatants of human myeloma cell lines and in BM plasma, low levels of BMP-6 were found using ELISA. [33] Another study found more BMP-2 in sera from multiple myeloma patients than in normal sera, but still at low levels (~ 60 pg/mL). [38] We found increased levels of BMP-9 in myeloma sera compared to normal sera.…”

“…[30][31][32][33][34] ALK6 (BMPR1B) is variably expressed. [31,35] The SMADs -1, -4 and -5 are also expressed, but not SMAD8.…”

“…[31,35] The SMADs -1, -4 and -5 are also expressed, but not SMAD8. [33] Expression of mRNA encoding the ligands BMP-6 and -4 has been found to be increased in plasma cells from multiple myeloma patients compared to healthy individuals. [31,33] Normal bone marrow stromal cells (BMSC) that have been passaged in cell culture have been shown to express BMP mRNA and protein.…”

“…[33] Expression of mRNA encoding the ligands BMP-6 and -4 has been found to be increased in plasma cells from multiple myeloma patients compared to healthy individuals. [31,33] Normal bone marrow stromal cells (BMSC) that have been passaged in cell culture have been shown to express BMP mRNA and protein. [36,37] In supernatants of human myeloma cell lines and in BM plasma, low levels of BMP-6 were found using ELISA.…”

“…[75] Recombinant sclerostin was proposed to antagonize the growth inhibitory effect of BMP-6 on a myeloma cell line in vitro, but the specificity was not entirely clear from this assay. [33] Sclerostin is expressed by osteocytes but can also be expressed by myeloma cells and high serum levels in myeloma patients correlated with advanced disease stage. [76,77] Another Wnt inhibitor, sFRP-2, is secreted by myeloma cells and suppresses bone formation.…”