Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Cancer Research and Biostatistics, Seattle, WA, USA.
Br J Haematol. 2019 Feb;184(4):578-593. doi: 10.1111/bjh.15669. Epub 2018 Nov 8.
Recent studies suggest that multiple myeloma (MM) induces proliferation and expansion of bone marrow (BM) mesenchymal stem cells (MSCs), but others showed that MM cells induce MSC senescence. To clarify the interaction between MM and MSCs, we exploited our established MSC gene signature to identify gene expression changes in myeloma MSCs and associated functional differences. Single MSCs from patients with MM had changes in expression of genes associated with cellular proliferation and senescence and a higher proportion of senescent cells and lower proliferative potential than those from age-matched healthy donors. Single MSCs from both sources heterogeneously express MSC genes associated with adipogenesis and osteoblastogenesis. We identified the gene encoding insulin-like growth factor-binding protein 2 (IGFBP2), an MSC gene commonly altered in high risk MM, as under-expressed. Morphologically, IGFBP2+ cells are underrepresented in MM BM compared to smouldering MM. Strong IGFBP2 and adiponectin co-expression was detected in a subset of small adipocytes. Co-culturing normal MSCs with myeloma cells suppressed MSC differentiation to adipocytes and osteoblasts, and reduced expression of IGFBP2 and adiponectin. Recombinant IGFBP2 blocked IGF1-mediated myeloma cell growth. Our data demonstrate that myeloma MSCs are less proliferative and that IGFBP2+ small adipocytes are a distinct mesenchymal cell population suppressed by myeloma.
最近的研究表明，多发性骨髓瘤（MM）可诱导骨髓（BM）间充质干细胞（MSC）的增殖和扩增，但也有研究表明 MM 细胞可诱导 MSC 衰老。为了阐明 MM 与 MSC 之间的相互作用，我们利用已建立的 MSC 基因特征来鉴定骨髓瘤 MSC 中的基因表达变化及其相关的功能差异。来自 MM 患者的单个 MSC 表达与细胞增殖和衰老相关的基因发生改变，衰老细胞比例较高，增殖潜力较低，而来自年龄匹配的健康供体的 MSC 则不然。来自两种来源的单个 MSC 均不均一地表达与脂肪生成和成骨细胞生成相关的 MSC 基因。我们鉴定出编码胰岛素样生长因子结合蛋白 2（IGFBP2）的基因，该基因是 MM 中常见的高危基因，表达下调。与冒烟型 MM 相比，MM BM 中 IGFBP2+细胞的形态学上代表性不足。在一小部分小脂肪细胞中检测到强烈的 IGFBP2 和脂联素共表达。正常 MSC 与骨髓瘤细胞共培养可抑制 MSC 向脂肪细胞和成骨细胞分化，并降低 IGFBP2 和脂联素的表达。重组 IGFBP2 可阻断 IGF1 介导的骨髓瘤细胞生长。我们的数据表明骨髓瘤 MSC 的增殖能力较低，IGFBP2+小脂肪细胞是一种受骨髓瘤抑制的独特间充质细胞群体。
