Department of Gasteroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Mol Med. 2011;17(7-8):790-8. doi: 10.2119/molmed.2011.00013. Epub 2011 Apr 28.
Multiple myeloma (MM) is a neoplasm of plasma cell origin that is largely confined to the bone marrow (BM). Chromosomal translocations and other genetic events are known to contribute to deregulation of signaling pathways that lead to transformation of plasma cells and progression to malignancy. However, the tumor stroma may also provide trophic support and enhance resistance to therapy. Phosphorylation of proteins on tyrosine, serine and threonine residues plays a pivotal role in cell growth and survival. Therefore, knowing the status of phosphorylation-based signaling pathways in cells may provide key insights into how cell growth and survival is promoted in tumor cells. To provide a more comprehensive molecular analysis of signaling disruptions in MM, we conducted a kinome profile comparison of normal plasma cells and MM plasma cells as well as their surrounding cells from normal BM and diseased BM. Integrated pathway analysis of the profiles obtained reveals deregulation of multiple signaling pathways in MM cells but also in surrounding bone marrow blood cells compared to their normal counterparts. The deregulated kinase activities identified herein, which include the mTOR (mammalian target of rapamycin)/p70S6K and ERK1/2 (extracellular signal-regulated kinases 1 and 2) pathways, are potential novel molecular targets in this lethal disease.
多发性骨髓瘤（MM）是一种起源于浆细胞的肿瘤，主要局限于骨髓（BM）。染色体易位和其他遗传事件已知会导致信号通路失调，从而导致浆细胞转化和恶性进展。然而，肿瘤基质也可能提供营养支持并增强对治疗的抵抗力。酪氨酸、丝氨酸和苏氨酸残基上的蛋白质磷酸化在细胞生长和存活中起着关键作用。因此，了解细胞中基于磷酸化的信号通路的状态可能为了解肿瘤细胞中细胞生长和存活的促进机制提供关键见解。为了更全面地分析 MM 中的信号中断，我们对正常浆细胞和 MM 浆细胞及其来自正常 BM 和患病 BM 的周围细胞进行了激酶组谱比较。对获得的图谱进行的综合途径分析显示，与正常对应物相比，MM 细胞及其周围骨髓血细胞中的多个信号通路发生了失调。本文鉴定的失调激酶活性，包括 mTOR（雷帕霉素的哺乳动物靶标）/p70S6K 和 ERK1/2（细胞外信号调节激酶 1 和 2）途径，是这种致命疾病的潜在新的分子靶点。
