Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
PLoS One. 2013 Aug 15;8(8):e71120. doi: 10.1371/journal.pone.0071120. eCollection 2013.
MYD88 is a key mediator of Toll-like receptor innate immunity signaling. Oncogenically active MYD88 mutations have recently been reported in lymphoid malignancies, but has not been described in MDS. To characterize MYD88 in MDS, we sequenced the coding region of the MYD88 gene in 40 MDS patients. No MYD88 mutation was detected. We next characterized MYD88 expression in bone marrow CD34+ cells (N = 64). Increased MYD88 RNA was detected in 40% of patients. Patients with higher MYD88 expression in CD34+ cells had a tendency for shorter survival compared to the ones with lower MYD88, which was significant when controlled for IPSS and age. We then evaluated effect of MYD88 blockade in the CD34+ cells of patients with lower-risk MDS. Colony formation assays indicated that MYD88 blockade using a MYD88 inhibitor resulted in increased erythroid colony formation. MYD88 blockade also negatively regulated the secretion of interleukin-8. Treatment of MDS CD34+ cells with an IL-8 antibody also increased formation of erythroid colonies. These results indicate that MYD88 plays a role in the pathobiology of MDS and may have prognostic and therapeutic value in the management of patients with this disease.
MYD88 是 Toll 样受体先天免疫信号的关键介质。最近在淋巴恶性肿瘤中报道了癌基因活性的 MYD88 突变，但在 MDS 中尚未描述。为了研究 MDS 中的 MYD88，我们对 40 例 MDS 患者的 MYD88 基因编码区进行了测序。未检测到 MYD88 突变。接下来，我们对骨髓 CD34+细胞中的 MYD88 表达进行了特征描述（N = 64）。在 40%的患者中检测到 MYD88 RNA 增加。与 MYD88 表达较低的患者相比，CD34+细胞中 MYD88 表达较高的患者生存时间有缩短趋势，当控制 IPSS 和年龄时，这种趋势具有统计学意义。然后，我们评估了在低危 MDS 患者的 CD34+细胞中 MYD88 阻断的效果。集落形成实验表明，使用 MYD88 抑制剂阻断 MYD88 导致红系集落形成增加。MYD88 阻断还负调节白细胞介素-8 的分泌。用抗白细胞介素-8 抗体治疗 MDS CD34+细胞也增加了红系集落的形成。这些结果表明，MYD88 在 MDS 的病理生物学中发挥作用，并且在管理这种疾病的患者方面可能具有预后和治疗价值。
