Runx1 Orchestrates Sphingolipid Metabolism and Glucocorticoid Resistance in Lymphomagenesis.
Runx1 Orchestrates Sphingolipid Metabolism and Glucocorticoid Resistance in Lymphomagenesis.
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DOI：
10.1002/jcb.25802
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发表时间：
2017-06
影响因子：
4
通讯作者：
Neil JC
中科院分区：
文献类型：
--
作者：
Kilbey A;Terry A;Wotton S;Borland G;Zhang Q;Mackay N;McDonald A;Bell M;Wakelam MJ;Cameron ER;Neil JC
RUNX基因家族由三个成员组成，包括人类白血病的主要突变靶点RUNX1，并显示出肿瘤抑制基因和癌基因的特征。在小鼠模型中，RUNX基因似乎起到了条件癌基因的作用，因为在正常细胞中，异位表达抑制了生长，但当与过表达的Myc或p53的丢失结合在一起时，却有力地推动了淋巴瘤的发展。潜在机制的线索以前出现在小鼠成纤维细胞中，其中任何RUNX基因的异位表达通过直接和间接调节鞘磷脂代谢中的关键酶来促进存活，这些关键酶与“鞘磷脂变阻器”从神经酰胺转变为鞘氨醇-1-磷酸(S1P)有关。因此，在淋巴瘤细胞中测试这种关系是一个高度优先的问题。我们发现，RUNX1在淋巴瘤细胞中的异位表达持续扰乱鞘脂变阻器，而RUNX1的一个重要生理作用是在Cre介导的部分切除后，正常脾中S1P水平的降低。此外，我们还发现RUNX1的异位表达增加了淋巴瘤细胞对糖皮质激素诱导的细胞凋亡的抵抗力，并通过Sgpp1阐明了糖皮质激素和鞘糖脂代谢之间的相互作用机制。地塞米松能有效地诱导T淋巴瘤细胞中Sgpp1的表达，并导致细胞死亡，而Sgpp1被shRNA部分敲除或通过异位RUNX1直接转录抑制Sgpp1而减少细胞死亡。综上所述，这些数据表明，RUNX1在正常发育中调节鞘脂变阻器发挥作用，这种细胞命运调节因子的扰动有助于RUNX驱动的淋巴肿大。J.细胞。生物化学。118：1432-1441,2017。©2016作者。《细胞生物化学杂志》由威利期刊出版公司出版。
The three‐membered RUNX gene family includes RUNX1, a major mutational target in human leukemias, and displays hallmarks of both tumor suppressors and oncogenes. In mouse models, the Runx genes appear to act as conditional oncogenes, as ectopic expression is growth suppressive in normal cells but drives lymphoma development potently when combined with over‐expressed Myc or loss of p53. Clues to underlying mechanisms emerged previously from murine fibroblasts where ectopic expression of any of the Runx genes promotes survival through direct and indirect regulation of key enzymes in sphingolipid metabolism associated with a shift in the “sphingolipid rheostat” from ceramide to sphingosine‐1‐phosphate (S1P). Testing of this relationship in lymphoma cells was therefore a high priority. We find that ectopic expression of Runx1 in lymphoma cells consistently perturbs the sphingolipid rheostat, whereas an essential physiological role for Runx1 is revealed by reduced S1P levels in normal spleen after partial Cre‐mediated excision. Furthermore, we show that ectopic Runx1 expression confers increased resistance of lymphoma cells to glucocorticoid‐mediated apoptosis, and elucidate the mechanism of cross‐talk between glucocorticoid and sphingolipid metabolism through Sgpp1. Dexamethasone potently induces expression of Sgpp1 in T‐lymphoma cells and drives cell death which is reduced by partial knockdown of Sgpp1 with shRNA or direct transcriptional repression of Sgpp1 by ectopic Runx1. Together these data show that Runx1 plays a role in regulating the sphingolipid rheostat in normal development and that perturbation of this cell fate regulator contributes to Runx‐driven lymphomagenesis. J. Cell. Biochem. 118: 1432–1441, 2017. © 2016 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc.