MEK and PI3K-AKT inhibitors synergistically block activated IL7 receptor signaling in T-cell acute lymphoblastic leukemia.
MEK and PI3K-AKT inhibitors synergistically block activated IL7 receptor signaling in T-cell acute lymphoblastic leukemia.
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DOI：
10.1038/leu.2016.83
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发表时间：
2016-09
期刊：
影响因子：
11.4
通讯作者：
Meijerink JP
中科院分区：
文献类型：
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作者：
Canté-Barrett K;Spijkers-Hagelstein JA;Buijs-Gladdines JG;Uitdehaag JC;Smits WK;van der Zwet J;Buijsman RC;Zaman GJ;Pieters R;Meijerink JP
我们在 49% 的儿童 T 细胞急性淋巴细胞白血病 (T-ALL) 患者中发现了 IL7Ra 基因或编码下游信号分子 JAK1、JAK3、STAT5B、N-RAS、K-RAS、NF1、AKT 和 PTEN 的基因突变。引人注目的是，这些突变（RAS/NF1 除外）是相互排斥的，这表明它们各自导致共同下游靶点的异常激活。表达这些突变信号分子（而不是其野生型对应分子）通过激活 RAS-MEK-ERK 和 PI3K-AKT 途径使 Ba/F3 细胞独立于 IL3。有趣的是，表达 IL7Ra 或 JAK 突变体的细胞对 JAK 抑制剂敏感，但对下游 RAS-MEK-ERK 和 PI3K-AKT-mTOR 途径抑制剂的反应不太强烈，表明仅抑制一种下游途径是不够的。在这里，我们发现抑制 MEK 和 PI3K-AKT 途径可协同阻止表达突变 IL7Ra、JAK 和 RAS 的 BaF3 细胞的增殖。此外，MEK 和 PI3K/AKT 的联合抑制对从 11 名原发性 T-ALL 患者中的 6 名获得的样本具有细胞毒性，其中包括 1 名在 IL7R 信号通路中没有突变的患者。综上所述，这些结果表明，应进一步研究抑制 MEK 和 PI3K/AKT 的有效细胞毒性作用，作为使用白血病异种移植模型的治疗选择。
We identified mutations in the IL7Ra gene or in genes encoding the downstream signaling molecules JAK1, JAK3, STAT5B, N-RAS, K-RAS, NF1, AKT and PTEN in 49% of patients with pediatric T-cell acute lymphoblastic leukemia (T-ALL). Strikingly, these mutations (except RAS/NF1) were mutually exclusive, suggesting that they each cause the aberrant activation of a common downstream target. Expressing these mutant signaling molecules—but not their wild-type counterparts—rendered Ba/F3 cells independent of IL3 by activating the RAS-MEK-ERK and PI3K-AKT pathways. Interestingly, cells expressing either IL7Ra or JAK mutants are sensitive to JAK inhibitors, but respond less robustly to inhibitors of the downstream RAS-MEK-ERK and PI3K-AKT-mTOR pathways, indicating that inhibiting only one downstream pathway is not sufficient. Here, we show that inhibiting both the MEK and PI3K-AKT pathways synergistically prevents the proliferation of BaF3 cells expressing mutant IL7Ra, JAK and RAS. Furthermore, combined inhibition of MEK and PI3K/AKT was cytotoxic to samples obtained from 6 out of 11 primary T-ALL patients, including 1 patient who had no mutations in the IL7R signaling pathway. Taken together, these results suggest that the potent cytotoxic effects of inhibiting both MEK and PI3K/AKT should be investigated further as a therapeutic option using leukemia xenograft models.