Constitutively activated MAPK and AKT signaling pathways are often found in solid tumors and leukemias. PTEN is one of the tumor suppressors that are frequently found deficient in patients with late-stage cancers or leukemias. In this study we demonstrate that a MAPK inhibitor, PD98059, inhibits both AKT and ERK phosphorylation in a human myeloid leukemia cell line (TF-1), but not in PTEN-deficient leukemia cells (TF-1a). Ectopic expression of wild-type PTEN in myeloid leukemia cells restored cytokine responsiveness at physiological concentrations of GM-CSF (<0.02 ng/mL) and significantly improved cell sensitivity to MAPK inhibitor. We also found that Early Growth Response 1 (EGR1) was constitutively over-expressed in cytokine-independent TF-1a cells, and ectopic expression of PTEN down-regulated EGR1 expression and restored dynamics of EGR1 expression in response to GM-CSF stimulation. Data from primary bone marrow cells from mice with Pten deletion further supports that PTEN is indispensible for myeloid leukemia cells in response to MAPK inhibitors. Finally, We demonstrate that the absence of EGR1 expression dynamics in response to GM-CSF stimulation is one of the mechanisms underlying drug resistance to MAPK inhibitors in leukemia cells with PTEN deficiency. Our data suggest a novel mechanism of PTEN in regulating expression of EGR1 in hematopoietic cells in response to cytokine stimulation. In conclusion, this study demonstrates that PTEN is dispensable for myeloid leukemia cells in response to MAPK inhibitors, and PTEN regulates EGR1 expression and contributes to the cytokine sensitivity in leukemia cells.

组成型激活的 MAPK 和 AKT 信号通路常见于实体瘤和白血病中。PTEN 是晚期癌症或白血病患者中经常发现缺乏的一种肿瘤抑制因子。在这项研究中，我们证明 MAPK 抑制剂 PD98059 抑制人髓系白血病细胞系 (TF-1) 中的 AKT 和 ERK 磷酸化，但不抑制 PTEN 缺陷型白血病细胞 (TF-1a)。髓系白血病细胞中野生型PTEN 的异位表达在生理浓度的 GM-CSF (<0.02 ng/mL) 下恢复细胞因子反应性，并显着提高细胞对 MAPK 抑制剂的敏感性。我们还发现早期生长反应 1 (EGR1) 在细胞因子非依赖性 TF-1a 细胞中组成型过度表达，PTEN异位表达下调 EGR1 表达并恢复响应 GM-CSF 刺激的 EGR1 表达动态。来自Pten小鼠原代骨髓细胞的数据删除进一步支持 PTEN 对于响应 MAPK 抑制剂的髓系白血病细胞是必不可少的。最后，我们证明了响应 GM-CSF 刺激的 EGR1 表达动力学的缺失是 PTEN 缺陷白血病细胞对 MAPK 抑制剂耐药的机制之一。我们的数据表明 PTEN 在响应细胞因子刺激时调节造血细胞中 EGR1 表达的新机制。总之，该研究表明 PTEN 对于响应 MAPK 抑制剂的髓系白血病细胞是可有可无的，并且 PTEN 调节 EGR1 表达并有助于白血病细胞的细胞因子敏感性。