MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia
MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia
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DOI：
10.1182/blood-2015-04-639138
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发表时间：
2015-11-05
期刊：
影响因子：
20.3
通讯作者：
Carroll, William L.
中科院分区：
文献类型：
--
作者：
Jones, Courtney L.;Gearheart, Christy M.;Carroll, William L.
小儿急性淋巴细胞白血病（ALL）患者复发的结果是令人沮丧的。复发性疾病的一个标志是对多种化疗药物，特别是糖皮质激素的获得性耐药。在这项研究中，我们进行了基因组尺度的短发夹RNA筛选，以鉴定ALL细胞系中强的松龙敏感性的介质。将这些数据与复发特异性遗传和表观遗传变化的综合分析相结合，使我们能够确定丝裂原活化蛋白激酶（MAPK）途径是儿童ALL中强的松龙耐药的中介。我们发现特异性MAPK通路成员MEK2和MEK4的敲除通过不同的机制增加了对强的松龙的敏感性。MEK4敲低通过增加糖皮质激素受体的水平特异性地增加了对强的松龙的敏感性。通过增加p53水平，MEK2敲除增加了对所有化疗药物的敏感性。此外，我们证明用曲美替尼抑制MEK1/2增加了ALL细胞和原代样品对体外和体内化疗的敏感性。为了确认MAPK信号在复发性ALL患者中的作用，我们测量了匹配诊断-复发原发性样本中MEK1/2靶ERK的激活，并观察到复发时磷酸化的ERK水平升高。此外，与异种移植模型中匹配的诊断样本相比，复发样本对MEK抑制的反应增强。总之，我们的数据表明，抑制MAPK通路增加了对糖皮质激素和其他药物的化学敏感性，MAPK通路是预防和/或治疗复发性疾病的一个有吸引力的靶点。
The outcome for pediatric acute lymphoblastic leukemia (ALL) patients who relapse is dismal. A hallmark of relapsed disease is acquired resistance to multiple chemotherapeutic agents, particularly glucocorticoids. In this study, we performed a genome-scale short hairpin RNA screen to identify mediators of prednisolone sensitivity in ALL cell lines. The incorporation of these data with an integrated analysis of relapse-specific genetic and epigenetic changes allowed us to identify the mitogen-activated protein kinase (MAPK) pathway as a mediator of prednisolone resistance in pediatric ALL. We show that knockdown of the specific MAPK pathway members MEK2 and MEK4 increased sensitivity to prednisolone through distinct mechanisms. MEK4 knockdown increased sensitivity specifically to prednisolone by increasing the levels of the glucocorticoid receptor. MEK2 knockdown increased sensitivity to all chemotherapy agents tested by increasing the levels of p53. Furthermore, we demonstrate that inhibition of MEK1/2 with trametinib increased sensitivity of ALL cells and primary samples to chemotherapy in vitro and in vivo. To confirm a role for MAPK signaling in patients with relapsed ALL, we measured the activation of the MEK1/2 target ERK in matched diagnosis-relapse primary samples and observed increased phosphorylated ERK levels at relapse. Furthermore, relapse samples have an enhanced response to MEK inhibition compared to matched diagnosis samples in xenograft models. Together, our data indicate that inhibition of the MAPK pathway increases chemosensitivity to glucocorticoids and possibly other agents and that the MAPK pathway is an attractive target for prevention and/or treatment of relapsed disease.