文章：

ATRA、丙戊酸和茶碱联合治疗急性髓性白血病的体内特异性细胞信号转导反应

Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia

原文发布日期：2011-02-11

DOI: 10.1038/bcj.2011.2

类型: Original Article

开放获取: 是

英文摘要：

Acute myeloid leukemia (AML) frequently comprises mutations in genes that cause perturbation in intracellular signaling pathways, thereby altering normal responses to growth factors and cytokines. Such oncogenic cellular signal transduction may be therapeutic if targeted directly or through epigenetic regulation. We treated 24 selected elderly AML patients with all-trans retinoic acid for 2 days before adding theophylline and the histone deacetylase inhibitor valproic acid (ClinicalTrials.gov NCT00175812; EudraCT no. 2004-001663-22), and sampled 11 patients for peripheral blood at day 0, 2 and 7 for single-cell analysis of basal level and signal-transduction responses to relevant myeloid growth factors (granulocyte-colony-stimulating factor, granulocyte/macrophage-colony-stimulating factor, interleukin-3, Flt3L, stem cell factor, erythropoietin, CXCL-12) on 10 signaling molecules (CREB, STAT1/3/5, p38, Erk1/2, Akt, c-Cbl, ZAP70/Syk and rpS6). Pretreatment analysis by unsupervised clustering and principal component analysis divided the patients into three distinguishable signaling clusters (non-potentiated, potentiated basal and potentiated signaling). Signal-transduction pathways were modulated during therapy and patients moved between the clusters. Patients with multiple leukemic clones demonstrated distinct stimulation responses and therapy-induced modulation. Individual signaling profiles together with clinical and hematological information may be used to early identify AML patients in whom epigenetic and signal-transduction targeted therapy is beneficial.

摘要翻译： 

急性髓系白血病（AML）常伴随导致细胞内信号通路扰动的基因突变，从而改变对生长因子和细胞因子的正常反应。这种致癌性细胞信号转导若通过直接靶向或表观遗传调控，或可成为治疗方向。我们在添加茶碱和组蛋白去乙酰化酶抑制剂丙戊酸前，对24例经筛选的老年AML患者进行了为期2天的全反式维甲酸预处理（临床试验注册号ClinicalTrials.gov NCT00175812；EudraCT编号2004-001663-22），并采集其中11例患者第0、2、7天的外周血样本，针对10种信号分子（CREB、STAT1/3/5、p38、Erk1/2、Akt、c-Cbl、ZAP70/Syk和rpS6），进行基础水平及相关髓系生长因子（粒细胞集落刺激因子、粒细胞/巨噬细胞集落刺激因子、白细胞介素-3、Flt3L、干细胞因子、促红细胞生成素、CXCL-12）刺激下的信号转导响应单细胞分析。通过无监督聚类和主成分分析对治疗前样本进行解析，将患者划分为三个可区分的信号集群（非强化型、基础强化型与信号强化型）。治疗过程中信号转导通路发生调控改变，患者在集群间发生转移。存在多个白血病克隆的患者表现出不同的刺激反应及治疗诱导的调控变化。个体化信号谱结合临床与血液学信息，或可用于早期识别表观遗传与信号转导靶向治疗获益的AML患者。

原文链接：

Specific cellular signal-transduction responses to in vivo combination therapy with ATRA, valproic acid and theophylline in acute myeloid leukemia