文章：

mTOR抑制剂依维莫司（everolimus, RAD001）在静止ph阳性急性淋巴细胞白血病中克服了对伊马替尼的耐药性

The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells

原文发布日期：2011-05-13

DOI: 10.1038/bcj.2011.16

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： 

在Ph阳性（Ph+）白血病中，静止细胞状态是对BCR-ABL激酶抑制剂伊马替尼产生耐药的原因之一。为探究静止状态导致的耐药机制及mTOR抑制剂依维莫司对此类耐药细胞群的作用，我们采用连续异种移植至NOD/SCID/IL2rγnull（NOG）小鼠体内的Ph+急性淋巴细胞白血病患者细胞进行研究。白血病小鼠脾脏细胞显示，CD34+CD38−细胞群中慢周期G0期细胞比例高于CD34+CD38+和CD34−细胞群。经体外伊马替尼处理后，CD34+CD38−细胞群中残留细胞数量多于其他群体。尽管慢周期G0细胞在BCR-ABL和CrkL去磷酸化后仍对伊马替尼不敏感，但联合使用依维莫司可诱导显著细胞死亡（包括CD34+CD38−群体），并伴随p70-S6 K去磷酸化和MCL-1表达下调。在白血病NOD/SCID小鼠模型中，伊马替尼与依维莫司的体内联合治疗有效降低了包括CD34+细胞在内的肿瘤负荷。这些结果表明依维莫司治疗可克服Ph+白血病中由静止状态引起的伊马替尼耐药。

原文链接：

The mTOR inhibitor, everolimus (RAD001), overcomes resistance to imatinib in quiescent Ph-positive acute lymphoblastic leukemia cells