Consecutive epigenetically-active agent combinations act in ID1-RUNX3-TET2 and HOXA pathways for Flt3ITD+ve AML.
Consecutive epigenetically-active agent combinations act in ID1-RUNX3-TET2 and HOXA pathways for Flt3ITD+ve AML.
复制标题
DOI：
10.18632/oncotarget.23655
复制
发表时间：
2018-01-19
期刊：
影响因子：
--
通讯作者：
Boswell HS
中科院分区：
文献类型：
--
作者：
Sayar H;Liu Y;Gao R;Zaid MA;Cripe LD;Weisenbach J;Sargent KJ;Nassiri M;Li L;Konig H;Suvannasankha A;Pan F;Shanmugam R;Goswami C;Kapur R;Xu M;Boswell HS
Flt 3 ITD和TET 2突变的同时发生通过表观遗传学抑制Wnt途径拮抗剂（包括RUNX 3）和编码Wnt激动剂的ID 1的过表达引发了AML动物模型。这些影响HOXA过表达和治疗抗性。在需要新干预的成人AML患者中发现了可比较的表观遗传表型。我们选择了在复发性/难治性AML中在信号转导和染色质重塑水平上作用于不同效应物的靶向药物的组合，包括Flt 3 ITD +ve，其描述了受抑制的肿瘤抑制基因的特征，涉及Wnt拮抗剂RUNX 3，与ID 1和HOXA过表达一起沿着发生。我们在连续的I期试验中追踪了患者对Flt 3/Raf抑制剂索拉非尼和Vorinostat（泛组蛋白脱乙酰酶抑制剂）联合治疗的反应，无论是否添加硼替佐米。观察到快速客观缓解（接近完全、完全缓解）与原位患者原始细胞内诱导的早期药效学变化（涉及这些效应物）显著相关，RUNX 3/Wnt拮抗剂去抑制（80%）和ID 1下调（85%）与缓解显著相关，之前还伴有HOXA 9深度抑制。在TET 2突变/亚型和Flt 3 ITD +ve突变同时发生的情况下发生缓解（83%的完全缓解）。在组合中加入硼替佐米对于在表现出这种Wnt途径失调的Flt 3 ITD +ve病例中实现完全应答至关重要。
Co-occurrence of Flt3ITD and TET2 mutations provoke an animal model of AML by epigenetic repression of Wnt pathway antagonists, including RUNX3, and by hyperexpression of ID1, encoding Wnt agonist. These affect HOXA over-expression and treatment resistance. A comparable epigenetic phenotype was identified among adult AML patients needing novel intervention. We chose combinations of targeted agents acting on distinct effectors, at the levels of both signal transduction and chromatin remodeling, in relapsed/refractory AML’s, including Flt3ITD+ve, described with a signature of repressed tumor suppressor genes, involving Wnt antagonist RUNX3, occurring along with ID1 and HOXA over-expressions. We tracked patient response to combination of Flt3/Raf inhibitor, Sorafenib, and Vorinostat, pan-histone deacetylase inhibitor, without or with added Bortezomib, in consecutive phase I trials. A striking association of rapid objective remissions (near-complete, complete responses) was noted to accompany induced early pharmacodynamic changes within patient blasts in situ, involving these effectors, significantly linking RUNX3/Wnt antagonist de-repression (80%) and ID1 downregulation (85%), to a response, also preceded by profound HOXA9 repression. Response occurred in context of concurrent TET2 mutation/hypomorphy and Flt3ITD+ve mutation (83% of complete responses). Addition of Bortezomib to the combination was vital to attainment of complete response in Flt3ITD+ve cases exhibiting such Wnt pathway dysregulation.