Microenvironmental Remodeling as a Parameter and Prognostic Factor of Heterogeneous Leukemogenesis in Acute Myelogenous Leukemia
Microenvironmental Remodeling as a Parameter and Prognostic Factor of Heterogeneous Leukemogenesis in Acute Myelogenous Leukemia
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DOI：
10.1158/0008-5472.can-14-3379
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发表时间：
2015-06-01
期刊：
影响因子：
11.2
通讯作者：
Oh, Il-Hoan
中科院分区：
文献类型：
--
作者：
Kim, Jin-A;Shim, Jae-Seung;Oh, Il-Hoan
急性髓系白血病(AML)是一种以骨髓干细胞样母细胞克隆性增殖为特征的异质性疾病，但其在骨髓微环境中独特的细胞相互作用及其功能意义尚不清楚。在这里，我们评估了AML患者的骨髓微环境，并证明了白血病干细胞诱导了正常间充质基质细胞(MSC)转录编程的变化。修饰的白血病生态位改变了MSCs中串扰分子(即CXCL12和JAG1)的表达，在正常细胞和白血病细胞之间提供明显的串扰，选择性地抑制正常原始造血细胞，同时支持白血病的发生和化疗耐药。值得注意的是，AML患者在骨髓间质改变方面表现出明显的异质性。初诊时白血病骨髓间质改变的独特模式与治疗后临床病程的不同有关，即维持5-8年的完全缓解和早期或晚期复发。因此，白血病细胞对间充质生态位的重塑是白血病发生的内在自我强化过程，可以作为白血病临床病程异质性的一个参数，从而成为一个潜在的预后因素。(C)2015年AACR。
Acute myelogenous leukemia (AML) is a heterogeneous disorder characterized by clonal proliferation of stem cell-like blasts in bone marrow (BM); however, their unique cellular interaction within the BM microenvironment and its functional significance remain unclear. Here, we assessed the BM microenvironment of AML patients and demonstrate that the leukemia stem cells induce a change in the transcriptional programming of the normal mesenchymal stromal cells (MSC). The modified leukemic niche alters the expressions of cross-talk molecules (i.e., CXCL12 and JAG1) in MSCs to provide a distinct cross-talk between normal and leukemia cells, selectively suppressing normal primitive hemato-poietic cells while supporting leukemogenesis and chemoresistance. Of note, AML patients exhibited distinct heterogeneity in the alteration of mesenchymal stroma in BM. The distinct pattern of stromal changes in leukemic BM at initial diagnosis was associated with a heterogeneous posttreatment clinical course with respect to the maintenance of complete remission for 5 to 8 years and early or late relapse. Thus, remodeling of mesenchymal niche by leukemia cells is an intrinsic self-reinforcing process of leukemogenesis that can be a parameter for the heterogeneity in the clinical course of leukemia and hence serve as a potential prognostic factor. (C) 2015 AACR.