Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, Singapore, 117599, Republic of Singapore.
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074, Republic of Singapore.
J Hematol Oncol. 2017 Jul 11;10(1):138. doi: 10.1186/s13045-017-0507-y.
Current conventional chemotherapy for acute myeloid leukemia (AML) can achieve remission in over 70% of patients, but a majority of them will relapse within 5 years despite continued treatment. The relapse is postulated to be due to leukemia stem cells (LSCs), which are different from normal hematopoietic stem cells (HSCs). LIN28B is microRNA regulator and stem cell reprogramming factor. Overexpression of LIN28B has been associated with advance human malignancies and cancer stem cells (CSCs), including AML. However, the molecular mechanism by which LIN28B contributes to the development of AML remains largely elusive.
We modulated LIN28B expression in AML and non-leukemic cells and investigated functional consequences in cell proliferation, cell cycle, and colony-forming assays. We performed a microarray-based analysis for LIN28B-silencing cells and interrogated gene expression data with different bioinformatic tools. AML mouse xenograft model was used to examine the in vivo function of LIN28B.
We demonstrated that targeting LIN28B in AML cells resulted in cell cycle arrest, inhibition of cell proliferation and colony formation, which was induced by de-repression of let-7a miRNA. On the other hand, overexpression of LIN28B promoted cell proliferation. Data point to a mechanism where that inhibition of LIN28B induces metabolic changes in AML cells. IGF2BP1 was confirmed to be a novel downstream target of LIN28B via let-7 miRNA in AML. Notably, ectopic expression of LIN28B increased tumorigenicity, while silencing LIN28B led to slow tumor growth in vivo.
In sum, these results uncover a novel mechanism of an important regulatory signaling, LIN28B/let-7/IGF2BP1, in leukemogenesis and provide a rationale to target this pathway as effective therapeutic strategy.
目前急性髓系白血病（AML）的常规化疗可以使超过 70%的患者缓解，但尽管继续治疗，大多数患者仍会在 5 年内复发。复发被认为是由于白血病干细胞（LSCs）所致，它们与正常造血干细胞（HSCs）不同。LIN28B 是 microRNA 调节因子和干细胞重编程因子。LIN28B 的过度表达与人类恶性肿瘤和癌症干细胞（CSCs）有关，包括 AML。然而，LIN28B 促进 AML 发展的分子机制在很大程度上仍不清楚。
我们在 AML 和非白血病细胞中调节 LIN28B 的表达，并在细胞增殖、细胞周期和集落形成测定中研究其功能后果。我们对 LIN28B 沉默细胞进行了基于微阵列的分析，并使用不同的生物信息学工具对基因表达数据进行了查询。使用 AML 小鼠异种移植模型来研究 LIN28B 在体内的功能。
我们证明，在 AML 细胞中靶向 LIN28B 会导致细胞周期停滞、抑制细胞增殖和集落形成，这是由 let-7a miRNA 的去抑制引起的。另一方面，LIN28B 的过表达促进了细胞增殖。数据表明，抑制 LIN28B 会诱导 AML 细胞发生代谢变化。IGF2BP1 被确认为 LIN28B 在 AML 中的一个新的下游靶标，通过 let-7 miRNA。值得注意的是，LIN28B 的异位表达增加了肿瘤发生能力，而沉默 LIN28B 则导致体内肿瘤生长缓慢。
总之，这些结果揭示了一个重要的调节信号 LIN28B/let-7/IGF2BP1 在白血病发生中的新机制，并为靶向该途径作为有效的治疗策略提供了依据。
