PO.BCS01.05 · 生物信息与计算
鉴定microRNA簇作为急性髓系白血病化疗反应的预测因子
Identification of microRNA clusters as predictors of chemotherapy response in acute myeloid leukemia
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摘要 Abstract
中文摘要
急性髓系白血病（AML）是一种髓系细胞谱系的癌症，其特征为获得性基因突变和染色体异常。我们此前已证明，通过对疾病发展过程中采集的外周血单个核细胞（PBMC）的时间序列信使RNA（mRNA）和microRNA（miRNA）测序数据应用状态转换理论，可以预测AML的起始和进展。我们证明，小鼠模型中AML的起始和进展可通过血液单个核细胞转录组进行追踪，并可建模为在双阱势能中进行布朗运动的粒子，其临界点对应健康、转换和白血病状态。在此框架基础上，我们当前的研究利用来自AML小鼠模型的时间序列测序数据评估化疗反应。我们绘制了mRNA和miRNA转录组随时间的轨迹，发现化疗最初使两条轨迹均从白血病状态偏离、趋向健康状态，随后复发回归白血病状态。值得注意的是，miRNA反应比mRNA滞后2周。为探究miRNA转录组对化疗反应延迟的原因，我们对miRNA表达谱进行了加权基因共表达网络分析（WGCNA）以识别共表达簇。通过将每个miRNA簇投影到白血病状态空间上，我们识别出一个对AML状态转换具有强贡献的簇。这是一个由30个miRNA组成的簇，表达模式协调一致，显著上调，并与化疗后延迟的转录组反应相关。值得注意的是，其中80%的miRNA位于DLK1-DIO3印记区域（人类染色体14q32，小鼠12qF1）内，该基因座此前被认为与应激反应、急性早幼粒细胞白血病（APL）、实体瘤和2型糖尿病相关。然而，它们在AML标准化疗反应中的作用此前尚未见报道。进一步的机制分析揭示了一种调控机制，即这些miRNA的高表达抑制了PI3K/mTOR信号通路。抑制PI3K/mTOR通路会降低活性氧（ROS）的产生，从而为白血病干细胞（LSC）的存活创造环境。由于化疗主要清除白血病原始细胞，LSC的持续存在可能显著促成复发。我们的发现凸显了状态空间建模在揭示动态调控机制、识别可能导致AML化疗后复发的miRNA驱动因素方面的强大能力。
查看英文原文 English abstract
Acute myeloid leukemia (AML) is a cancer of the myeloid cell lineage characterized by acquired gene mutations and chromosomal abnormalities. We have previously shown that AML initiation and progression can be predicted by applying a state-transition theory to the analysis of time-series messenger RNA (mRNA) and microRNA (miRNA) sequencing data from peripheral blood mononuclear cells (PBMCs) collected during disease development. We showed that AML initiation and progression in mouse models can be tracked via blood mononuclear cell transcriptomes and modeled as particle undergoing Brownian motion in a double-well potential with critical points for health, transition, and leukemia. Building on this framework, our current study evaluates chemotherapy response using time-series sequencing data from an AML mouse model. We plotted mRNA and miRNA transcriptome trajectories over time and found that chemotherapy initially shifted both trajectories away from the leukemic state toward the healthy state, followed by relapse back toward leukemic state. Notably, miRNA responses showed a delay of 2 weeks behind mRNA. To investigate the cause of delayed miRNA transcriptomic response to chemotherapy, we performed Weighted Gene Co-expression Network Analysis (WGCNA) on miRNA expression profiles to identify co-expressed clusters. By projecting each miRNA cluster onto the leukemia state-space[YK1] , we identified a cluster that exhibit strong contribution to the AML state transition. This is a cluster of 30 miRNAs with coordinated expression patterns, significantly upregulated and associated with delayed transcriptomic response post-chemotherapy.Notably, 80% of these miRNAs are located within the DLK1-DIO3 imprinted region (chromosome 14q32 in humans, 12qF1 in mice), a locus previously implicated in stress response, acute promyelocytic leukemia (APL), solid tumors, and type 2 diabetes. However, their involvement in standard-of-care chemotherapy responses in AML has not been previously reported.Further mechanistic analysis revealed a regulatory mechanism in which high expression of these miRNAs suppresses the PI3K/mTOR signaling pathway. Inhibiting the PI3K/mTOR pathway lowers reactive oxygen species (ROS) production, which creates an environment for leukemia stem cells (LSC) to survive. Since chemotherapy primarily eliminates leukemic blast cells, the persistence of LSCs may significantly contribute to relapse.Our findings highlight the power of state-space modeling to uncover dynamic regulatory mechanisms and identify miRNA-driven factors that may lead to AML relapse after chemotherapy.
利益披露 Disclosure
Z. Chen, None.