FUS与PTBP1通过转录及转录后调控协同促进慢性髓系白血病进展

doi:10.19586/j.2095-2341.2026.0010

生物技术进展 ›› 2026, Vol. 16 ›› Issue (3): 677-685.DOI: 10.19586/j.2095-2341.2026.0010

FUS与PTBP1通过转录及转录后调控协同促进慢性髓系白血病进展

林乐萱¹(), 金煦¹, 贺芳¹(), 石莉红¹^,²()

^1.北京协和医学院，中国医学科学院血液病医院（中国医学科学院血液学研究所），血液与健康全国重点实验室，国家血液系统疾病临床医学研究中心，细胞生态海河实验室，天津 300020
^2.天津医学健康研究院，天津 301600

收稿日期:2026-01-16 接受日期:2026-04-02 出版日期:2026-05-25 发布日期:2026-07-14
通讯作者: 贺芳,石莉红
作者简介:林乐萱 E-mail: linlexuan@ihcams.ac.cn
基金资助:
中国医学科学院北京协和医学院中央高校基本科研业务费(3332025180);中国医学科学院北京协和医学院中央高校基本科研业务费(3332025060);国家重点研发计划项目(2024YFC2510500);国家自然科学基金项目(82300141);国家自然科学基金项目(82500165);国家自然科学基金项目(82400148);天津市科技计划项目(24ZXRKSY00010);医科院医学与健康科技创新工程项目(2023-I2M-2-007);医科院医学与健康科技创新工程项目(2025-I2M-XHXX-136);医科院医学与健康科技创新工程项目(2025-I2M-XHXX-129)

FUS and PTBP1 Cooperatively Promote Chronic Myeloid Leukemia Progression via Transcriptional and Post-transcriptional Regulation

Lexuan LIN¹(), Xu JIN¹, Fang HE¹(), Lihong SHI¹^,²()

^1.State Key Laboratory of Experimental Hematology，National Clinical Research Center for Blood Disease，Haihe Laboratory of Cell Ecosystem，Institute of Hematology Blood Diseases Hospital，Chinese Academy of Medical Sciences Peking Union Medical College，Tianjin 300020，China
^2.Tianjin Institutes of Health Science，Tianjin 301600，China

Received:2026-01-16 Accepted:2026-04-02 Online:2026-05-25 Published:2026-07-14
Contact: Fang HE,Lihong SHI

摘要/Abstract

摘要：

异质核糖核蛋白（heterogeneous nuclear ribonucleoproteins，hnRNPs）家族参与多种肿瘤的发生发展，但其在慢性髓系白血病（chronic myelogenous leukemia，CML）中的作用尚不明确。已有研究证实，肉瘤融合蛋白（fused in sarcoma, FUS）是维持CML细胞增殖的关键基因，其高表达与患者不良预后相关。研究整合成簇规律间隔短回文重复序列（clustered regularly interspaced short palindromic repeats, CRISPR）筛选、RNA干扰及细胞功能实验，系统验证了FUS在CML中的关键作用。敲降FUS可显著抑制K562细胞增殖，导致静止期（G0期）阻滞并促进细胞凋亡。核内FUS结合于启动子区，与转录共激活因子溴结构域蛋白4（bromodomain protein 4，BRD4）及染色质重塑因子1（brahma-related gene 1， BRG1）存在靶基因重叠，可能协同调控染色质结构及转录活性。同时，FUS可与多聚嘧啶束结合蛋白1（polypyrimidine tract binding protein 1，PTBP1）相互作用，二者可能协同调控基因表达与转录后加工，共同促进CML细胞生存。综上，FUS可能通过调控染色质空间构象维持致癌转录程序，并与PTBP1在转录及转录后层面形成功能协同网络，共同促进CML进展。

关键词: 慢性髓系白血病, FUS, PTBP1

Abstract:

The heterogeneous nuclear ribonucleoproteins （hnRNPs） family is involved in the development of various tumors， but its role in chronic myeloid leukemia （CML） remains unclear. Previous studies have confirmed that fused in sarcoma （FUS） is a key gene maintaining CML cell proliferation， and its high expression is associated with poor patient prognosis. The study integrated clustered regularly interspaced short palindromic repeats （CRISPR） screening， RNA interference， and cell function experiments to systematically verify the key role of FUS in CML. Knockdown of FUS significantly inhibited the proliferation of K562 cells， leading to quiescent phase （G0 phase） arrest and promoting apoptosis. Nuclear FUS binds to promoter regions and shows overlapping target genes with the transcriptional co-activator bromodomain protein 4 （BRD4） and the chromatin remodeler brahma-related gene 1 （BRG1）， suggesting potential collaborative regulation of chromatin structure and transcriptional activity. Additionally， FUS can interact with polypyrimidine tract binding protein 1 （PTBP1）， and the two may cooperatively regulate gene expression and post-transcriptional processing， jointly promoting CML cell survival. In summary， FUS may maintain oncogenic transcriptional programs by regulating chromatin spatial architecture and forms a functional cooperative network with PTBP1 at both transcriptional and post-transcriptional levels， collectively driving CML progression.

Key words: chronic myeloid leukemia, FUS, PTBP1

中图分类号:

Q291

林乐萱, 金煦, 贺芳, 石莉红. FUS与PTBP1通过转录及转录后调控协同促进慢性髓系白血病进展[J]. 生物技术进展, 2026, 16(3): 677-685.

Lexuan LIN, Xu JIN, Fang HE, Lihong SHI. FUS and PTBP1 Cooperatively Promote Chronic Myeloid Leukemia Progression via Transcriptional and Post-transcriptional Regulation[J]. Current Biotechnology, 2026, 16(3): 677-685.

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链接本文: https://swjsjz.magtechjournal.com/CN/10.19586/j.2095-2341.2026.0010

https://swjsjz.magtechjournal.com/CN/Y2026/V16/I3/677

图/表 5

表1 本研究中的shRNA序列

Table 1 shRNA sequences in this study

引物名称	shRNA序列（5'→3')	引物名称	shRNA序列（5'→3')
shFUS-1	5'-GGACAGCAGCAAAGCTATA-3'	shPTBP1-1	5'-GCTTCTGCAGCAAACGGAAAT-3'
shFUS-2	5'-GATCAATCCTCCATGAGTA-3'	shPTBP1-2	5'-GCGTGAAGATCCTGTTCAATA-3'
shFUS-3	5'-GATGAATGCAACCAGTGTAAGG-3'	shPTBP1-3	5'-GCTCAACGTCAAGTACAACAAT-3'
shFUS-4	5'-GCAATTCCTGATCACCCAAGGG-3'	shPTBP1-4	5'-GACGCGGAGAGAACCGATTAAA-3'

图1 FUS对CML细胞增殖的作用A：基于K562细胞的CRISPR/Cas9增殖筛选数据，显示正向调控基因的评分与排名；B：CRISPR筛选结果中部分基因对数变化的柱状图；C：CML患者FUS高表达组与FUS低表达组生存分析

Fig. 1 Effect of FUS on CML cell proliferation

图2 敲降FUS对CML细胞周期及其凋亡的影响A：左—Western Blot检测4条靶向FUS的shRNA（shFUS-1~4）在K562细胞中的敲降效率；右—FUS蛋白表达水平的定量分析；B：感染shRNA-1~4及对照的K562细胞在第0、2、4 d的细胞数量增殖曲线，n=5；C：对照组和FUS敲降组K562细胞凋亡流式图，流式图中Annexin V-DAPI-为活细胞；Annexin V+DAPI-为早期凋亡细胞；Annexin V+DAPI+为晚期凋亡细胞；D：对照组和FUS敲降组细胞凋亡检测统计图，n=5； E：对照组和FUS敲降组K562细胞周期检测流式图，流式图中Ki67-Hoechst-为G0期细胞，Ki67+Hoechst-为G1期细胞，Ki67+Hoechst+为S/G2M期细胞；F：对照组和FUS敲降组细胞周期检测统计图，n=5。*、**、***、****分别表示在P0.05、P0.01、P0.001及P0.000 1水平上具有统计学意义，ns表示无统计学意义。

Fig. 2 Effect of knockdown of FUS on cell cycle progression and apoptosis in CML cells

图3 核内FUS通过调控染色质空间构象参与转录激活过程A：在K562细胞中敲降FUS后转录组测序分析差异表达基因的GO富集分析（下调通路）；B：免疫荧光显示K562细胞中过表达FUS-eGFP（绿色）的亚细胞定位，细胞核经DAPI（蓝色）染色；比例尺=5 μm；C：K562细胞中FUS ChIP-seq靶基因的GO富集分析；D：K562细胞中FUS、BRD4和BRG1结合峰在TSS附近的分布密度；E：K562细胞中FUS、BRD4和BRG1在全基因组范围内的结合区域分布统计；F：K562细胞中FUS、BRD4与BRG1靶基因的重叠情况

Fig. 3 Nuclear FUS participates in transcriptional activation by regulating chromatin spatial conformation

图4 FUS可能协同PTBP1共同参与CML细胞的调控A：Western blot检测在K562细胞中用4条shRNA（shFUS-1~4）敲降FUS后PTBP1的表达水平；B：在K562细胞中敲降FUS后PTBP1蛋白表达水平的定量分析；C：FUS与PTBP1的蛋白质相互作用网络分析；D：左—Western blot检测4条靶向PTBP1的shRNA（shPTBP1-1~4）在K562细胞中的敲降效率；右—PTBP1蛋白表达水平的定量分析；E：对照组和PTBP1敲降组K562细胞凋亡流式图，流式图中Annexin V-DAPI-为活细胞，Annexin V+DAPI-为早期凋亡细胞，Annexin V+DAPI+为晚期凋亡细胞；F：对照组和PTBP1敲降组细胞凋亡检测统计图，n=3；G：对照组和PTBP1敲降组K562细胞周期检测流式图，流式图中Ki67-Hoechst-为G0期细胞，Ki67+Hoechst-为G1期细胞，Ki67+Hoechst+为S/G2M期细胞；H：对照组和PTBP1敲降组细胞周期检测统计图，n=3；I：在K562细胞中敲降PTBP1后转录组测序分析差异表达基因的GO富集分析（下调通路）；J：免疫荧光显示K562细胞中过表达FUS-eGFP（绿色）及PTBP1（红色）的亚细胞定位，细胞核经DAPI（蓝色）染色；比例尺=5 μm。*、**、***、****分别表示在P0.05、P0.01、P0.001及P0.0001水平上具有统计学意义，ns表示无统计学意义。

Fig. 4 FUS potentially cooperates with PTBP1 in the regulation of CML cells

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FUS与PTBP1通过转录及转录后调控协同促进慢性髓系白血病进展

FUS and PTBP1 Cooperatively Promote Chronic Myeloid Leukemia Progression via Transcriptional and Post-transcriptional Regulation

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