A novel fusion protein TBLR1-RARα acts as an oncogene to induce murine promyelocytic leukemia: identification and treatment strategies.
A novel fusion protein TBLR1-RARα acts as an oncogene to induce murine promyelocytic leukemia: identification and treatment strategies.
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一种新型融合蛋白 TBLR1-RAR α 作为癌基因诱导小鼠早幼粒细胞白血病：鉴定和治疗策略
DOI：
10.1038/s41419-021-03889-0
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发表时间：
2021-06-11
影响因子：
9
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Li S;Yang X;Liu S;Chen Y;Xing H;Tang K;Tian Z;Xu Y;Rao Q;Wang M;Wang J
急性早幼粒细胞白血病（APL）的特点是涉及RARα及其融合伙伴的特定染色体易位。几十年来，全反式维甲酸（ATRA）与三氧化二砷（As2O3）协同作用的出现，使大多数APL从高度致命转变为高度可治愈。TBLR1-RARα (TR)是我们前期研究中发现的第10个APL融合基因，其在APL发病机制中的致癌作用尚未完全阐明。在本研究中，我们发现TR在小鼠造血祖细胞中的表达可诱导分化阻断，并增强体外增殖能力。通过在谱系阴性的骨髓单核细胞中表达TR融合基因，建立了一种新的小鼠可移植白血病模型。原发性TR小鼠的特征显示出侵袭性白血病的快速发作并伴有出血特征，这比其他模型更准确地概括了人类APL。尽管体外对ATRA诱导的细胞分化具有敏感性，但ATRA单药或与As2O3联合治疗均不能给TR小鼠带来生存益处，这与TR融合基因APL患者的临床预后较差一致。基于生物信息学分析显示的组蛋白去乙酰化表型，HDAC抑制剂在TR小鼠的生存中表现出显著的生存优势，从而为治疗罕见类型APL的临床疗效提供了新的见解。
Acute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation involving RARα and its fusion partners. For decades, the advent of all-trans retinoic acid (ATRA) synergized with arsenic trioxide (As2O3) has turned most APL from highly fatal to highly curable. TBLR1-RARα (TR) is the tenth fusion gene of APL identified in our previous study, with its oncogenic role in the pathogenesis of APL not wholly unraveled. In this study, we found the expression of TR in mouse hematopoietic progenitors induces blockade of differentiation with enhanced proliferative capacity in vitro. A novel murine transplantable leukemia model was then established by expressing TR fusion gene in lineage-negative bone marrow mononuclear cells. Characteristics of primary TR mice revealed a rapid onset of aggressive leukemia with bleeding diathesis, which recapitulates human APL more accurately than other models. Despite the in vitro sensitivity to ATRA-induced cell differentiation, neither ATRA monotherapy nor combination with As2O3 confers survival benefit to TR mice, consistent with poor clinical outcome of APL patients with TR fusion gene. Based on histone deacetylation phenotypes implied by bioinformatic analysis, HDAC inhibitors demonstrated significant survival superiority in the survival of TR mice, yielding insights into clinical efficacy against rare types of APL.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
5.4
作者：
Li Y;Seto E
通讯作者：
Seto E
DOI：
10.1073/pnas.93.15.7900
发表时间：
1996-07-23
影响因子：
11.1
作者：
Early, E;Moore, MAS;Dmitrovsky, E
通讯作者：
Dmitrovsky, E
DOI：
10.1073/pnas.94.10.5302
发表时间：
1997-05-13
影响因子：
11.1
作者：
He, LZ;Tribioli, C;Pandolfi, PP
通讯作者：
Pandolfi, PP
CS055 (Chidamide/HBI-8000) 是一种新型组蛋白脱乙酰酶抑制剂，可诱导人白血病细胞 G1 期阻滞、ROS 依赖性细胞凋亡和分化
影响因子：
4.1
作者：
Gong, Ke;Xie, Jia;Li, Wenhua
通讯作者：
Li, Wenhua