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研究发现不同信号通路的输入破坏B细胞转化
2020-07-23 16:01

美国希望之城综合癌症中心Markus Mschen研究组的一项最新研究发现,不同信号通路的输入破坏了B细胞转化。相关论文于2020年7月22日在线发表在《自然》杂志上。

研究人员分析了1,148例患者来源的B细胞白血病(B-ALL)样本,发现单个突变不会促进白细胞生成,除非它们会聚在转化B细胞分化阶段的单个致癌通路上。与该中心致癌驱动因子不一致的突变会激活不同的信号通路并破坏转化。B-ALL中的致癌性病变通常发生在前B细胞阶段(通过激活信号转导蛋白STAT5)或更成熟细胞中的前B细胞受体(通过激活蛋白激酶ERK)。 STAT5和ERK激活性病变很常见,但仅在约3%的病例中同时发生(P = 2.2×10-16)。

单细胞突变和磷酸化蛋白分析揭示了致癌性STAT5和ERK激活与竞争性克隆的分离。 STAT5和ERK分别参与由转录因子MYC和BCL6调控的相反生化和转录程序。趋异(受抑制)途径的遗传再活化是以主要致癌驱动因子为代价的,并逆转转化。

相反地,不同途径组分的缺失加速白细胞生成。因此,不同信号通路的持久性代表了转化的强大屏障,而在一个主要驱动因子上的融合则决定了白血病起始的中心事件。抑制不同途径的药理学激活与主要致癌驱动因子的抑制作用密切协同。因此,不同途径的重新激活可以作为先前未知的策略来增强治疗反应。

据悉,通常恶性转化的细胞包涵多个遗传损伤,其综合活性导致癌症。

附:英文原文

Title: Signalling input from divergent pathways subverts B cell transformation

Author: Lai N. Chan, Mark A. Murakami, Mark E. Robinson, Rebecca Caeser, Teresa Sadras, Jaewoong Lee, Kadriye Nehir Cosgun, Kohei Kume, Vishal Khairnar, Gang Xiao, Mohamed A. Ahmed, Eamon Aghania, Gauri Deb, Christian Hurtz, Seyedmehdi Shojaee, Chao Hong, Petri Plnen, Matthew A. Nix, Zhengshan Chen, Chun Wei Chen, Jianjun Chen, Andreas Vogt, Merja Heinniemi, Olli Lohi, Arun P. Wiita, Shai Izraeli, Huimin Geng, David M. Weinstock, Markus Mschen

Issue&Volume: 2020-07-22

Abstract: Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer1. Here we analyse 1,148 patient-derived B-cell leukaemia (B-ALL) samples, and find that individual mutations do not promote leukaemogenesis unless they converge on one single oncogenic pathway that is characteristic of the differentiation stage of transformed B cells. Mutations that are not aligned with this central oncogenic driver activate divergent pathways and subvert transformation. Oncogenic lesions in B-ALL frequently mimic signalling through cytokine receptors at the pro-B-cell stage (via activation of the signal-transduction protein STAT5)2,3,4 or pre-B-cell receptors in more mature cells (via activation of the protein kinase ERK)5,6,7,8. STAT5- and ERK-activating lesions are found frequently, but occur together in only around 3% of cases (P = 2.2 × 1016). Single-cell mutation and phospho-protein analyses reveal the segregation of oncogenic STAT5 and ERK activation to competing clones. STAT5 and ERK engage opposing biochemical and transcriptional programs that are orchestrated by the transcription factors MYC and BCL6, respectively. Genetic reactivation of the divergent (suppressed) pathway comes at the expense of the principal oncogenic driver and reverses transformation. Conversely, deletion of divergent pathway components accelerates leukaemogenesis. Thus, persistence of divergent signalling pathways represents a powerful barrier to transformation, while convergence on one principal driver defines a central event in leukaemia initiation. Pharmacological reactivation of suppressed divergent circuits synergizes strongly with inhibition of the principal oncogenic driver. Hence, reactivation of divergent pathways can be leveraged as a previously unrecognized strategy to enhance treatment responses.

DOI: 10.1038/s41586-020-2513-4

Source: https://www.nature.com/articles/s41586-020-2513-4

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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