Convergence of oncogenic cooperation at single-cell and single-gene levels drives leukemic transformation.
Convergence of oncogenic cooperation at single-cell and single-gene levels drives leukemic transformation.
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DOI：
10.1038/s41467-021-26582-4
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发表时间：
2021-11-03
影响因子：
16.6
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Liu Y;Gu Z;Cao H;Kaphle P;Lyu J;Zhang Y;Hu W;Chung SS;Dickerson KE;Xu J
癌症是从体细胞突变的积累中发展而来的，但目前尚不清楚致癌病变如何协同推动癌症进展。使用小鼠模型窝藏NRasG12D和EZH2突变，概括白血病的进展，我们采用单细胞转录组学分析映射细胞组成和基因表达的改变，在健康或患病的骨髓白血病。在细胞水平上，NRasG12D诱导髓系偏向性分化，EZH2缺陷损害髓系细胞成熟，而它们通过转录程序失调共同促进髓系肿瘤。在基因水平上，NRasG12D和EZH2缺陷独立且协同地解除基因表达。我们整合了组织病理学、白血病再增殖和白血病起始细胞检测的结果，以验证基于转录组的细胞谱。我们利用这一资源与白血病表型的发展层次，在单细胞和单基因水平上评估致癌合作，并确定GEM作为白血病启动细胞的调节因子。我们的研究建立了一种综合方法，以体内单细胞分辨率去卷积癌症演变。确定遗传改变如何在癌症中合作是具有挑战性的。在这里，作者使用单细胞RNA测序分析了具有致癌NRAS和EZH2突变的白血病小鼠模型，评估了致癌合作，并将GEM鉴定为白血病起始细胞的调节因子。
Cancers develop from the accumulation of somatic mutations, yet it remains unclear how oncogenic lesions cooperate to drive cancer progression. Using a mouse model harboring NRasG12D and EZH2 mutations that recapitulates leukemic progression, we employ single-cell transcriptomic profiling to map cellular composition and gene expression alterations in healthy or diseased bone marrows during leukemogenesis. At cellular level, NRasG12D induces myeloid lineage-biased differentiation and EZH2-deficiency impairs myeloid cell maturation, whereas they cooperate to promote myeloid neoplasms with dysregulated transcriptional programs. At gene level, NRasG12D and EZH2-deficiency independently and synergistically deregulate gene expression. We integrate results from histopathology, leukemia repopulation, and leukemia-initiating cell assays to validate transcriptome-based cellular profiles. We use this resource to relate developmental hierarchies to leukemia phenotypes, evaluate oncogenic cooperation at single-cell and single-gene levels, and identify GEM as a regulator of leukemia-initiating cells. Our studies establish an integrative approach to deconvolute cancer evolution at single-cell resolution in vivo. Identifying how genetic alterations cooperate in cancer is challenging. Here the authors analyze leukemia mouse models with both oncogenic NRAS and EZH2 mutations using single-cell RNA-sequencing, evaluate oncogenic cooperation, and identify GEM as a regulator of leukemia-initiating cells.
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