Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Department of Pediatrics, Harold C. Simmons Comprehensive Cancer Center, and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Nat Commun. 2021 Nov 3;12(1):6323. doi: 10.1038/s41467-021-26582-4.
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 NRas 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, NRas 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, NRas 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.
癌症是由体细胞突变积累引起的，但目前尚不清楚致癌病变如何合作推动癌症进展。我们使用一种携带有 NRas 和 EZH2 突变的小鼠模型，该模型模拟了白血病的进展，通过单细胞转录组谱分析来绘制白血病发生过程中健康或患病骨髓中的细胞组成和基因表达变化。在细胞水平上，NRAS 诱导髓系偏向分化，EZH2 缺陷会损害髓系细胞成熟，而它们合作促进了转录程序失调的髓系肿瘤。在基因水平上，NRAS 和 EZH2 缺陷独立且协同地上调基因表达。我们整合了组织病理学、白血病再增殖和白血病起始细胞测定的结果，以验证基于转录组的细胞图谱。我们利用这一资源将发育层次结构与白血病表型联系起来，在单细胞和单基因水平评估致癌合作，并确定 GEM 是白血病起始细胞的调节剂。我们的研究建立了一种整合方法，可在体内以单细胞分辨率解析癌症进化。
