Convergence of oncogenic cooperation at single-cell and single-gene levels drives leukemic transformation

• DOI: 10.1038/s41467-021-26582-4
• Publication Date: 2021-11-05T14:10:44Z
• Authors: Yuxuan Liu; Zhimin Gu; Hui Cao; Pranita Kaphle; Junhua Lyu; Yuannyu Zhang; Wenhuo Hu; Stephen S. Chung; Kathryn E. Dickerson; Jian Xu
• Keywords: Epigenomics; 0301 basic medicine; Carcinogenesis; Science; Apoptosis; Article; GTP Phosphohydrolases; Genetic Heterogeneity; 03 medical and health sciences; Animals; Humans; Enhancer of Zeste Homolog 2 Protein; Myeloid Cells; Mice, Knockout; Leukemia; Q; Cell Cycle; Membrane Proteins; Oncogenes; 3. Good health; Gene Expression Regulation, Neoplastic; Leukemia, Myeloid, Acute; Phenotype; Mutation; Single-Cell Analysis; Transcriptome

Abstract 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 G12D and EZH2 mutations that recapitulates leukemic progression, we employ single-cell transcriptomic profiling map cellular composition gene expression alterations in healthy or diseased bone marrows during leukemogenesis. At level, induces myeloid lineage-biased differentiation EZH2-deficiency impairs cell maturation, whereas they promote neoplasms with dysregulated transcriptional programs. independently synergistically deregulate expression. We integrate results histopathology, leukemia repopulation, leukemia-initiating assays validate transcriptome-based profiles. use this resource relate developmental hierarchies phenotypes, evaluate cooperation at single-gene levels, identify GEM as regulator cells. Our studies establish an integrative approach deconvolute evolution resolution vivo.