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RNA-seq analysis of transcriptomic changes in control (shLuc) and GEM knockdown (shGem) bone marrow LSK cells

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 NRasG12D and EZH2 mutations that recapitulates leukemic progression, we employed single-cell RNA sequencing to map cellular composition and gene expression alterations in healthy or diseased bone marrows during leukemogenesis. At cellular level, NRasG12D induces myeloid-biased differentiation and EZH2-deficiency impairs myeloid cell maturation, whereas they cooperate to promote myeloid expansion with dysregulated transcriptional programs. At gene level, NRasG12D and EZH2-deficiency independently and synergistically control gene expression in single cells. We integrated results from histopathology, leukemia repopulation, and leukemia-initiating cell assays to validate transcriptome-based cellular profiles. We used this resource to relate developmental hierarchies to leukemia phenotypes, evaluated oncogenic cooperation at single-cell and single-gene levels, and identified GEM as a new regulator of leukemia-initiating cells. Our studies establish an integrative approach to deconvolute cancer evolution in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE179083 | GEO | 2021/09/28

REPOSITORIES: GEO

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Single cell RNA-seq analysis of transcriptomics in WT and E2-KO, G12D and G12D/E2-KO HSPCs from mouse bone marrow

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