Transcriptomics

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Oncogenic Nras has a bimodal effect on hematopoietic stem cells promoting proliferation and self-renewal


ABSTRACT: Pre-leukemic mutations are thought to promote clonal expansion of hematopoietic stem cells (HSCs) by increasing self-renewal and competitiveness. However, mutations that increase HSC proliferation tend to reduce competitiveness and self-renewal potential, raising the question of how a mutant HSC can sustainably outcompete wild-type HSCs. Activating mutations in NRAS are prevalent in human myeloproliferative disease and leukemia. Here we show that a single allele of oncogenic NrasG12D increases HSC proliferation but also increases reconstituting and self-renewal potential upon serial transplantation in irradiated mice, all without immortalizing HSCs or causing leukemia in our experiments. NrasG12D also confers long-term self-renewal potential upon multipotent progenitors. To explore the mechanism by which NrasG12D promotes HSC proliferation and self-renewal we assessed HSC cell cycle kinetics using H2B-GFP label retention. We found that NrasG12D had a bimodal effect on HSCs, increasing the proliferation of some HSCs while increasing the quiescence and competitiveness of other HSCs. One signal can therefore increase HSC proliferation, competitiveness, and self-renewal through a bimodal effect that promotes proliferation in some HSCs and quiescence in others. 12 RNA samples from mouse bone marrows were analyzed. There are three biological replicates for each subtype.

REANALYSED by: E-GEOD-45194

ORGANISM(S): Mus musculus  

SUBMITTER: Jeffery Magee   Natacha Bohin  Shann-Ching Chen  Kevin Shannon  Tiffany Wen  Sean Morrison  Qing Li 

PROVIDER: E-GEOD-45194 | ArrayExpress | 2014-03-14

SECONDARY ACCESSION(S): GSE45194PRJNA193193

REPOSITORIES: GEO, ArrayExpress

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Publications

Oncogenic Nras has bimodal effects on stem cells that sustainably increase competitiveness.

Li Qing Q   Bohin Natacha N   Wen Tiffany T   Ng Victor V   Magee Jeffrey J   Chen Shann-Ching SC   Shannon Kevin K   Morrison Sean J SJ  

Nature 20131127 7478


'Pre-leukaemic' mutations are thought to promote clonal expansion of haematopoietic stem cells (HSCs) by increasing self-renewal and competitiveness; however, mutations that increase HSC proliferation tend to reduce competitiveness and self-renewal potential, raising the question of how a mutant HSC can sustainably outcompete wild-type HSCs. Activating mutations in NRAS are prevalent in human myeloproliferative neoplasms and leukaemia. Here we show that a single allele of oncogenic Nras(G12D) in  ...[more]

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