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

‘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 NrasG12D increases HSC proliferation but also increases reconstituting and self-renewal potential upon serial transplantation in irradiated mice, all prior to leukaemia initiation. NrasG12D also confers long-term self-renewal potential to multipotent progenitors. To explore the mechanism by which NrasG12D promotes HSC proliferation and self-renewal, we assessed cell-cycle kinetics using H2B–GFP label retention and 5-bromodeoxyuridine (BrdU) incorporation. NrasG12D had a bimodal effect on HSCs, increasing the frequency with which some HSCs divide and reducing the frequency with which others divide. This mirrored bimodal effects on reconstituting potential, as rarely dividing NrasG12D HSCs outcompeted wild-type HSCs, whereas frequently dividing NrasG12D HSCs did not. NrasG12D caused these effects by promoting STAT5 signalling, inducing different transcriptional responses in different subsets of HSCs. One signal can therefore increase HSC proliferation, competitiveness and self-renewal through bimodal effects on HSC gene expression, cycling and reconstituting potential.

• Publication year

  2013

• Venue

  Nature

• Publication date

  2013-11-27

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/nature12830PMID 24284627PMCID 4128640
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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