title: Oncogenic Nras has bimodal effects on stem cells that sustainably increase competitiveness.
abstract: '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) increases HSC proliferation but also increases reconstituting and self-renewal potential upon serial transplantation in irradiated mice, all prior to leukaemia initiation. Nras(G12D) also confers long-term self-renewal potential to multipotent progenitors. To explore the mechanism by which Nras(G12D) promotes HSC proliferation and self-renewal, we assessed cell-cycle kinetics using H2B-GFP label retention and 5-bromodeoxyuridine (BrdU) incorporation. Nras(G12D) 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 Nras(G12D) HSCs outcompeted wild-type HSCs, whereas frequently dividing Nras(G12D) HSCs did not. Nras(G12D) 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.
authors.affiliation: Department of Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Natacha
authors.initials: N
authors.lastname: Bohin
authors.affiliation: Department of Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Wen
authors.affiliation: Department of Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Ng
authors.affiliation: Howard Hughes Medical Institute, Department of Pediatrics, and Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Magee
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Shann-Ching
authors.initials: SC
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, California 94158, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
authors.affiliation: Howard Hughes Medical Institute, Department of Pediatrics, and Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Morrison
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D011905:Genes, ras / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D013997:Time Factors