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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.

ORGANISM(S): Mus musculus

PROVIDER: GSE45194 | GEO | 2014/03/14

SECONDARY ACCESSION(S): PRJNA193193

REPOSITORIES: GEO

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

Project description: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.

2014-03-14 | E-GEOD-45194 | biostudies-arrayexpress

Global Gene Expression of hematopoietic stem cells expressing endogenous NrasG12D/G12D, NrasG12D/+, Nras+/+

Project description:Oncogenic NRAS mutations are frequently identified in human myeloid leukemias. In mice, expression of endogenous oncogenic Nras (NrasG12D/+) in hematopoietic cells leads to expansion of myeloid progenitors, increased long-term reconstitution of bone marrow cells, and a chronic myeloproliferative neoplasm (MPN). However, acute expression of NrasG12D/+ in a pure C57BL/6 background does not induce hyperactivated GM-CSF signaling or increased proliferation in myeloid progenitors. It is thus unclear how NrasG12D/+ signaling promotes leukemogenesis. Here we show that hematopoietic stem cells (HSCs) expressing NrasG12D/+ serve as MPN initiating cells. They undergo moderate hyperproliferation with increased self-renewal. The aberrant NrasG12D/+ HSC function is associated with hyperactivation of ERK1/2 in HSCs. Conversely, downregulation of MEK/ERK by pharmacological and genetic approaches attenuates the cycling of NrasG12D/+ HSCs and prevents the expansion of NrasG12D/+ HSCs and myeloid progenitors. Our data delineate critical mechanisms of oncogenic Nras signaling in HSC function and leukemogenesis. three NrasG12D/G12D HSCs samples, three NrasG12D/+ HSCs samples, two Nras+/+ HSCs control samples.

2013-05-29 | E-GEOD-46948 | biostudies-arrayexpress

Global Gene Expression of hematopoietic stem cells expressing endogenous NrasG12D/G12D, NrasG12D/+, Nras+/+

2013-05-29 | GSE46948 | GEO

Synergy of Nras mutation and Nup98-Hoxa10HD gene fusion efficiently preserves the stemness of single hematopoietic stem cells after feeder-free culture

Project description:Hematopoietic stem cell (HSC) gives rise to all the hematopoietic cells. The stemness of HSC is strictly controlled by some transcription factors. Here we show that both of Nras mutation (NrasG12D) and Nup98-Hoxa10HD (NA) improve the transplantation competition ability of HSC. Pathways and differential expression genes analysis show that NrasG12D and NA proteins enhance the competitiveness of HSCs via distinct signaling mechanisms.

2019-08-27 | GSE118809 | GEO

FoxM1 is essential for quiescence and maintenance of hematopoietic stem cell

Project description:FoxM1, a mammalian Forkhead Box M1 protein, is known as a typical proliferation-associated transcription factor that regulates of G1/S and G2/M transition in the proliferating cells. However, the in vivo function of FoxM1 in adult stem cells remains unknown. Here, we found that FoxM1 is highly expressed in hematopoietic stem cells (HSCs) and is essential for maintaining quiescence and self-renewal of HSCs in vivo. FoxM1-deficient mice developed leukopenia, thrombocytopenia and neutropenia with an approximately 6-fold decrease in HSC pool size, which is associated with a failure of G0 cell cycle regulation and increased cell cycling in HSCs. FoxM1 absence did not affect lineage commitment of HSCs and progenitors. However, FoxM1 loss significantly reduced the repopulating capacity and self-renewal of long-term HSC in a cell-autonomous manner. Mechanistically, FoxM1 loss markedly down-regulates the expression of orphan nuclear receptor Nurr1, known to regulate HSC quiescence. We found that FoxM1 directly bound the promoter region of Nurr1 and induced transcriptional activity of Nurr1 promoter in vitro, and forced expression of Nurr1 rescued FoxM1-deletion-induced G0 loss of HSC-enriched population in vitro. Thus, our studies show a previously unrecognized role of FoxM1 as a critical regulator of HSC quiescence and self-renewal by controlling Nurr1-mediated pathways. The Hematopoietic Stem Cells (HSCs) were sorted from FoxM1[fl/fl] and Tie2-Cre FoxM1[fl/fl] mice, then amplified with Ovation Pico WTA System V2 before microarray analysis. There are 3 samples from FoxM1[fl/fl]mice and 3 samples from Tie2-Cre FoxM1[fl/fl] mice.

2015-06-15 | E-GEOD-62360 | biostudies-arrayexpress

Tgif1 regulates quiescence and self-renewal signaling pathways of hematopoietic stem cells (HSCs)

Project description:In this study we demonstrate that Tgif1 has a role in HSCs maintenance, self-renewal and quiescence. RNA sequencing data of LSK cells (HSCs enriched cell population) from Tgif1-/- and wild type mice implicates that multiple pathways involved in HSC quiescence and self-renewal are disturbed in Tgif1 deficient mice. RNA expression profiles of wild type (WT) and Tgif1-/- LSK cells were generated by RNA sequencing, in triplicate, using Illumina HiSeq 2000.

2013-09-10 | E-GEOD-50739 | biostudies-arrayexpress

Tgif1 regulates quiescence and self-renewal signaling pathways of hematopoietic stem cells (HSCs)

2013-09-10 | GSE50739 | GEO

FoxM1 is essential for quiescence and maintenance of hematopoietic stem cell

2015-06-15 | GSE62360 | GEO

Bulk and single cell profing of CD45+ LSK cells collected from WT and TET2 deficient mice under normoxia and hypoxia (physioxia) conditions (CITE-SEQ)

Project description:Hematopoietic stem cells (HSCs) manifest impaired recovery and self-renewal with a concomitant increase in progenitor content (HPCs) when exposed to ambient air as opposed to physioxia. Mechanisms behind this distinction are poorly understood but have the potential to enhance HSC function for bone marrow transplantation. High resolution transcriptomic analysis revealed that HSCs under physioxia (HSCs- P) upregulate genes involved in self-renewal and quiescence but downregulate genes involved in apoptosis and differentiation compared to HSCs-A. Remarkably, among several genes, Tet2 was significantly downregulated in HSC-Ps compared to HSC-As, which was associated with reduced 5-hydroxymethylcytosine (5-hmC) levels in HSC-Ps. Interestingly, individuals carrying the TET2 mutation in their HSCs are at a higher risk of developing clonal hematopoiesis, myeloid leukemias and cardiovascular disease. Loss of Tet2 in mice results in more HSCs and enhanced self-renewal. TET enzymes are α-ketoglutarate, iron and oxygen-dependent dioxygenases that convert 5-methylcytosine to 5-hydroxymethylcytosine thereby promoting active transcription. We evaluated whether physioxia affects the numbers and function of HSCs and HPCs from Tet2-/- mice similar to wildtype (WT) mice. In contrast to WT-HSCs, we observed complete non-responsiveness of Tet2-/- HSCs to changes in oxygen tension. Tet2-/- HSCs and HPCs exhibited similar numbers and function under physioxia and ambient air. The lack of functional responsiveness to changes in oxygen tension in Tet2-/- HSCs was associated with similar changes in genes involved in self-renewal and quiescence among WT-HSC-Ps, Tet2-/- HSC-Ps and Tet2-/- HSC-As. Our findings define a novel molecular program involving Tet2 in regulating the self-renewal of HSCs under physioxia.

2022-01-07 | GSE192992 | GEO

Bulk and single cell profiling of CD45+ LSK cells collected from WT and TET2 deficient mice under normoxia and hypoxia (physioxia) conditions (BULK RNA-SEQ)

2022-01-07 | GSE192988 | GEO

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