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Clonal analysis of lineage fate in unperturbed hematopoiesis

ABSTRACT: The classical tenet of hematopoiesis posits well-accepted lineage trees that arise from progressively restricted oligopotent and unipotent progenitor populations. However, because fate in hematopoiesis has mostly been studied in the context of transplantation, it is unclear whether these lineage branches and such proposed oligopotent progenitors exist in an unperturbed hematopoietic system. Here, we utilize endogenous transposon tagging to trace the fate of thousands of progenitors and stem cells over time to re-evaluate these dogmas. Our results describe a novel clonal roadmap where the megakaryocyte lineage arises independently of lymphoid and myeloid/erythroid fates. Our data also demonstrate that true oligopotency is largely restricted to the multipotent progenitor (MPP) compartment. Analysis of thousands of stem cell and progenitor transcriptomes demonstrates that lineage determination starts at the MPP stage and identifies a functional hierarchy within this population that drives hematopoiesis. Finally, our results demonstrate that long-term hematopoietic stem cells behave physiologically as megakaryocyte lineage progenitors. Our data provide evidence for a substantially revised hematopoietic roadmap, and highlights unique properties of MPPs and HSCs in situ.

ORGANISM(S): Mus musculus

PROVIDER: GSE90742 | GEO | 2018/01/03

SECONDARY ACCESSION(S): PRJNA355645

REPOSITORIES: GEO

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Project description:Disrupting mutations of the RUNX1 gene are found in 10% of patients with myelodysplasia (MDS) and 30% of patients with acute myeloid leukemia (AML). Previous studies have revealed an increase in hematopoietic stem cells (HSCs) and multipotent progenitor (MPP) cells in conditional Runx1-knockout (KO) mice, but the molecular mechanism is unresolved. We investigated the myeloid progenitor (MP) compartment in KO mice, arguing that disruptions at the HSC/MPP level may be amplified in downstream cells. We demonstrate that the MP compartment is increased more than fivefold in Runx1 KO mice, with a prominent skewing toward megakaryocyte (Meg) progenitors. Runx1- deficient granulocyte-macrophage progenitors are characterized by increased cloning capacity, impaired development into mature cells, and HSC and Meg transcription signatures. An HSC/MPP subpopulation expressing Meg markers was also increased in Runx1-deficient mice. Rescue experiments coupled with transcriptome analysis and Runx1 DNA-binding assays demonstrated that commitment is marked by Runx1 suppression of genes encoding adherence and motility proteins (Tek, Jam3, Plxnc1, Pcdh7, and Selp) that support HSCâMeg interactions with the BM niche. In vitro assays confirmed that enforced Tek expression in HSCs/MPPs increases Meg output. Interestingly, besides this key repressor function of Runx1 to control lineage decisions and cell numbers in progenitors, our study also revealed a critical activating function in erythroblast differentiation, in addition to its known importance in Meg and granulocyte/monocyte (G/M) maturation. Thus both repressor and activator functions of Runx1 at multiple hematopoietic stages and lineages likely contribute to the tumor suppressor activity in MDS and AML. GMP were isolated either from Runx1+/+-Tg(vav-Cre) and Runx1fl/fl-Tg(vav-Cre) mice or from mice transplanted with Runx1fl/fl-Tg(vav-Cre) progenitors engineered to express GFP with RUNX1-ERt2 or ERt2. RUNX1-ERt2 activity was induced by i.p. injection of tamoxifen on 3 consecutive days prior to GMP isolation.

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Clonal analysis of lineage fate in unperturbed hematopoiesis

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