PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress

Chavez, James; Rabe, Jennifer L.; Loeffler, Dirk; Higa, Kelly; Hernández, Giovanni; Mills, Taylor; Ahmed, Nouraiz; Gessner, Rachel; Ke, Zhonghe; Idler, Beau M.; Niño, Katia E.; Kim, Hyunmin; Myers, Jason R.; Stevens, Brett M.; Davizon‐Castillo, Pavel; Jordan, Craig T.; Nakajima, Hitoshi; Ashton, John M.; Welner, Robert S.; Schroeder, Timm; DeGregori, James; Pietras, Eric M.

doi:10.1084/jem.20201169

Cited by 51 publications

(40 citation statements)

References 109 publications

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“…S10D), suggesting that the earliest consequence of the treatment is the activation of SPI1 expression. Of clinical relevance, and in line with a recent investigation that shows that SPI1 expression under inflam-matory stress is required to restrict hematopoietic stem cell expansion (Chavez et al 2021), our findings present SPI1 as a potential target for myeloproliferative diseases.…”

Section: Dna Hypermethylation On Gene Promoters Returns To Normal Levels After Hc Treatmentsupporting

confidence: 87%

Hydroxycarbamide effects on DNA methylation and gene expression in myeloproliferative neoplasms

et al. 2021

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Hydroxycarbamide (HC, hydroxyurea) is a cytoreductive drug inducing cell cycle blockade. However, emerging evidence suggests that HC plays a role in the modulation of transcription through the activity of transcription factors and DNA methylation. Examining the global mechanism of action of HC in the context of myeloproliferative neoplasms (MPNs), for which HC is the first-line treatment, will provide a better understanding of its molecular effects. To explore the effects of HC genome-wide, transcriptomic analyses were performed on two clinically relevant cell types at different stages of differentiation treated with HC in a murine MPN model. This study was replicated in MPN patients by profiling genome-wide gene expression and DNA methylation using patient blood samples collected longitudinally, before and following HC exposure. The effects of HC on the transcriptome were not only associated with cell cycle interruption but also with hematopoietic functions. Moreover, a group of genes were restored to normal expression levels in murine hematopoietic stem cells (HSCs) following drug treatment, including the master regulator of hematopoiesis, RUNX1. In humans, HC significantly modifies DNA methylation levels in HSCs at several distal regulatory regions, which we show to be associated with SPI1 binding sites and at the SPI1 locus itself. We have identified novel targets of HC that include pivotal transcription factors involved in hematopoiesis, and for the first time we report abnormal methylation patterns in MPN patients at the master regulator gene SPI1 and its distal binding sites, which HC is able to restore to normal levels.

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Section: Dna Hypermethylation On Gene Promoters Returns To Normal Levels After Hc Treatmentsupporting

confidence: 87%

Hydroxycarbamide effects on DNA methylation and gene expression in myeloproliferative neoplasms

et al. 2021

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“…This quiescent state under chronic inflammation is due to the repression of cell cycle and protein synthesis genes, which are mediated by activation of the transcription factor PU.1 and direct PU.1 binding at repressed target genes. Consistently, PU.1-deficient HSCs displayed overexpressed cell cycle and protein synthesis genes [82]. Aged HSCs display cell cycle arrest [90,91], which is associated with replicative stress [90].…”

Section: Hscs Are Transiently Activated Under Chronic Inflammationmentioning

confidence: 83%

“…The loss of C/EBPβ attenuates an IL-1β-driven myeloid gene program and expands hematopoietic stem and progenitor cells (HSPCs) [92]. It also has been shown that the induction of myeloid differentiation by IL-1β and TNF-α is likely due to the activation of PU.1 [36,82,93] and mice lacking the PU.1 upstream regulatory severely attenuated myeloid differentiation. The overexpression of PU.1 has been shown to accelerate the myeloid output of HSCs in vitro [36].…”

Section: Inflammation-associated Signals Are Activated In Aged Hscsmentioning

confidence: 99%

Inflammation and Aging of Hematopoietic Stem Cells in Their Niche

Yang

Haan

2021

Cells

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Hematopoietic stem cells (HSCs) sustain the lifelong production of all blood cell lineages. The functioning of aged HSCs is impaired, including a declined repopulation capacity and myeloid and platelet-restricted differentiation. Both cell-intrinsic and microenvironmental extrinsic factors contribute to HSC aging. Recent studies highlight the emerging role of inflammation in contributing to HSC aging. In this review, we summarize the recent finding of age-associated changes of HSCs and the bone marrow niche in which they lodge, and discuss how inflammation may drive HSC aging.

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“…We further show that the maintenance of low CEPBA activity by AMLs is important for their fitness, as ectopic expression of CEBPA conferred a competitive disadvantage on AMLs, coinciding with increased differentiation and reduced expression of stemness genes. AMLs may need to evolve reduced CEPBA activity to convert IL-1β from a negative regulator of HSPC fitness ( Pietras et al, 2016 ; Chavez et al, 2021 ) into a positive contributor to AML fitness ( Carey et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Chronic interleukin-1 exposure triggers selection for Cebpa-knockout multipotent hematopoietic progenitors

Higa

Goodspeed

Chavez

et al. 2021

Journal of Experimental Medicine

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The early events that drive myeloid oncogenesis are not well understood. Most studies focus on the cell-intrinsic genetic changes and how they impact cell fate decisions. We consider how chronic exposure to the proinflammatory cytokine, interleukin-1β (IL-1β), impacts Cebpa-knockout hematopoietic stem and progenitor cells (HSPCs) in competitive settings. Surprisingly, we found that Cebpa loss did not confer a hematopoietic cell–intrinsic competitive advantage; rather chronic IL-1β exposure engendered potent selection for Cebpa loss. Chronic IL-1β augments myeloid lineage output by activating differentiation and repressing stem cell gene expression programs in a Cebpa-dependent manner. As a result, Cebpa-knockout HSPCs are resistant to the prodifferentiative effects of chronic IL-1β, and competitively expand. We further show that ectopic CEBPA expression reduces the fitness of established human acute myeloid leukemias, coinciding with increased differentiation. These findings have important implications for the earliest events that drive hematologic disorders, suggesting that chronic inflammation could be an important driver of leukemogenesis and a potential target for intervention.

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PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress

Cited by 51 publications

References 109 publications

Hydroxycarbamide effects on DNA methylation and gene expression in myeloproliferative neoplasms

Hydroxycarbamide effects on DNA methylation and gene expression in myeloproliferative neoplasms

Inflammation and Aging of Hematopoietic Stem Cells in Their Niche

Chronic interleukin-1 exposure triggers selection for Cebpa-knockout multipotent hematopoietic progenitors

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