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

Rabe, Jennifer L.; Loeffler, Dirk; Higa, Kelly; Hernandez, Giovanny; Mills, Taylor; Ahmed, Nouraiz; Gessner, Rachel; Ke, Zhonghe; Kim, Hyun Min; Myers, Jason R.; Stevens, Brett M.; Jordan, Craig T.; Nakajima, Hitoshi; Ashton, John M.; Welner, Robert S.; Schroeder, Timm; DeGregori, James; Pietras, Eric M.

doi:10.1101/2020.05.18.102830

Cited by 7 publications

(6 citation statements)

References 98 publications

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“…Interestingly, in the ageing brain, changes in the niche enforce increased neuronal stem cell quiescence [38]. Future studies will have to consider the further complexity that arises in humans with age, due to niche-driven effects, life histories of infection/inflammation [39,40] as well as age-related clonal hematopoiesis [19].…”

Section: All Hsc/mpps Are Quiescent But Very Few Are Truly Dormantmentioning

confidence: 99%

Beyond “to divide or not to divide”: Kinetics matters in hematopoietic stem cells

Johnson

Belluschi

Laurenti

2020

Experimental Hematology

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Section: All Hsc/mpps Are Quiescent But Very Few Are Truly Dormantmentioning

confidence: 99%

Beyond “to divide or not to divide”: Kinetics matters in hematopoietic stem cells

Johnson

Belluschi

Laurenti

2020

Experimental Hematology

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“…Quiescence is a hallmark of HSCs as it prevents stem cell exhaustion ( Blank and Karlsson, 2015 ), differentiation to downstream progenitors ( Pietras et al, 2015 ), and protects HSCs from mutations acquired during cell division that could lead to carcinogenic transformation ( Walter et al, 2015 ). HSCs can respond directly to inflammatory insults, such as infection, however, and IL-1R-dependent signals can activate LT-HSCs and reduce quiescence ( Chavez et al, 2021 ). Since type I IFNs can promote inflammasome activation ( Kader et al, 2017 ), we examined the impact of IFNs and IOE on inflammasome-dependent cytokines, IL-1β and IL-18.…”

Section: Discussionmentioning

confidence: 99%

IL-18R-mediated HSC quiescence and MLKL-dependent cell death limit hematopoiesis during infection-induced shock

et al. 2021

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Summary Severe infection can dramatically alter blood production, but the mechanisms driving hematopoietic stem and progenitor cell (HSC/HSPC) loss have not been clearly defined. Using Ixodes ovatus Ehrlichia (IOE), a tick-borne pathogen that causes severe shock-like illness and bone marrow (BM) aplasia, type I and II interferons (IFNs) promoted loss of HSPCs via increased cell death and enforced quiescence. IFN-αβ were required for increased interleukin 18 (IL-18) expression during infection, correlating with ST-HSC loss. IL-18 deficiency prevented BM aplasia and increased HSC/HSPCs. IL-18R signaling was intrinsically required for ST-HSC quiescence, but not for HSPC cell death. To elucidate cell death mechanisms, MLKL- or gasdermin D-deficient mice were infected; whereas Mlkl − / − mice exhibited protected HSC/HSPCs, no such protection was observed in Gsdmd − / − mice during infection. MLKL deficiency intrinsically protected HSCs during infection and improved hematopoietic output upon recovery. These studies define MLKL and IL-18R signaling in HSC loss and suppressed hematopoietic function in shock-like infection.

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“…In addition to DNA replication, cell cycle regulation, and proliferation-related gene sets, which are likely secondary to DNA damage after cytarabine, our gene expression studies uncovered signatures of deregulated cell adhesion, proteostasis, as well as repressed OXPHOS and fatty acid metabolism, and RNA splicing, all of which are critical for hematopoietic stem cell function and are commonly deregulated during aging and in myeloid malignancies. Notably, deregulation of ribosome biogenesis and protein degradation may reflect loss of stemness 84,85 , whereas increased reliance on OXPHOS and fatty acid metabolism are characteristic of chemoresistant acute myeloid leukemia 49,52,86 and together with altered splicing engender potential therapeutic vulnerabilities 50,87,88 . It will be interesting to investigate if these processes contribute to the leukemic progression in individuals with clonal hematopoiesis with DNMT3A mutations [89][90][91][92][93][94] to serve as biomarkers for high risk of AML development.…”

Section: Discussionmentioning

confidence: 99%

DNMT3A harboring leukemia-associated mutations directs sensitivity to DNA damage at replication forks

Venugopal

Nowialis

Feng

et al. 2021

Preprint

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Mutations in the DNA methyltransferase 3A (DNMT3A) gene are recurrent in de novo acute myeloid leukemia (AML) and are associated with resistance to standard chemotherapy, disease relapse, and poor prognosis, especially in advanced-age patients. Previous gene expression studies in cells with DNMT3A mutations identified deregulation of cell cycle-related signatures implicated in DNA damage response and replication fork integrity, suggesting sensitivity to replication stress. Here we tested whether pharmacologically-induced replication fork stalling creates a therapeutic vulnerability in cells with DNMT3A(R882) mutations. We observed increased sensitivity to nucleoside analogs such as cytarabine in multiple cellular systems expressing mutant DNMT3A, ectopically or endogenously, in vitro and in vivo. Analysis of DNA damage signaling in response to cytarabine revealed persistent intra-S phase checkpoint activation, accompanied by accumulation of DNA damage in the DNMT3A(R882) overexpressing cells, which was only partially resolved after drug removal and carried through mitosis, resulting in micronucleation. Pulse-chase double-labeling experiments with EdU and BrdU after cytarabine wash-out demonstrated that cells with DNMT3A(mut) were able to restart replication but showed a higher rate of fork collapse. Gene expression profiling by RNA-seq identified deregulation of pathways associated with cell cycle progression and p53 activation, as well as metabolism and chromatin. Together, our studies show that cells with DNMT3A mutations have a defect in recovery from replication fork arrest and subsequent accumulation of unresolved DNA damage, which may have therapeutic tractability. These results demonstrate that, in addition to its role in epigenetic control, DNMT3A contributes to preserving genome integrity during DNA replication.

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

Cited by 7 publications

References 98 publications

Beyond “to divide or not to divide”: Kinetics matters in hematopoietic stem cells

Beyond “to divide or not to divide”: Kinetics matters in hematopoietic stem cells

IL-18R-mediated HSC quiescence and MLKL-dependent cell death limit hematopoiesis during infection-induced shock

DNMT3A harboring leukemia-associated mutations directs sensitivity to DNA damage at replication forks

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