Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD–induced myeloproliferation

Mead, Adam J.; Neo, Wen Hao; Barkas, Nikolaos; Matsuoka, Satoshi; Giustacchini, Alice; Facchini, R; Thongjuea, Supat; Jamieson, Lauren E.; Booth, Christopher A.G.; Fordham, Nicholas; Genua, Cristina Di; Atkinson, Deborah; Chowdhury, Onima; Repapi, Emmanouela; Gray, Nicola E.; Kharazi, Shabnam; S-A., Clark; Bouriez, Tiphaine; Woll, Petter S.; Suda, Toshio; Nerlov, Claus; Jacobsen, Sten Eirik W.

doi:10.1084/jem.20161418

Cited by 45 publications

(47 citation statements)

References 58 publications

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“…29 At the same time, overexpression of PU.1 and TNF stimulation reduces HSC selfrenewal and induces myeloid differentiation. 21,30,31 The online version of this article contains a data supplement.…”

Section: Resultsmentioning

confidence: 99%

Inflammatory signals directly instruct PU.1 in HSCs via TNF

Etzrodt¹,

Ahmed²,

Hoppe³

et al. 2019

Blood

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The molecular mechanisms governing the transition from hematopoietic stem cells (HSCs) to lineage-committed progenitors remain poorly understood. Transcription factors (TFs) are powerful cell intrinsic regulators of differentiation and lineage commitment, while cytokine signaling has been shown to instruct the fate of progenitor cells. However, the direct regulation of differentiation-inducing hematopoietic TFs by cell extrinsic signals remains surprisingly difficult to establish. PU.1 is a master regulator of hematopoiesis and promotes myeloid differentiation. Here we report that tumor necrosis factor (TNF) can directly and rapidly upregulate PU.1 protein in HSCs in vitro and in vivo. We demonstrate that in vivo, niche-derived TNF is the principal PU.1 inducing signal in HSCs and is both sufficient and required to relay signals from inflammatory challenges to HSCs.

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Section: Resultsmentioning

confidence: 99%

Inflammatory signals directly instruct PU.1 in HSCs via TNF

Etzrodt¹,

Ahmed²,

Hoppe³

et al. 2019

Blood

Self Cite

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“…37 Decreased expression of these genes in AML MSCs and MPCs could affect HSC retention and quiescence and eventually exhaust the normal HSC pool while promoting leukemic cell proliferation, leading to the progression of leukemia, as reported previously. 13,14,38 Accumulated evidence indicates that inflammatory cytokines such as Tgfb1 and Il6 are involved in the development of myeloid malignancies 11,12 and are often increased in patients with myeloproliferative neoplasms. 39,40 We here report that Il6 and Tgfb1 transcripts are upregulated in AML BM MSPCs and ECs, respectively.…”

Section: Discussionmentioning

confidence: 99%

Distinct roles of mesenchymal stem and progenitor cells during the development of acute myeloid leukemia in mice

et al. 2018

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Despite increasing evidence for the involvement of bone marrow (BM) hematopoietic stem cell niche in leukemogenesis, how BM mesenchymal stem and progenitor cells (MSPCs) contribute to leukemia niche formation and progression remains unclear. Using an MLL-AF9 acute myeloid leukemia (AML) mouse model, we demonstrate dynamic alterations of BM cellular niche components, including MSPCs and endothelial cells during AML development and its association with AML engraftment. Primary patient AML cells also induced similar niche alterations in xenografted mice. AML cell infiltration in BM causes an expansion of early B-cell factor 2 (Ebf2) MSPCs with reduced expression and enhanced generation of more differentiated mesenchymal progenitor cells. Importantly, in vivo fate-mapping indicates that Ebf2 MSPCs participated in AML niche formation. Ebf2 cell deletion accelerated the AML development. These data suggest that native BM MSPCs may suppress AML. However, they can be remodeled by AML cells to form leukemic niche that might contribute to AML progression. AML induced dysregulation of hematopoietic niche factors like ,, ,, , and in AML BM MSPCs, which was associated with AML engraftment and partially appeared before the massive expansion of AML cells, indicating the possible involvement of the niche factors in AML progression. Our study demonstrates distinct dynamic features and roles of BM MSPCs during AML development.

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“…Increasing evidence in myeloid neoplasms suggests that malignant HSPCs and their progeny remodel the BM microenvironment to their advantage. 3,6,23,24 The fact that no recurrent somatic mutations have been found in patient-derived MSCs argues that malignant stromal alterations are of epigenetic nature. 25 Only recently, it was shown that ex vivo-expanded MSCs from MDS patients exhibit not only an altered phenotype 6,26 but also an aberrant methylation signature that is reverted in patients responding to AZA.…”

Section: Discussionmentioning

confidence: 99%

Direct modulation of the bone marrow mesenchymal stromal cell compartment by azacitidine enhances healthy hematopoiesis

et al. 2018

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Key Points• AZA treatment of MSCs in MDS leads to preferential expansion of healthy over malignant hematopoiesis.• AZA regulates key MSC genes crucial for support of hematopoiesis, providing proof of concept for epigenetic therapy of MSCs in MDS. Mesenchymal stromal cells (MSCs) are crucial components of the bone marrow (BM) microenvironment essential for regulating self-renewal, survival, and differentiation of hematopoietic stem/progenitor cells (HSPCs) in the stem cell niche. MSCs are functionally altered in myelodysplastic syndromes (MDS) and exhibit an altered methylome compared with MSCs from healthy controls, thus contributing to disease progression. To determine whether MSCs are amenable to epigenetic therapy and if this affects their function, we examined growth, differentiation, and HSPC-supporting capacity of ex vivo-expanded MSCs from MDS patients in comparison with age-matched healthy controls after direct treatment in vitro with the hypomethylating agent azacitidine (AZA). Strikingly, we find that AZA exerts a direct effect on healthy as well as MDS-derived MSCs such that they favor support of healthy over malignant clonal HSPC expansion in coculture experiments. RNA-sequencing analyses of MSCs identified stromal networks regulated by AZA. Notably, these comprise distinct molecular pathways crucial for HSPC support, foremost extracellular matrix molecules (including collagens) and interferon pathway components. Our study demonstrates that the hypomethylating agent AZA exerts its antileukemic activity in part through a direct effect on the HSPC-supporting BM niche and provides proof of concept for the therapeutic potential of epigenetic treatment of diseased MSCs. In addition, our comprehensive data set of AZA-sensitive gene networks represents a valuable framework to guide future development of targeted epigenetic niche therapy in myeloid malignancies such as MDS and acute myeloid leukemia.

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Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD–induced myeloproliferation

Cited by 45 publications

References 58 publications

Inflammatory signals directly instruct PU.1 in HSCs via TNF

Inflammatory signals directly instruct PU.1 in HSCs via TNF

Distinct roles of mesenchymal stem and progenitor cells during the development of acute myeloid leukemia in mice

Direct modulation of the bone marrow mesenchymal stromal cell compartment by azacitidine enhances healthy hematopoiesis

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