Leukemic marrow infiltration reveals a novel role for Egr3 as a potent inhibitor of normal hematopoietic stem cell proliferation

Cheng, Hui; Hao, Sha; Liu, Yanfeng; Pang, Yakun; Ma, Shihui; Fang, Dong; Xu, Jing; Zheng, Guoguang; Li, Shaoguang; Yuan, Weiping; Cheng, Tao

doi:10.1182/blood-2015-01-623645

Cited by 95 publications

(139 citation statements)

References 39 publications

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“…Unlike the depletion of highly susceptible HSPC, HSC have proved to be more resilient during leukemic invasion, and multiple groups reported the relative accumulation of primitive hematopoietic cells in both murine models and xenograft studies [8,15,16,[21][22][23]. Unlike the depletion of highly susceptible HSPC, HSC have proved to be more resilient during leukemic invasion, and multiple groups reported the relative accumulation of primitive hematopoietic cells in both murine models and xenograft studies [8,15,16,[21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Extracellular vesicles impose quiescence on residual hematopoietic stem cells in the leukemic niche

et al. 2019

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Progressive remodeling of the bone marrow microenvironment is recognized as an integral aspect of leukemogenesis. Expanding acute myeloid leukemia (AML) clones not only alter stroma composition, but also actively constrain hematopoiesis, representing a significant source of patient morbidity and mortality. Recent studies revealed the surprising resistance of long‐term hematopoietic stem cells (LT‐HSC) to elimination from the leukemic niche. Here, we examine the fate and function of residual LT‐HSC in the BM of murine xenografts with emphasis on the role of AML‐derived extracellular vesicles (EV). AML‐EV rapidly enter HSC, and their trafficking elicits protein synthesis suppression and LT‐HSC quiescence. Mechanistically, AML‐EV transfer a panel of miRNA, including miR‐1246, that target the mTOR subunit Raptor, causing ribosomal protein S6 hypo‐phosphorylation, which in turn impairs protein synthesis in LT‐HSC. While HSC functionally recover from quiescence upon transplantation to an AML‐naive environment, they maintain relative gains in repopulation capacity. These phenotypic changes are accompanied by DNA double‐strand breaks and evidence of a sustained DNA‐damage response. In sum, AML‐EV contribute to niche‐dependent, reversible quiescence and elicit persisting DNA damage in LT‐HSC.

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Section: Introductionmentioning

confidence: 99%

Extracellular vesicles impose quiescence on residual hematopoietic stem cells in the leukemic niche

et al. 2019

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“…By simply removing the leukemic-effect terms from the model while keeping everything else unchanged, we could see that the normal kinetics, ie, hematopoietic cells as well as HSCs/HPCs were maintained at nearly steady levels [11], were reproduced (Additional file 2: Figure S2). Thus the model not only accurately represented the leukemia-conditioned hematopoietic dynamics; it could also faithfully reflect the situation under the normal condition.…”

Section: Resultsmentioning

confidence: 99%

Digitalization of a non-irradiated acute myeloid leukemia model

Cheng

et al. 2016

BMC Syst Biol

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BackgroundComputer-aided, interdisciplinary researches for biomedicine have valuable prospects, as digitalization of experimental subjects provide opportunities for saving the economic costs of researches, as well as promoting the acquisition of knowledge. Acute myeloid leukemia (AML) is intensively studied over long periods of time. Till nowaday, most of the studies primarily focus on the leukemic cells rather than how normal hematopoietic cells are affected by the leukemic environment. Accordingly, the conventional animal models for AML are mostly myeloablated as leukemia can be induced with short latency and complete penetrance. Meanwhile, most previous computational models focus on modeling the leukemic cells but not the multi-tissue leukemic body resided by both leukemic and normal blood cells. Recently, a non-irradiated AML mouse model has been established; therefore, normal hematopoietic cells can be investigated during leukemia development. Experiments based on the non-irradiated animal model have monitored the kinetics of leukemic and (intact) hematopoietic cells in multiple tissues simultaneously; and thus a systematic computational model for the multi-tissue hematopoiesis under leukemia has become possible.ResultsIn the present work, we adopted the modeling methods in previous works, but aimed to model the tri-tissue (peripheral blood, spleen and bone marrow) dynamics of hematopoiesis under leukemia. The cell kinetics generated from the non-irradiated experimental model were used as the reference data for modeling. All mathematical formulas were systematically enumerated, and model parameters were estimated via numerical optimization. Multiple validations by additional experimental data were then conducted for the established computational model. In the results, we illustrated that the important fact of functional depression of hematopoietic stem/progenitor cells (HSC/HPC) in leukemic bone marrow (BM), which must require additional experiments to be established, could also be inferred from our computation model that utilized only the cell kinetics data as the input.ConclusionThe digitalized AML model established in the present work is effective for reconstructing the hematopoiesis under leukemia as well as simulating the hematopoietic response to leukemic cell expansion. Given the validity and efficiency, the model can be of potential utilities in future biomedical studies; additionally, the modeling method itself can be also applied elsewhere.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-016-0308-x) contains supplementary material, which is available to authorized users.

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“…Recently, an even more interesting observation indicated that except for pre-established leukemic disease, primary leukemia-initiating cells (L-ICs) were consistently outperformed by normal cord blood (CB) CD341 cells for BM niche occupancy in a cell dose dependent manner [32]. Notably, the results achieved by both of these studies might be explained by the recent observation that leukemic infiltration can induce progressive HSC quiescence by down-regulating cell-cycle genes and up-regulating several genes including Hes-1 and Egr3 [33]. However, in mice transplanted with AML, knock-down experiments have revealed that only Egr3 is responsible for HSC quiescence, an event that targets marrowresident but not spleen-resident HSCs.…”

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confidence: 77%

Therapeutically targeting SELF‐reinforcing leukemic niches in acute myeloid leukemia: A worthy endeavor?

et al. 2016

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A tight relationship between the acute myeloid leukemia (AML) population and the bone marrow (BM) microenvironment has been convincingly established. The AML clone contains leukemic stem cells (LSCs) that compete with normal hematopoietic stem cells (HSCs) for niche occupancy and remodel the niche; whereas, the BM microenvironment might promote AML development and progression not only through hypoxia and homing/adhesion molecules, but also through genetic defects. Although it is still unknown whether the niche influences treatment results or contains any potential target for treatment, this dynamic AML-niche interaction might be a promising therapeutic objective to significantly improve the AML cure rate.

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Leukemic marrow infiltration reveals a novel role for Egr3 as a potent inhibitor of normal hematopoietic stem cell proliferation

Abstract: Key Points Increased quiescence of HSCs and HPCs in leukemogenesis, and reversible suppression of HSCs was observed in leukemic bone marrow. A novel inhibitory role of Egr3 in HSC proliferation was revealed by leukemic infiltration in bone marrow.

Cited by 95 publications

References 39 publications

Extracellular vesicles impose quiescence on residual hematopoietic stem cells in the leukemic niche

Extracellular vesicles impose quiescence on residual hematopoietic stem cells in the leukemic niche

Digitalization of a non-irradiated acute myeloid leukemia model

Therapeutically targeting SELF‐reinforcing leukemic niches in acute myeloid leukemia: A worthy endeavor?

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