Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML

Saito, Yoriko; Uchida, Naoyuki; Tanaka, Satoshi; Suzuki, Naohiko; Tomizawa-Murasawa, Mariko; Sone, Akiko; Najima, Yuho; Takagi, Shinsuke; Aoki, Yuki; Wake, Atsushi; Taniguchi, Shuichi; Shultz, Leonard D.; Ishikawa, Fumihiko

doi:10.1038/nbt.1607

Cited by 369 publications

(310 citation statements)

References 37 publications

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“…In xenograft models of human acute myeloid leukemia (AML), "normal" environmental structures are restored after these models are released from leukemic burden by chemotherapy [38,39]. Changes in BM environment may have resulted from anatomical "crowding out" of normal blood cells and mesenchymal cells.…”

Section: Dissemination Of Malignant Cells Alters Normal Bm Nichesmentioning

confidence: 99%

“…These blasts are tightly anchored by OPN in this niche and induced into a quiescent phase by other unknown factors in a local microenvironment [52]. Therefore, the induction of cell cycle entry facilitates cytotoxic agents to eliminate LSCs in mouse models [38,52] and may be translated to clinical treatments.…”

Section: Lscs Hide In Distinct Preferential Niches In Response To Thementioning

confidence: 99%

“…LSCs localize and engraft in normal endosteal niches which used to keep HSCs in quiescence and chemoresistance (Fig. 2a) [38,39]. Leukemia engrafted in HSC niches induces alteration in this niche.…”

Section: Lscs Hide In Distinct Preferential Niches In Response To Thementioning

confidence: 99%

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Neoplasms in the bone marrow niches: disturbance of the microecosystem

Fang

Guo

et al. 2017

Int J Hematol

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Section: Dissemination Of Malignant Cells Alters Normal Bm Nichesmentioning

confidence: 99%

Section: Lscs Hide In Distinct Preferential Niches In Response To Thementioning

confidence: 99%

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Neoplasms in the bone marrow niches: disturbance of the microecosystem

Fang

Guo

et al. 2017

Int J Hematol

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“…Those drugresistant cells are localized in the osteoblastic niche of the bone marrow (Ishikawa et al, 2007;Saito et al, 2010). They are quiescent and thus are not killed by antiproliferative chemotherapeutic regimens targeting cell cycle or DNA replication.…”

Section: Introductionmentioning

confidence: 99%

“…In cases of disease remission where elimination of cycling progenitors is achieved, relapses are frequent because of resistant LSCs and the prognosis is poor. The two main options proposed to eradicate LSCs aim at pushing LSCs out of their protective bone marrow niche (Jin et al, 2006;Saito et al, 2010) or killing them by targeting their specific signaling pathways (Guzman et al, 2005;Xu et al, 2005). However, a large number of primary cells from patients are refractive to these treatments, suggesting that new strategies are likely needed to eradicate LSCs.…”

Section: Introductionmentioning

confidence: 99%

Sex differences in the GSK3β-mediated survival of adherent leukemic progenitors

et al. 2011

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Therapeutic resistance of acute myeloid leukemia stem cells, enriched in the CD34 þ 38 À 123 þ progenitor population, is supported by extrinsic factors such as the bone marrow niche. Here, we report that when adherent onto fibronectin or osteoblast components, CD34 þ 38 À 123 þ progenitors survive through an integrin-dependent activation of glycogen synthase kinase 3b (GSK3b) by serine 9-dephosphorylation. Strikingly, GSK3b-mediated survival was restricted to leukemic progenitors from female patients. GSK3b inhibition restored sensitivity to etoposide, and impaired the clonogenic capacities of adherent leukemic progenitors from female patients. In leukemic progenitors from female but not male patients, the scaffolding protein RACK1, activated downstream of a 5 b 1 -integrin engagement, was specifically upregulated and controlled GSK3b activation through the phosphatase protein phosphatase 2A (PP2A). In a mirrored manner, survival of adherent progenitors (CD34 þ 38 À ) from male but not female healthy donors was partially dependent on this pathway. We conclude that the GSK3b-dependent survival pathway might be sex-specific in normal immature population and flip-flopped upon leukemogenesis. Taken together, our results strengthen GSK3b as a promising target for leukemic stem cell therapy and reveal gender differences as a new parameter in anti-leukemia therapy.

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The palette of techniques for cell cycle analysis

Eastman

Guo

2020

FEBS Letters

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The cell division cycle is the generational period of cellular growth and propagation. Cell cycle progression needs to be highly regulated to preserve genomic fidelity while increasing cell number. In multicellular organisms, the cell cycle must also coordinate with cell fate specification during development and tissue homeostasis. Altered cell cycle dynamics play a central role also in a number of pathophysiological processes. Thus, extensive effort has been made to define the biochemical machineries that execute the cell cycle and their regulation, as well as implementing more sensitive and accurate cell cycle measurements. Here, we review the available techniques for cell cycle analysis, revisiting the assumptions behind conventional population-based measurements and discussing new tools to better address cell cycle heterogeneity in the single-cell era. We weigh the strengths, weaknesses, and trade-offs of methods designed to measure temporal aspects of the cell cycle. Finally, we discuss emerging techniques for capturing cell cycle speed at single-cell resolution in live animals.

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Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML

Cited by 369 publications

References 37 publications

Neoplasms in the bone marrow niches: disturbance of the microecosystem

Neoplasms in the bone marrow niches: disturbance of the microecosystem

Sex differences in the GSK3β-mediated survival of adherent leukemic progenitors

The palette of techniques for cell cycle analysis

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