Concise Review: Genetic Dissection of Hypoxia Signaling Pathways in Normal and Leukemic Stem Cells

Gezer, Deniz; Vukovic, Milica; Soga, Tomoyoshi; Pollard, Patrick J.; Kranc, Kamil R.

doi:10.1002/stem.1657

Cited by 28 publications

(19 citation statements)

References 66 publications

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“…The exposure of HSCs to hypoxia or pharmacological hydroxylase inhibition (which activates HIF) promotes HSC quiescence in a HIF-dependent manner 83,84 . The mechanism by which hypoxia regulates HSC quiescence, self-renewal and proliferation remains an area of considerable investigation; however, some studies indicate that the mechanism involves HIF1-dependent control of metabolism 85,86 . Furthermore, hypoxia, through the HIF pathway, regulates stem cell development in other niches, including the carotid body 87,88 .…”

Section: Hypoxia In Physiological Immune Nichesmentioning

confidence: 99%

Regulation of immunity and inflammation by hypoxia in immunological niches

2017

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Immunological niches are focal sites of immune activity that can have varying microenvironmental features. Hypoxia is a feature of physiological and pathological immunological niches. The impact of hypoxia on immunity and inflammation can vary depending on the microenvironment and immune processes occurring in a given niche. In physiological immunological niches, such as the bone marrow, lymphoid tissue, placenta and intestinal mucosa, physiological hypoxia controls innate and adaptive immunity by modulating immune cell proliferation, development and effector function, largely via transcriptional changes driven by hypoxia-inducible factor (HIF). By contrast, in pathological immunological niches, such as tumours and chronically inflamed, infected or ischaemic tissues, pathological hypoxia can drive tissue dysfunction and disease development through immune cell dysregulation. Here, we differentiate between the effects of physiological and pathological hypoxia on immune cells and the consequences for immunity and inflammation in different immunological niches. Furthermore, we discuss the possibility of targeting hypoxia-sensitive pathways in immune cells for the treatment of inflammatory disease.

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Section: Hypoxia In Physiological Immune Nichesmentioning

confidence: 99%

Regulation of immunity and inflammation by hypoxia in immunological niches

2017

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“…hypoxia-inducible factor 1α | chondrocyte | osteoarthritis | Wnt signaling | matrix metalloprotease 13 L ow oxygen tension (hypoxia) orchestrates several cell functions and is critical in health and disease (1)(2)(3)(4). Hypoxiainducible factor 1α (HIF1α) is an essential factor to maintain chondrocyte homeostasis and allow cell differentiation (5,6).…”

mentioning

confidence: 99%

Interaction of HIF1α and β-catenin inhibits matrix metalloproteinase 13 expression and prevents cartilage damage in mice

Bouaziz

Sigaux

Modrowski

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

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Low oxygen tension (hypoxia) regulates chondrocyte differentiation and metabolism. Hypoxia-inducible factor 1α (HIF1α) is a crucial hypoxic factor for chondrocyte growth and survival during development. The major metalloproteinase matrix metalloproteinase 13 (MMP13) is also associated with chondrocyte hypertrophy in adult articular cartilage, the lack of which protects from cartilage degradation and osteoarthritis (OA) in mice. MMP13 is up-regulated by the Wnt/β-catenin signaling, a pathway involved in chondrocyte catabolism and OA. We studied the role of HIF1α in regulating Wnt signaling in cartilage and OA. We used mice with conditional knockout of Hif1α (ΔHif1α chon ) with joint instability. Specific loss of HIF1α exacerbated MMP13 expression and cartilage destruction. Analysis of Wnt signaling in hypoxic chondrocytes showed that HIF1α lowered transcription factor 4 (TCF4)-β-catenin transcriptional activity and inhibited MMP13 expression. Indeed, HIF1α interacting with β-catenin displaced TCF4 from MMP13 regulatory sequences. Finally, ΔHif1α chon mice with OA that were injected intraarticularly with PKF118-310, an inhibitor of TCF4-β-catenin interaction, showed less cartilage degradation and reduced MMP13 expression in cartilage. Therefore, HIF1α-β-catenin interaction is a negative regulator of Wnt signaling and MMP13 transcription, thus reducing catabolism in OA. Our study contributes to the understanding of the role of HIF1α in OA and highlights the HIF1α-β-catenin interaction, thus providing new insights into the impact of hypoxia in articular cartilage.hypoxia-inducible factor 1α | chondrocyte | osteoarthritis | Wnt signaling | matrix metalloprotease 13

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“…A subset of LICs with active Wnt signaling has proven to reside preferentially within hypoxic niches in a mouse model of Notch-driven T-ALL. In particular, HIF1α upregulates the expression of β-catenin at the transcriptional level, which in turn potentiates Wnt signaling [55,56]. Targeting these key signaling cascades represents an attractive strategy.…”

Section: Breaking the Alliancementioning

confidence: 99%

A Sanctuary for cancer cells: Microenvironment in T-cell acute lymphoblastic leukemia survival and drug resistance

Giacomo¹,

Fiore²,

Kyriakides³

et al. 2017

Clin Diagn Pathol

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T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous malignancy associated with a high risk of treatment failure. Efforts to improve outcomes have focused on underlying genetic defects. However, strong evidence suggests that leukemic cells prime a maladapted niche that in turn provides signals capable of sustaining the dormancy of leukemia initiating cells and protects them from toxic chemotherapeutic agents. Here, we aim to describe how key components of the bone marrow microenvironment are essential for leukemia initiation and progression. Although many mechanisms have been recently discovered, further studies are required to fully dissect the molecular mechanisms governing the bidirectional interactions between tumor and host cells. We predict that these new discoveries will pave the way for the implementation of novel therapeutic strategies and will eventually lead to the eradication of the drug-resistant cells, substantially and ultimately enhancing cure rates for T-ALL patients.

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Concise Review: Genetic Dissection of Hypoxia Signaling Pathways in Normal and Leukemic Stem Cells

Cited by 28 publications

References 66 publications

Regulation of immunity and inflammation by hypoxia in immunological niches

Regulation of immunity and inflammation by hypoxia in immunological niches

Interaction of HIF1α and β-catenin inhibits matrix metalloproteinase 13 expression and prevents cartilage damage in mice

A Sanctuary for cancer cells: Microenvironment in T-cell acute lymphoblastic leukemia survival and drug resistance

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