The emerging roles of Notch signaling in leukemia and stem cells

Liu, Na; Zhang, Jingru; Ji, Chunyan

doi:10.1186/2050-7771-1-23

Cited by 35 publications

(22 citation statements)

References 72 publications

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“…The pathogenetic role of Notch signaling in leukemic diseases, such as T-ALL and CLL, has been ascribed to the presence of activating mutations in genes coding for components of the Notch pathway (33). However, Notch pathway overexpression due to paracrine signals between leukemic cells and stromal cell microenvironment may result in enhanced leukemia cell survival, as shown in vitro both in B-ALL (14) and AML cells (5,22,23) that normally lack activating Notch mutations (34).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Notch Signaling Enhances Chemosensitivity in B-cell Precursor Acute Lymphoblastic Leukemia

et al. 2019

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Notch3 and Notch4 support survival of primary B-cell acute lymphoblastic leukemia (B-ALL) cells, suggesting a role for Notch signaling in drug response. Here we used in vitro, in silico, and in vivo mouse xenograft model-based approaches to define the role of the Notch pathway in BALL chemosensitivity. We observed significant Notch receptor and ligand expression in BALL primary cells and cell lines. Primary leukemia cells from high-risk patients overexpressed Notch3, Notch4, and Jagged2 while displaying a reduction in expression levels of Notch1-4 following chemotherapy. We then analyzed in vitro cell survival of BALL cells treated with conventional chemotherapeutic agents alone or in combination with Notch signaling inhibitors. Gamma-secretase inhibitors (GSI) and anti-Notch4 were all capable of potentiating drug-induced cell death in BALL cells by upregulating intracellular levels of reactive oxygen species, which in turn modulated mTOR, NF-kB, and ERK expression. In NOG-mouse-based xenograft models of BALL , co-administration of the Notch inhibitor GSI-XII with the chemotherapeutic agent Ara-C lowered bone marrow leukemic burden compared with DMSO or Ara-C alone, thus prolonging mouse survival. Overall, our results support the potential effectiveness of Notch inhibitors in patients with BALL. Significance: Inhibition of Notch signaling enhances the chemosensitivity of BALL cells, suggesting Notch inhibition as a potential therapeutic strategy to improve the outcome of patients with BALL .

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Section: Discussionmentioning

confidence: 99%

Inhibition of Notch Signaling Enhances Chemosensitivity in B-cell Precursor Acute Lymphoblastic Leukemia

et al. 2019

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“…The Notch signaling pathway is a short-range communication transducer that is involved in regulating many cellular processes (proliferation, stem cell and stem cell niche maintenance, cell fate specification, differentiation, and cell death) during development and renewal of adult tissues. The human Notch family includes four cell-bound notch receptors, namely Notch 1-4, and five Notch ligands, Jagged 1 (JAG1), JAG2, Delta-like 1 (DLL1), DLL3 and DLL4 [23,24]. There are 36 tandem EGF-like repeats in the Notch extracellular domain [25], they were modified by O-linked fucose, glucose, or N-acetylglucosamine (GlcNAc) [26].…”

Section: Xxylt1 and Notch Signal And Cancermentioning

confidence: 99%

C3orf21 and Notch Signaling in Cancer：A Potential Biomarker

Zhang¹,

Dehou²,

Bao³

2018

Int J Pathol Clin Res

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C3orf21 (chromosome 3 open reading frame 21), also known as xyloside xylosyltransferase 1 (XXYLT1), is located on chromosome 3q29. C3orf21 belongs to the glycosyltransferase 8 family, furthermore, it is a retaining glycosyltransferase. In the extracellular domain of target proteins, XXYLT1 catalyzes addition of the second sylose, and then elongates the O-linked xylose-glucose disaccharide attached to EGF-like repeats. XXYLT1 negatively regulates Notch signaling, and aberrations in the Notch signaling pathway were associated with a few types of cancers. So, C3orf21 must be associated with cancer development. Our previous research has found that the C3orf21 polymorphisms were associated with lung cancer risk, and the ablation of C3orf21 gene (XXYLT1) promoted lung cancer MSTO-211H cell proliferation, inhibited apoptosis and accelerated cell migration. Understanding the role of C3orf21 in the cancer development may provide insights into the potential of C3orf21 as a cancer biomarker. Here, we reviewed several representative studies for understanding the C3orf21 and Notch signaling in cancer.

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“…Among many others, these pathways include PI3K/Akt/mTOR[38], Wnt/beta-catenin[39,40], Hedgehog[41,42], NF-kB[43,44], Notch[45] and Bcl-2[46,47]. Several drugs targeting these pathways are in different stages of preclinical and clinical development (Figure 1).…”

Section: Biology Of Lscsmentioning

confidence: 99%

Update on acute myeloid leukemia stem cells: New discoveries and therapeutic opportunities

Stahl

Kim

Zeidan

2016

WJSC

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The existence of cancer stem cells has been well established in acute myeloid leukemia. Initial proof of the existence of leukemia stem cells (LSCs) was accomplished by functional studies in xenograft models making use of the key features shared with normal hematopoietic stem cells (HSCs) such as the capacity of self-renewal and the ability to initiate and sustain growth of progenitors in vivo. Significant progress has also been made in identifying the phenotype and signaling pathways specific for LSCs. Therapeutically, a multitude of drugs targeting LSCs are in different phases of preclinical and clinical development. This review focuses on recent discoveries which have advanced our understanding of LSC biology and provided rational targets for development of novel therapeutic agents. One of the major challenges is how to target the self-renewal pathways of LSCs without affecting normal HSCs significantly therefore providing an acceptable therapeutic window. Important issues pertinent to the successful design and conduct of clinical trials evaluating drugs targeting LSCs will be discussed as well.

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The emerging roles of Notch signaling in leukemia and stem cells

Cited by 35 publications

References 72 publications

Inhibition of Notch Signaling Enhances Chemosensitivity in B-cell Precursor Acute Lymphoblastic Leukemia

Inhibition of Notch Signaling Enhances Chemosensitivity in B-cell Precursor Acute Lymphoblastic Leukemia

C3orf21 and Notch Signaling in Cancer：A Potential Biomarker

Update on acute myeloid leukemia stem cells: New discoveries and therapeutic opportunities

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