Pleiotropic roles of Notch signaling in normal, malignant, and developmental hematopoiesis in the human

Kushwah, Rahul; Guezguez, Borhane; Lee, Jung Bok; Hopkins, Claudia I.; Bhatia, Mickie

doi:10.15252/embr.201438842

Cited by 32 publications

(21 citation statements)

References 108 publications

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“…The highly conserved Notch signaling pathway is a major mediator of proliferation, differentiation and cell survival during embryonic development, in regenerating adult tissue, and during breast cancer development [255,256,259]. Notch signaling is unique from the other signaling pathways in that it relies on the ability of a ligand on the neighboring cells to bring about proteolysis of the Notch receptors (NR1, 2, 3, and 4) resulting in release of the Notch intracellular domain (NICD) of these receptors [159,260]. In the case of canonical signaling, the NICD will interact with DNAbinding protein CSL [159,260] and form complexes with transcriptional activators such as MAMML1 and P300, leading to initiation of transcription at the promoter of the Notch target genes such as the HES family of transcription factors [118].…”

Section: Introductionmentioning

confidence: 99%

“…Notch signaling is unique from the other signaling pathways in that it relies on the ability of a ligand on the neighboring cells to bring about proteolysis of the Notch receptors (NR1, 2, 3, and 4) resulting in release of the Notch intracellular domain (NICD) of these receptors [159,260]. In the case of canonical signaling, the NICD will interact with DNAbinding protein CSL [159,260] and form complexes with transcriptional activators such as MAMML1 and P300, leading to initiation of transcription at the promoter of the Notch target genes such as the HES family of transcription factors [118]. In addition to the canonical signaling, the CSL-independent (non-canonical) signaling by Notch receptors has also been reported [261].…”

Section: Introductionmentioning

confidence: 99%

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Notch-Induced Expression of FZD7 Requires Noncanonical NOTCH3 Signaling in Human Breast Epithelial Cells

Bhat

Sun

Weger

et al. 2016

Stem Cells and Development

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The evolutionarily conserved Notch and Wnt signaling pathways have demonstrated roles in normal mammary gland development and in breast carcinogenesis. We previously reported that in human mammary gland, signaling through NOTCH3 alone regulates the commitment of the undifferentiated bipotential progenitors to the luminal cell fate, indicating that NOTCH3 may regulate the expression of unique genes apart from the other Notch receptors. In this study, we used gain of function and loss of function experiments and found that a Wnt signaling receptor, Frizzled7 (FZD7), is a unique and nonredundant target of NOTCH3 in human breast epithelial cells. Interestingly, neither the constitutively active forms of NOTCH1-2, 4 nor loss of expression of these receptors were able to alter expression of FZD7 in human breast epithelial cells. We further show that FZD7-expressing cells are found more frequently in the luminal progenitor-enriched subpopulation of cells obtained from breast reduction samples compared with the undifferentiated bipotent progenitors. Also, we show that NOTCH3-induced expression of FZD7 occurs in the absence of CSL (CBF1-Suppressor of Hairless-Lag-1). Our data suggest that noncanonical Notch signaling through NOTCH3 could modulate Wnt signaling via FZD7 and in this way, might be involved in luminal cell differentiation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Notch-Induced Expression of FZD7 Requires Noncanonical NOTCH3 Signaling in Human Breast Epithelial Cells

Bhat

Sun

Weger

et al. 2016

Stem Cells and Development

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“…Notch regulates different target genes in distinct cell types through complex interactions with multiple regulators (reviewed in [48] and [49]), predicting the existence of lineage-specific response elements. Two groups identified a T-lineage specific Notch-dependent MYC enhancer (NDME) ~1.4 Mb downstream of MYC [50,51].…”

Section: Transcriptional Regulation Of Oncogenic Notch Target Genesmentioning

confidence: 99%

Oncogenic Notch signaling in T-cell and B-cell lymphoproliferative disorders

Chiang¹,

Radojčić²,

Maillard

2016

Current Opinion in Hematology

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Purpose of review Highlight recent discoveries about Notch activation and its oncogenic functions in lymphoid malignancies, and discuss the therapeutic potential of Notch inhibition. Recent findings NOTCH mutations arise in a broad spectrum of lymphoid malignancies and are increasingly scrutinized as putative therapeutic targets. In T cell acute lymphoblastic leukemia (T-ALL), NOTCH1 mutations affect the extracellular negative regulatory region and lead to constitutive Notch activation, although mutated receptors remain sensitive to Notch ligands. Other NOTCH1 mutations in T-ALL and NOTCH1/2 mutations in multiple B cell malignancies truncate the C-terminal PEST domain, leading to decreased Notch degradation after ligand-mediated activation. Thus, targeting Notch ligand-receptor interactions could provide therapeutic benefits. In addition, we discuss recent reports on clinical testing of Notch inhibitors in T-ALL that influenced contemporary thinking on the challenges of targeting Notch in cancer. We review advances in the laboratory to address these challenges in regards to drug targets, the Notch-driven metabolome, and the sophisticated protein-protein interactions at Notch-dependent super-enhancers that underlie oncogenic Notch functions. Summary Notch signaling is a recurrent oncogenic pathway in multiple T and B cell lymphoproliferative disorders. Understanding the complexity and consequences of Notch activation is critical to define optimal therapeutic strategies targeting the Notch pathway.

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“…While Wnt signaling promotes the proliferation and viability of HSCs, Notch signaling maintains an undifferentiated state of HSCs (97). Ontogeny of HSCs provided new understanding about the prominent aspect of Notch in early hematopoietic development (98). Wnt16 determines the somitic expression of the Notch ligands deltaC (dlc) and deltaD (dld), suggesting that the two pathways govern the fate of HSC.…”

Section: Notch Signalingmentioning

confidence: 99%

Adult Hematopoietic Stem Cells: Niche Cross-Talks to Affect the Cell Fate

Sharma¹,

Gangenahalli²

2016

Niche

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Hematopoietic stem cells have dissimilar proliferative capacities; although some remain in quiescence, some consistently undergo multiple rounds of cell division stimulating hematopoiesis to maintain homeostasis and protect stem cell exhaustion. The stringent equilibrium between quiescence, self-renewal, proliferation, and differentiation is maintained by the operational selectiveness of intrinsic factors and extrinsic cues provided by the specialized microenvironment called the "niche" that provides homeness to hematopoietic stem cells (HSCs). The niche is defined by a heterogeneous identity involving the complex interaction of various other cells, cytokines, adhesion molecules, and extracellular matrix via several surface receptors and soluble factors, which work in paracrine coordination and protect stem cells from depletion while eliciting proliferation. The widespread investigations have shed light on the mechanistic underpinnings in niche, which coordinate the balance between relative hematopoietic quiescence and proliferation. In this paper, we discuss the recent findings concerning how these complex niche interactions facilitate the regulation of hematopoietic stem cells during homeostasis and further extend the discussion to their involvement in expansion and tumorigenesis, the two biological phenomena that are intimately associated with stem cells.

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Pleiotropic roles of Notch signaling in normal, malignant, and developmental hematopoiesis in the human

Cited by 32 publications

References 108 publications

Notch-Induced Expression of FZD7 Requires Noncanonical NOTCH3 Signaling in Human Breast Epithelial Cells

Notch-Induced Expression of FZD7 Requires Noncanonical NOTCH3 Signaling in Human Breast Epithelial Cells

Oncogenic Notch signaling in T-cell and B-cell lymphoproliferative disorders

Adult Hematopoietic Stem Cells: Niche Cross-Talks to Affect the Cell Fate

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