Overexpression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines

Houde, Christiane; Li, Yulin; Song, Lynda L.; Barton, Kevin; Zhang, Qing; Godwin, John; Nand, Sucha; Toor, Amir A.; Alkan, Serhan; Smadja, N; Avet-Loiseau, Hervé; Lima, Carmen S. P.; Miele, Lucio; Coignet, Lionel

doi:10.1182/blood-2003-12-4114

Cited by 157 publications

(164 citation statements)

References 34 publications

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“…The detailed events downstream of JAG2 in the Notch signaling pathway are clearly important to delineate for a richer understanding of the Myc, JAG2, and Notch connection in additional studies, which are beyond the scope of the current report. The Notch signaling cascade is involved in the development of several hematological malignancies, particularly T-cell leukemias (26) and multiple myeloma (8). In addition to previous studies showing that endogenous Myc is a downstream target of Notch and that Myc and Notch could collaborate in T-cell leukemogenesis (27,28), our findings provide evidence that ectopic Myc transactivation of JAG2 contributes to P493-6 cell tumorigenesis.…”

Section: High Myc State Increases Notch Signaling Components With Jagsupporting

confidence: 70%

“…A recent study reports that selected B-cell lines are sensitive to the GSIs, suggesting a therapeutic role for GSIs in B lymphoid malignancies (20). Interestingly, Jagged2 levels are increased in samples from multiple myeloma patients (8), which often have Myc overexpression (8,11). Our demonstration of an increased expression of JAG2 in the higher grade, HIGH-Myc-expressing anaplastic medulloblastoma versus classic medulloblastoma further suggests the potential importance of the direct Myc target gene JAG2 in tumorigenesis.…”

Section: High Myc State Increases Notch Signaling Components With Jagsupporting

confidence: 57%

“…Although the role of Notch signaling has not been thoroughly dissected in B-cell lymphomas, Jagged2 overexpression is prevalent in the B-cell malignancy multiple myeloma (8). Recent evidence suggests that Notch may synergize with the B-cell receptor to enhance B-cell activation (9).…”

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confidence: 99%

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Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model

Yustein¹,

Liu²,

Gao³

et al. 2010

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

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Ectopic Myc expression plays a key role in human tumorigenesis, and Myc dose-dependent tumorigenesis has been well established in transgenic mice, but the Myc target genes that are dependent on Myc levels have not been well characterized. In this regard, we used the human P493-6 B cells, which have a preneoplastic state dependent on the Epstein–Barr viral EBNA2 protein and a neoplastic state with ectopic inducible Myc, to identify putative ectopic Myc target genes. Among the ectopic targets, JAG2 that encodes a Notch receptor ligand Jagged2, was directly induced by Myc. Inhibition of Notch signaling through RNAi targeting JAG2 or the γ-secretase Notch inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) preferentially inhibited the neoplastic state in vitro. Furthermore, P493-6 tumorigenesis was inhibited by DAPT in vivo. Ectopic expression of JAG2 did not enhance aerobic cell proliferation, but increased proliferation of hypoxic cells in vitro and significantly increased in vivo tumorigenesis. Furthermore, the expression of Jagged2 in P493-6 tumors often overlapped with regions of hypoxia. These observations suggest that Notch signaling downstream of Myc enables cells to adapt in the tumor hypoxic microenvironment.

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Section: High Myc State Increases Notch Signaling Components With Jagsupporting

confidence: 70%

Section: High Myc State Increases Notch Signaling Components With Jagsupporting

confidence: 57%

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Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model

Yustein¹,

Liu²,

Gao³

et al. 2010

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

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“…Deregulated Notch signaling is also involved in the pathogenesis of multiple myeloma. Overexpression of Jagged1, Jagged2, Notch1 and Notch2 proteins are found in samples of human multiple myeloma (15). Acute myelogenous leukemia (AML) is characterized by overexpression of Jagged1 mRNA/protein and Notch1 protein (16).…”

Section: Notch Signaling Pathway Its Components and Their Role In Camentioning

confidence: 99%

Association between Notch signaling pathway and cancer

Lachej¹,

Didžiapetrienė²,

Kazbarienė³

et al. 2013

AML

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Background. The components of the Notch signaling pathway are important in maintaining the balance involved in cell proliferation, apoptosis and differentiation. Therefore, dysfunction of the Notch prevents differentiation, ultimately guiding undifferentiated cells toward malignant transformation. The aim of this article is to present recently published data concerning the role of the Notch signaling pathway components in development and prognosis of oncologic diseases, in occurrence of resistance to cytostatic agents and importance in creating of new cancer treatment approaches. Materials and methods. The Pubmed was the main source of looking for information for this article. Results. Recent investigations show that disorders of the Notch signaling pathway are associated with development of some human haematological and solid cancers. In different tissues and organs this active pathway can act as a tumor suppressor or an oncogene. Accordingly, the increased or decreased expression of its components is defined. Most of published data show that the increased expression of Notch pathway components correlates with a worse prognosis of cancer and a shorter survival. Recently, the Notch pathway has been reported to be involved in drug resistance. The modulation of the Notch signaling pathway could be helpful in treatment of some tumors with abnormal activity of this pathway’s components. Therefore changes in the expression of Notch components could become important predictive factors, helpful in selecting the proper treatment method. Conclusions. The results of recent studies are very important, since the detecting of the prognostic and predictive value of components of the Notch signaling pathway can allow creating new and improving already known methods of cancer diagnostic and treatment.

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“…Dysregulation of Notch signaling due to overexpression of receptors including Notch1 and Notch2 and/or ligands Jagged1 and Jagged2 has been demonstrated for MM cell lines and primary MM cells. 1,3,20,21 Moreover, overexpression of Jagged2 was detected in plasma cells in patients with monoclonal gammopathy of undetermined significance, an early phase of MM disease progression, indicating that the activation of Notch signaling could be an essential event in the pathogenesis of MM. 21 Overexpression of Notch receptors and ligands on MM cells resulted in the activation of Notch due to tumor cell-cell interaction.…”

Section: Introductionmentioning

confidence: 99%

Anti-myeloma effect of pharmacological inhibition of Notch/gamma-secretase with RO4929097 is mediated by modulation of tumor microenvironment

Pisklakova

Grigson

Ozerova

et al. 2016

Cancer Biology & Therapy

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Multiple myeloma (MM), a blood cancer characterized by the uncontrolled proliferation of plasma cells, remains incurable by current therapy. Notch signaling has been implicated in the growth and chemoresistance of various cancer types including MM, and therefore we hypothesized that targeting the Notch pathway could be beneficial for the treatment of this disease. Here, we report an anti-tumor effect of Notch/g-secretase inhibitor RO4929097 in a pre-clinical model of MM. We demonstrate that this effect was associated with decreased angiogenesis and significant down-regulation of TGF-b1. In addition, we also show that treatment with RO4929097 results in decreased number and functional activity of osteoclasts. Taken together, our data indicate that targeting Notch may be considered as a new strategy to be tested for MM therapy.

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Overexpression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines

Cited by 157 publications

References 34 publications

Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model

Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model

Association between Notch signaling pathway and cancer

Anti-myeloma effect of pharmacological inhibition of Notch/gamma-secretase with RO4929097 is mediated by modulation of tumor microenvironment

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