Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-κB-dependent manner

Lin Wang, Huajia Zhang, Sonia Rodriguez, Liyun Cao, Jonathan Parish, Christen Mumaw, Amy Zollman, Malgorzata Kamocka, Jian Mu, Danny Z. Chen, Edward Srour, Brahmananda R. Chitteti, Harm HogenEsch, Xiaolin Tu, Teresita Bellido, H. Boswell, Taghi Manshouri, Srdan Verstovsek, Mervin Yoder, Reuben KapurAngelo A. Cardoso, Nadia Carlesso

Research output: Contribution to journalArticle

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Abstract

The microRNA miR-155 has been implicated in regulating inflammatory responses and tumorigenesis, but its precise role in linking inflammation and cancer has remained elusive. Here, we identify a connection between miR-155 and Notch signaling in this context. Loss of Notch signaling in the bone marrow (BM) niche alters hematopoietic homeostasis and leads to lethal myeloproliferative- like disease. Mechanistically, Notch signaling represses miR-155 expression by promoting binding of RBPJ to the miR-155 promoter. Loss of Notch/RBPJ signaling upregulates miR-155 in BM endothelial cells, leading to miR-155-mediated targeting of the nuclear factor κB (NF-κB) inhibitor κB-Ras1, NF-κB activation, and increased proinflammatory cytokine production. Deletion of miR-155 in the stroma of RBPJ-/- mice prevented the development of myeloproliferative-like disease and cytokine induction. Analysis of BM from patients carrying myeloproliferative neoplasia also revealed elevated expression of miR-155. Thus, the Notch/miR-155/κB-Ras1/NF-κB axis regulates the inflammatory state of the BM niche and affects the development of myeloproliferative disorders.

Original languageEnglish
Pages (from-to)51-65
Number of pages15
JournalCell Stem Cell
Volume15
Issue number1
DOIs
StatePublished - Jul 3 2014

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Hematopoiesis
Bone Marrow
Cytokines
Myeloproliferative Disorders
MicroRNAs
Bone Marrow Cells
Neoplasms
Carcinogenesis
Homeostasis
Up-Regulation
Endothelial Cells
Inflammation

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine
  • Genetics

Cite this

Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-κB-dependent manner. / Wang, Lin; Zhang, Huajia; Rodriguez, Sonia; Cao, Liyun; Parish, Jonathan; Mumaw, Christen; Zollman, Amy; Kamocka, Malgorzata; Mu, Jian; Chen, Danny Z.; Srour, Edward; Chitteti, Brahmananda R.; HogenEsch, Harm; Tu, Xiaolin; Bellido, Teresita; Boswell, H.; Manshouri, Taghi; Verstovsek, Srdan; Yoder, Mervin; Kapur, Reuben; Cardoso, Angelo A.; Carlesso, Nadia.

In: Cell Stem Cell, Vol. 15, No. 1, 03.07.2014, p. 51-65.

Research output: Contribution to journalArticle

Wang, L, Zhang, H, Rodriguez, S, Cao, L, Parish, J, Mumaw, C, Zollman, A, Kamocka, M, Mu, J, Chen, DZ, Srour, E, Chitteti, BR, HogenEsch, H, Tu, X, Bellido, T, Boswell, H, Manshouri, T, Verstovsek, S, Yoder, M, Kapur, R, Cardoso, AA & Carlesso, N 2014, 'Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-κB-dependent manner', Cell Stem Cell, vol. 15, no. 1, pp. 51-65. https://doi.org/10.1016/j.stem.2014.04.021
Wang, Lin ; Zhang, Huajia ; Rodriguez, Sonia ; Cao, Liyun ; Parish, Jonathan ; Mumaw, Christen ; Zollman, Amy ; Kamocka, Malgorzata ; Mu, Jian ; Chen, Danny Z. ; Srour, Edward ; Chitteti, Brahmananda R. ; HogenEsch, Harm ; Tu, Xiaolin ; Bellido, Teresita ; Boswell, H. ; Manshouri, Taghi ; Verstovsek, Srdan ; Yoder, Mervin ; Kapur, Reuben ; Cardoso, Angelo A. ; Carlesso, Nadia. / Notch-dependent repression of miR-155 in the bone marrow niche regulates hematopoiesis in an NF-κB-dependent manner. In: Cell Stem Cell. 2014 ; Vol. 15, No. 1. pp. 51-65.
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abstract = "The microRNA miR-155 has been implicated in regulating inflammatory responses and tumorigenesis, but its precise role in linking inflammation and cancer has remained elusive. Here, we identify a connection between miR-155 and Notch signaling in this context. Loss of Notch signaling in the bone marrow (BM) niche alters hematopoietic homeostasis and leads to lethal myeloproliferative- like disease. Mechanistically, Notch signaling represses miR-155 expression by promoting binding of RBPJ to the miR-155 promoter. Loss of Notch/RBPJ signaling upregulates miR-155 in BM endothelial cells, leading to miR-155-mediated targeting of the nuclear factor κB (NF-κB) inhibitor κB-Ras1, NF-κB activation, and increased proinflammatory cytokine production. Deletion of miR-155 in the stroma of RBPJ-/- mice prevented the development of myeloproliferative-like disease and cytokine induction. Analysis of BM from patients carrying myeloproliferative neoplasia also revealed elevated expression of miR-155. Thus, the Notch/miR-155/κB-Ras1/NF-κB axis regulates the inflammatory state of the BM niche and affects the development of myeloproliferative disorders.",
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AU - Rodriguez, Sonia

AU - Cao, Liyun

AU - Parish, Jonathan

AU - Mumaw, Christen

AU - Zollman, Amy

AU - Kamocka, Malgorzata

AU - Mu, Jian

AU - Chen, Danny Z.

AU - Srour, Edward

AU - Chitteti, Brahmananda R.

AU - HogenEsch, Harm

AU - Tu, Xiaolin

AU - Bellido, Teresita

AU - Boswell, H.

AU - Manshouri, Taghi

AU - Verstovsek, Srdan

AU - Yoder, Mervin

AU - Kapur, Reuben

AU - Cardoso, Angelo A.

AU - Carlesso, Nadia

PY - 2014/7/3

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N2 - The microRNA miR-155 has been implicated in regulating inflammatory responses and tumorigenesis, but its precise role in linking inflammation and cancer has remained elusive. Here, we identify a connection between miR-155 and Notch signaling in this context. Loss of Notch signaling in the bone marrow (BM) niche alters hematopoietic homeostasis and leads to lethal myeloproliferative- like disease. Mechanistically, Notch signaling represses miR-155 expression by promoting binding of RBPJ to the miR-155 promoter. Loss of Notch/RBPJ signaling upregulates miR-155 in BM endothelial cells, leading to miR-155-mediated targeting of the nuclear factor κB (NF-κB) inhibitor κB-Ras1, NF-κB activation, and increased proinflammatory cytokine production. Deletion of miR-155 in the stroma of RBPJ-/- mice prevented the development of myeloproliferative-like disease and cytokine induction. Analysis of BM from patients carrying myeloproliferative neoplasia also revealed elevated expression of miR-155. Thus, the Notch/miR-155/κB-Ras1/NF-κB axis regulates the inflammatory state of the BM niche and affects the development of myeloproliferative disorders.

AB - The microRNA miR-155 has been implicated in regulating inflammatory responses and tumorigenesis, but its precise role in linking inflammation and cancer has remained elusive. Here, we identify a connection between miR-155 and Notch signaling in this context. Loss of Notch signaling in the bone marrow (BM) niche alters hematopoietic homeostasis and leads to lethal myeloproliferative- like disease. Mechanistically, Notch signaling represses miR-155 expression by promoting binding of RBPJ to the miR-155 promoter. Loss of Notch/RBPJ signaling upregulates miR-155 in BM endothelial cells, leading to miR-155-mediated targeting of the nuclear factor κB (NF-κB) inhibitor κB-Ras1, NF-κB activation, and increased proinflammatory cytokine production. Deletion of miR-155 in the stroma of RBPJ-/- mice prevented the development of myeloproliferative-like disease and cytokine induction. Analysis of BM from patients carrying myeloproliferative neoplasia also revealed elevated expression of miR-155. Thus, the Notch/miR-155/κB-Ras1/NF-κB axis regulates the inflammatory state of the BM niche and affects the development of myeloproliferative disorders.

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