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  EBF1 and Pax5 safeguard leukemic transformation by limiting IL-7 signaling, Myc expression, and folate metabolism

Ramamoorthy, S., Kometani, K., Herman, J. S., Bayer, M., Boller, S., Edwards-Hicks, J., et al. (2020). EBF1 and Pax5 safeguard leukemic transformation by limiting IL-7 signaling, Myc expression, and folate metabolism. Genes and Development, 34, 1503-1519. doi:10.1101/gad.340216.120.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0007-62F7-4 Version Permalink: http://hdl.handle.net/21.11116/0000-0007-AC90-4
Genre: Journal Article

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 Creators:
Ramamoorthy, Senthilkumar1, Author
Kometani, Kohei1, Author
Herman, Josip S.1, Author
Bayer, Marc1, Author
Boller, Sören1, Author              
Edwards-Hicks, Joy1, Author
Ramachandran, Haribaskar1, Author              
Li, Rui1, Author
Klein-Geltink, Ramon2, Author              
Pearce, Erika L.2, Author              
Grün, Dominic3, Author              
Grosschedl, Rudolf1, Author              
Affiliations:
1Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243641              
2Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243648              
3Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243642              

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Free keywords: EBF1, Pax5, B-ALL, IL-7 signaling, cMyc, folate pathway
 Abstract: EBF1 and PAX5 mutations are associated with the development of B progenitor acute lymphoblastic leukemia (B-ALL) in humans. To understand the molecular networks driving leukemia in the Ebf1+/−Pax5+/− (dHet) mouse model for B-ALL, we interrogated the transcriptional profiles and chromatin status of leukemic cells, preleukemic dHet pro-B, and wild-type pro-B cells with the corresponding EBF1 and Pax5 cistromes. In dHet B-ALL cells, many EBF1 and Pax5 target genes encoding pre-BCR signaling components and transcription factors were down-regulated, whereas Myc and genes downstream from IL-7 signaling or associated with the folate pathway were up-regulated. We show that blockade of IL-7 signaling in vivo and methotrexate treatment of leukemic cells in vitro attenuate the expansion of leukemic cells. Single-cell RNA-sequencing revealed heterogeneity of leukemic cells and identified a subset of wild-type pro-B cells with reduced Ebf1 and enhanced Myc expression that show hallmarks of dHet B-ALL cells. Thus, EBF1 and Pax5 may safeguard early stage B cells from transformation to B-ALL by limiting IL-7 signaling, folate metabolism and Myc expression.

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Language(s): eng - English
 Dates: 2020
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1101/gad.340216.120
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Title: Genes and Development
Source Genre: Journal
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Publ. Info: Cold Spring Harbor Laboratory Press
Pages: - Volume / Issue: 34 Sequence Number: - Start / End Page: 1503 - 1519 Identifier: ISSN: 0890-9369
CoNE: https://pure.mpg.de/cone/journals/resource/954925557453