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

Ramamoorthy, Senthilkumar; Kometani, Kohei; Herman, Josip S.; Bayer, Marc; Boller, Sören; Edwards-Hicks, Joy; Ramachandran, Haribaskar; Li, Rui; Klein-Geltink, Ramon; Pearce, Erika L.; Grün, Dominic; Grosschedl, Rudolf

doi:10.1101/gad.340216.120

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

MPS-Authors

Ramamoorthy, Senthilkumar
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Kometani, Kohei
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Herman, Josip S.
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Bayer, Marc
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons190994

Boller, Sören
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Edwards-Hicks, Joy
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Ramachandran, Haribaskar
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Li, Rui
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Klein-Geltink, Ramon
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons201431

Pearce, Erika L.
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Grün, Dominic
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons191076

Grosschedl, Rudolf
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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http://genesdev.cshlp.org/content/34/21-22/1503.long
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Citation

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.

Cite as: https://hdl.handle.net/21.11116/0000-0007-62F7-4

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.