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Acute lymphoblastic leukemia

Deregulation of kinase signaling and lymphoid development in EBF1-PDGFRB ALL leukemogenesis

Leukemia volume 32, pages 38–48 (2018)Cite this article

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Abstract

The chimeric fusion oncogene early B-cell factor 1–platelet-derived growth factor receptor-β (EBF1-PDGFRB) is a recurrent lesion observed in Philadelphia-like B-acute lymphoblastic leukemia (B-ALL) and is associated with particularly poor prognosis. While it is understood that this fusion activates tyrosine kinase signaling, the mechanisms of transformation and importance of perturbation of EBF1 activity remain unknown. EBF1 is a nuclear transcription factor required for normal B-lineage specification, commitment and development. Conversely, PDGFRB is a receptor tyrosine kinase that is normally repressed in lymphocytes, yet PDGFRB remains a common fusion partner in leukemias. Here, we demonstrate that the EBF1-PDGFRB fusion results in loss of EBF1 function, multimerization and autophosphorylation of the fusion protein, activation of signal transducer and activator of transcription 5 (STAT5) signaling and gain of interleukin-7 (IL-7)-independent cell proliferation. Deregulation and loss of EBF1 function is critically dependent on the nuclear export activity of the transmembrane (TM) domain of PDGFRB. Deletion of the TM domain partially rescues EBF1 function and restores IL-7 dependence, without requiring kinase inhibition. Moreover, we demonstrate that EBF1-PDGFRB synergizes with loss of IKAROS function in a fully penetrant B-ALL in vivo. Thus, we establish that EBF1-PDGFRB is sufficient to drive leukemogenesis through TM-dependent loss of transcription factor function, increased proliferation and synergy with additional genetic insults including loss of IKAROS function.

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Acknowledgements

We would like to thank Jay Hesselberth, John Cambier, Mark Johnston, Laurent Gapin, Aaron M Johnson, Hua Huang and Mikael Sigvardsson for helpful suggestions and reagents. We also thank the National Jewish Health Flow Cytometry Core and Josh Loomis for support and technical assistance, the St Jude Children’s Research Hospital Flow Cytometry and Cell Sorting Shared Resource and Cell and Tissue Imaging Center. This work was funded by grants to JH from the National Institutes of Health R01 AI081878 and AI098417, The Wendy Siegel Fund for Leukemia and Cancer Research and the Cancer League of Colorado. The Victor W Bolie and Earleen D Bolie Graduate Scholarship Fund supported SJW. This work was supported by the American Lebanese Syrian Associated Charities of St Jude Children’s Research Hospital. CGM was supported by a St Baldrick’s Foundation Scholar Award, a St Baldrick’s Foundation Robert J Arceci Innovation Award, a Specialized Center of Research Award from the Leukemia and Lymphoma Society and an Outstanding Investigator Award (R35 CA197695) from the National Cancer Institute.

Author contributions

Conceptualization and methodology: SJW, MLC, MT, CGM and JH; investigation: SJW, MLC and MT; writing: SJW, MLC, CGM and JH.

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  1. S J Welsh and M L Churchman: These authors contributed equally to this work.

  2. C G Mullighan and J Hagman: Co-senior authors.

Authors and Affiliations

  1. Program in Molecular Biology, University of Colorado School of Medicine, Aurora, CO, USA

    S J Welsh & J Hagman

  2. Department of Pathology, St Jude Children’s Research Hospital, Memphis, TN, USA

    M L Churchman, M Togni & C G Mullighan

  3. Department of Biomedical Research, National Jewish Health, Denver, CO, USA

    J Hagman

  4. University of Colorado Cancer Center, Colorado University Anschutz Medical Campus, Aurora, CO, USA

    J Hagman

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  1. S J Welsh
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Correspondence to C G Mullighan or J Hagman.

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Welsh, S., Churchman, M., Togni, M. et al. Deregulation of kinase signaling and lymphoid development in EBF1-PDGFRB ALL leukemogenesis. Leukemia 32, 38–48 (2018). https://doi.org/10.1038/leu.2017.166

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