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Stem cell biology

DPP4 truncated GM-CSF and IL-3 manifest distinct receptor-binding and regulatory functions compared with their full-length forms

Leukemia volume 31, pages 2468–2478 (2017)Cite this article

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Abstract

Dipeptidylpeptidase 4 (DPP4/CD26) enzymatically cleaves select penultimate amino acids of proteins, including colony-stimulating factors (CSFs), and has been implicated in cellular regulation. To better understand the role of DPP4 regulation of hematopoiesis, we analyzed the activity of DPP4 on the surface of immature blood cells and then comparatively assessed the interactions and functional effects of full-length (FL) and DPP4 truncated (T) factors (T-granulocyte–macrophage-CSF (T-GM-CSF)) and T-interleukin-3 (T-IL-3)) on both in vitro and in vivo models of normal and leukemic cells. T-GM-CSF and -IL-3 had enhanced receptor binding, but decreased CSF activity, compared with their FL forms. Importantly, T-GM-CSF and -IL-3 significantly, and reciprocally, blunted receptor binding and myeloid progenitor cell proliferation activity of both FL-GM-CSF and -IL-3 in vitro and in vivo. Similar effects were apparent in vitro using cluster-forming cells from patients with acute myeloid leukemia regardless of cytogenetic or molecular alterations and in vivo using animal models of leukemia. This suggests that DPP4 T-molecules have modified binding and functions compared with their FL counterparts and may serve regulatory roles in normal and malignant hematopoiesis.

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Acknowledgements

These studies were supported by (1) US Public Health Service Grants from the National Institutes of Health: R01HL112669, R01HL67384, R01HL56416, P01DK90948 and U54DK106846 (to HEB) and (2) Indiana University Bioinformatics Core Proposal Grant (to HAO). HAO and MC were supported by NIH T32DK07519 (HEB). We thank Giao Hangoc for help with some of the experiments and Heath D Skinner for clinical insight.

Author contributions

HAO provided concepts, designed and performed experiments and wrote the manuscript. CM, SC and MC performed experiments, HSB provided clinical samples/knowledge, RK, BR, RC, LD and CKQ provided mouse models of leukemia and insight into their use. HEB provided concepts, designed and performed experiments and helped in writing and editing of the manuscript. All authors read the manuscript and provided feedback for clarity and context.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA

    H A O’Leary, M Capitano, S Cooper, C Mantel & H E Broxmeyer

  2. Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, USA

    H A O’Leary & H S Boswell

  3. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA

    R Kapur, B Ramdas & R Chan

  4. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    R Chan & L Deng

  5. Department of Pediatrics, Division of Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA

    C-K Qu

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  1. H A O’Leary
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Correspondence to H A O’Leary or H E Broxmeyer.

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HEB is a member of the Medical Scientific Advisory Board (MSAB) of Corduse, a cord blood banking company.

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O’Leary, H., Capitano, M., Cooper, S. et al. DPP4 truncated GM-CSF and IL-3 manifest distinct receptor-binding and regulatory functions compared with their full-length forms. Leukemia 31, 2468–2478 (2017). https://doi.org/10.1038/leu.2017.98

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