Dipeptidylpeptidase 4 promotes survival and stemness of acute myeloid leukemia stem cells

  • Cell Rep. 2023 Feb 28;42(2):112105. doi: 10.1016/j.celrep.2023.112105.
Chen Wang  1 ,  Ravi Nistala  2 ,  Min Cao  1 ,  Yi Pan  1 ,  Madelaine Behrens  1 ,  Donald Doll  3 ,  Richard D Hammer  4 ,  Puja Nistala  3 ,  Hui-Ming Chang  5 ,  Edward T H Yeh  6 ,  XunLei Kang  7
Affiliations
  • 1. Center for Precision Medicine, Department of Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA.
  • 2. Center for Precision Medicine, Department of Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA; Division of Nephrology, Department of Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA.
  • 3. Division of Hematology and Oncology, Department of Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA.
  • 4. Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO 65212, USA.
  • 5. Department of Pharmacology and Toxicology, The University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; Department of Internal Medicine, The University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
  • 6. Department of Internal Medicine, The University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
  • 7. Center for Precision Medicine, Department of Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA; Division of Hematology and Oncology, Department of Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA. Electronic address: [email protected].
PMID: 36807138 DOI: 10.1016/j.celrep.2023.112105
Abstract

Leukemic-stem-cell-specific targeting may improve the survival of patients with acute myeloid leukemia (AML) by avoiding the ablative effects of standard regimens on normal hematopoiesis. Herein, we perform an unbiased screening of compounds targeting cell surface proteins and identify clinically used DPP4 inhibitors as strong suppressors of AML development in both murine AML models and primary human AML cells xenograft model. We find in retrovirus-induced AML mouse models that DPP4-deficient AML cell-transplanted mice exhibit delay and reversal of AML development, whereas deletion of DPP4 has no significant effect on normal hematopoiesis. DPP4 activates and sustains survival of AML stem cells that are critical for AML development in both human and animal models via binding with Src kinase and activation of nuclear factor κB (NF-κB) signaling. Thus, inhibition of DPP4 is a potential therapeutic strategy against AML development through suppression of survival and stemness of AML cells.

Keywords
AML; CP: Cancer; DPP4; DPP4 inhibitors; apoptosis; cell surface protein; hematopoietic stem cell; leukemic stem cell; linagliptin; normal hematopoiesis; stemness.
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