Dipeptidylpeptidase 4 promotes survival and stemness of acute myeloid leukemia stem cells
Chen Wang,
Ravi Nistala,
Min Cao,
Yi Pan,
Madelaine Behrens,
Donald Doll,
Richard D. Hammer,
Puja Nistala,
Hui-Ming Chang,
Edward T.H. Yeh,
XunLei Kang
Affiliations
Chen Wang
Center for Precision Medicine, Department of Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA
Ravi Nistala
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
Min Cao
Center for Precision Medicine, Department of Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA
Yi Pan
Center for Precision Medicine, Department of Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA
Madelaine Behrens
Center for Precision Medicine, Department of Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA
Donald Doll
Division of Hematology and Oncology, Department of Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA
Richard D. Hammer
Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO 65212, USA
Puja Nistala
Division of Hematology and Oncology, Department of Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA
Hui-Ming Chang
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
Edward T.H. Yeh
Department of Internal Medicine, The University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
XunLei Kang
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; Corresponding author
Summary: 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.
