DPP4 truncated GM-CSF and IL-3 manifest distinct receptor-binding and regulatory functions compared with their full-length forms.
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.
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, USA.
H A
HA
O'Leary
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
M
M
Capitano
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
S
S
Cooper
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
C
C
Mantel
Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN, USA.
H S
HS
Boswell
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
R
R
Kapur
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
B
B
Ramdas
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
R
R
Chan
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
L
L
Deng
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
CK
Qu
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
H E
HE
Broxmeyer
D000818:Animals; D049109:Cell Proliferation; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism*
D007377:Interleukin-3; D011956:Receptors, Cell Surface; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4