title: Ara-C and anti-CD47 antibody combination therapy eliminates acute monocytic leukemia THP-1 cells in vivo and in vitro.
abstract: Leukemia stem cells (LSCs) are regarded as the origin of leukemia and its recurrence. Side population (SP) cells possess some intrinsic stem cell properties and contain numerous LSCs. In this study, we examined the prognostic significance of cluster differentiation 47 (CD47) and identified the appropriate target for eliminating LSCs. We determined the percentage of SP cells in a THP-1 cell population and analyzed CD47 expression in different cell subsets. We then explored whether CD47 affected the phagocytic ability of macrophages to LSCs in vitro. Finally, the effect of anti-CD47 monoclonal antibodies, alone or combination with cytarabine, against leukemic cells was evaluated in vitro and in vivo to identify the optimal targets for the treatment of leukemia. We observed an SP sub-fraction at low frequency (1.81 ± 0.99%), which was a likely candidate for LSC enrichment. CD47 was more highly expressed on THP-1 LSCs (P < 0.05) and was an independent predictor of survival and refractory disease in THP-1-engrafted mice. Furthermore, the anti-CD47 monoclonal antibody stimulated preferential phagocytosis of LSCs by macrophages in vitro. Finally, single or combination treatment of THP-1 LSC-engrafted mice with cytarabine and anti-CD47 antibody resulted in targeting of LSCs and depletion of leukemia cells. These findings suggest that CD47 is an antibody target in LSCs and combination treatment with cytarabine and anti-CD47 monoclonal antibody represents an attractive option for the therapeutic targeting of acute monocytic leukemia.
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: C
authors.initials: C
authors.lastname: Yin
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: L
authors.initials: L
authors.lastname: Feng
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
authors.forename: G
authors.initials: G
authors.lastname: Sheng
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D051928:CD47 Antigen / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003561:Cytarabine / Q000008:administration & dosage; D006801:Humans; D007948:Leukemia, Monocytic, Acute / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010587:Phagocytosis; D011379:Prognosis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D051928:CD47 Antigen; C497894:CD47 protein, human; D003561:Cytarabine