title: Am80-GCSF synergizes myeloid expansion and differentiation to generate functional neutrophils that reduce neutropenia-associated infection and mortality.
abstract: Neutrophils generated by granulocyte colony-stimulating factor (GCSF) are functionally immature and, consequently, cannot effectively reduce infection and infection-related mortality in cancer chemotherapy-induced neutropenia (CCIN). Am80, a retinoic acid (RA) agonist that enhances granulocytic differentiation by selectively activating transcription factor RA receptor alpha (RARα), alternatively promotes RA-target gene expression. We found that in normal and malignant primary human hematopoietic specimens, Am80-GCSF combination coordinated proliferation with differentiation to develop complement receptor-3 (CR3)-dependent neutrophil innate immunity, through altering transcription of RA-target genes RARβ2,C/EBPε, CD66, CD11b, and CD18 This led to generation of functional neutrophils capable of fighting infection, whereas neutralizing neutrophil innate immunity with anti-CD18 antibody abolished neutrophil bactericidal activities induced by Am80-GCSF Further, Am80-GCSF synergy was evaluated using six different dose-schedule-infection mouse CCIN models. The data demonstrated that during "emergency" granulopoiesis in CCIN mice undergoing transient systemic intravenous bacterial infection, Am80 effect on differentiating granulocytic precursors synergized with GCSF-dependent myeloid expansion, resulting in large amounts of functional neutrophils that reduced infection. Importantly, extensive survival tests covering a full cycle of mouse CCIN with perpetual systemic intravenous bacterial infection proved that without causing myeloid overexpansion, Am80-GCSF generated sufficient numbers of functional neutrophils that significantly reduced infection-related mortality in CCIN mice. These findings reveal a differential mechanism for generating functional neutrophils to reduce CCIN-associated infection and mortality, providing a rationale for future therapeutic approaches.
authors.affiliation: Department of Pathology, Children's Hospital Los Angeles Saban Research Institute, Los Angeles, CA, USA.|Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Children's Hospital Los Angeles Saban Research Institute, Los Angeles, CA, USA.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Qi
authors.affiliation: Pediatric Hematology-Oncology, Blood and Marrow Transplantation, Children's Hospital Los Angeles Saban Research Institute, Los Angeles, CA, USA.|University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Weili
authors.initials: W
authors.lastname: Sun
authors.affiliation: Pediatric Hematology-Oncology, Blood and Marrow Transplantation, Children's Hospital Los Angeles Saban Research Institute, Los Angeles, CA, USA.|University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Hisham
authors.initials: H
authors.lastname: Abdel-Azim
authors.affiliation: Department of Pathology, Children's Hospital Los Angeles Saban Research Institute, Los Angeles, CA, USA.
authors.forename: Siyue
authors.initials: S
authors.lastname: Lou
authors.affiliation: Department of Pathology, Children's Hospital Los Angeles Saban Research Institute, Los Angeles, CA, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: University of Southern California Keck School of Medicine, Los Angeles, CA, USA.|Division of Infectious Diseases, Children's Hospital Los Angeles Saban Research Institute, Los Angeles, CA, USA.
authors.forename: Nemani V
authors.initials: NV
authors.lastname: Prasadarao
authors.affiliation: Department of Pathology, Children's Hospital Los Angeles Saban Research Institute, Los Angeles, CA, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Zhou
authors.affiliation: Department of Pathology, Children's Hospital Los Angeles Saban Research Institute, Los Angeles, CA, USA.|University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Japan Pharmaceutical Information Center, Shibuya-ku, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Shudo
authors.affiliation: Pediatric Hematology-Oncology, Blood and Marrow Transplantation, Children's Hospital Los Angeles Saban Research Institute, Los Angeles, CA, USA.|University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Yong-Mi
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Pediatric Hematology-Oncology, Blood and Marrow Transplantation, Children's Hospital Los Angeles Saban Research Institute, Los Angeles, CA, USA.
authors.forename: Sajad
authors.initials: S
authors.lastname: Khazal
authors.affiliation: Institute of Pharmacology and Toxicology, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Qiaojun
authors.initials: Q
authors.lastname: He
authors.affiliation: Developmental Biology and Regenerative Medicine Program, Children's Hospital Los Angeles Saban Research Institute, Los Angeles, CA, USA.|University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Warburton
authors.affiliation: Department of Pathology, Children's Hospital Los Angeles Saban Research Institute, Los Angeles, CA, USA lwu@chla.usc.edu lwu@therapeuticapp.org.|University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: Lingtao
authors.identifier: 0000-0002-8970-6952
authors.initials: L
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D016470:Bacteremia / Q000276:immunology*; D001565:Benzoates / Q000008:administration & dosage*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D007155:Immunologic Factors / Q000008:administration & dosage*; D051379:Mice; D009503:Neutropenia / Q000139:chemically induced / Q000628:therapy*; D009504:Neutrophils / Q000276:immunology* / Q000502:physiology; D016019:Survival Analysis; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; D007155:Immunologic Factors; D013764:Tetrahydronaphthalenes; C061133:tamibarotene; D016179:Granulocyte Colony-Stimulating Factor
keywords: functional neutrophils; innate immunity; myeloid expansion; neutrophil bactericidal activity; neutrophil differentiation