title: Cis-vaccenic acid induces differentiation and up-regulates gamma globin synthesis in K562, JK1 and transgenic mice erythroid progenitor stem cells.
abstract: Gamma globin induction remains a promising pharmacological therapeutic treatment mode for sickle cell anemia and beta thalassemia, however Hydroxyurea remains the only FDA approved drug which works via this mechanism. In this regard, we assayed the γ-globin inducing capacity of Cis-vaccenic acid (CVA). CVA induced differentiation of K562, JK1 and transgenic mice primary bone marrow hematopoietic progenitor stem cells. CVA also significantly up-regulated γ-globin gene expression in JK-1 and transgenic mice bone marrow erythroid progenitor stem cells (TMbmEPSCs) but not K562 cells without altering cell viability. Increased γ-globin expression was accompanied by KLF1 suppression in CVA induced JK-1 cells. Erythropoietin induced differentiation of JK-1 cells 24h before CVA induction did not significantly alter CVA induced differentiation and γ-globin expression in JK-1 cells. Inhibition of JK-1 and Transgenic mice bone marrow erythroid progenitor stem cells Fatty acid elongase 5 (Elovl5) and Δ(9) desaturase suppressed the γ-globin inductive effects of CVA. CVA treatment failed to rescue γ-globin expression in Elovl5 and Δ(9)-desaturase inhibited cells 48 h post inhibition in JK-1 cells. The data suggests that CVA directly modulates differentiation of JK-1 and TMbmEPSCs, and indirectly modulates γ-globin gene expression in these cells. Our findings provide important clues for further evaluations of CVA as a potential fetal hemoglobin therapeutic inducer.
authors.affiliation: Department of Biochemistry, Ahmadu Bello University, Zaria 800001, Nigeria; Africa Center for Excellence on Neglected Tropical Diseases and Forensic Biotechnology, Ahmadu Bello University, Zaria 800001, Nigeria; Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029, USA. Electronic address: idowuaimola@gmail.com.
authors.forename: Idowu A
authors.initials: IA
authors.lastname: Aimola
authors.affiliation: Department of Biochemistry, Ahmadu Bello University, Zaria 800001, Nigeria; Africa Center for Excellence on Neglected Tropical Diseases and Forensic Biotechnology, Ahmadu Bello University, Zaria 800001, Nigeria.
authors.forename: Hajiya M
authors.initials: HM
authors.lastname: Inuwa
authors.affiliation: Department of Biochemistry, Ahmadu Bello University, Zaria 800001, Nigeria; Africa Center for Excellence on Neglected Tropical Diseases and Forensic Biotechnology, Ahmadu Bello University, Zaria 800001, Nigeria.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Nok
authors.affiliation: Department of Hematology, Ahmadu Bello University Teaching Hospital, Zaria 800001, Nigeria.
authors.forename: Aisha I
authors.initials: AI
authors.lastname: Mamman
authors.affiliation: Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Bieker
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D004921:Erythropoietin / Q000494:pharmacology; D000081031:Fatty Acid Elongases; D005333:Fetus / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009829:Oleic Acids / Q000494:pharmacology*; D010670:Phenylthiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors; D013859:Thiocarbamates / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*; D055545:gamma-Globins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
chemical_list: C000630954:ELOVL5 protein, human; D006454:Hemoglobins; D051741:Kruppel-Like Transcription Factors; D009829:Oleic Acids; D012333:RNA, Messenger; D013859:Thiocarbamates; C080774:erythroid Kruppel-like factor; D055545:gamma-Globins; D004921:Erythropoietin; C100189:thiocarlide; C065593:cis-vaccenic acid; D010670:Phenylthiourea; D013230:Stearoyl-CoA Desaturase; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases; C017157:cycloate
keywords: Cis-vaccenic acid; Erythroid progenitor stem cells; Fetal hemoglobin; Gamma globin; Mono-unsaturated fatty acid; Sickle cell anemia