title: The KDM2B- let-7b -EZH2 axis in myelodysplastic syndromes as a target for combined epigenetic therapy.
abstract: Both DNA and histone methylation are dysregulated in the myelodysplastic syndromes (MDS). Based on preliminary data we hypothesized that dysregulated interactions of KDM2B, let-7b and EZH2 signals lead to an aberrant epigenetic landscape. Gene expression in CD34+ cells from MDS marrows was analyzed by NanoString miR array and validated by real-time polymerase chain reaction (PCR). The functions of KDM2B, let-7b and EZH2 were characterized in myeloid cell lines and in primary MDS cells. Let-7b levels were significantly higher, and KDM2B and EZH2 expression was lower in primary CD34+ MDS marrow cells (n = 44) than in healthy controls (n = 21; p<0.013, and p<0.0001, respectively). Overexpression of let-7b reduced EZH2 and KDM2B protein levels, and decreased cells in S-phase while increasing G0/G1 cells (p = 0.0005), accompanied by decreased H3K27me3 and cyclin D1. Silencing of KDM2B increased let-7b expression. Treatment with the cyclopentanyl analog of 3-deazaadenosine, DZNep, combined with the DNA hypomethylating agent 5-azacitidine, decreased levels of EZH2, suppressed methylation of di- and tri-methylated H3K27, and increased p16 expression, associated with cell proliferation. Thus, KDM2B, via let-7b/EZH2, promotes transcriptional repression. DZNep bypassed the inhibitory KDM2B/let-7b/EZH2 axis by preventing H3K27 methylation and reducing cell proliferation. DZNep might be able to enhance the therapeutic effects of DNA hypomethylating agents such as 5-azacitidine, currently considered standard therapy for patients with MDS.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Ekapun
authors.initials: E
authors.lastname: Karoopongse
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Anatomic Pathology, University of Washington, Seattle, Washington, United States of America.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Yeung
authors.affiliation: Department of Hematology, University of Washington, Seattle, Washington, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Byon
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Aravind
authors.initials: A
authors.lastname: Ramakrishnan
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Zaneta J
authors.initials: ZJ
authors.lastname: Holman
authors.affiliation: Medical Oncology, Providence Regional Cancer Partnership and the Everett Clinic, Everett, Washington, United States of America.
authors.forename: Peter Y Z
authors.initials: PY
authors.lastname: Jiang
authors.affiliation: Cancer Biology and Pharmacology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: H Joachim
authors.initials: HJ
authors.lastname: Deeg
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: A Mario
authors.initials: AM
authors.lastname: Marcondes
mesh_terms: D001374:Azacitidine / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D044783:F-Box Proteins / Q000235:genetics*; D015870:Gene Expression; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics*; D008745:Methylation; D035683:MicroRNAs / Q000235:genetics*; D058990:Molecular Targeted Therapy; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D063151:Polycomb Repressive Complex 2 / Q000235:genetics*
chemical_list: D044783:F-Box Proteins; D006657:Histones; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D001374:Azacitidine