title: Epigenetic silencing of microRNA-193a contributes to leukemogenesis in t(8;21) acute myeloid leukemia by activating the PTEN/PI3K signal pathway.
abstract: t(8;21) is one of the most frequent chromosomal translocations occurring in acute myeloid leukemia (AML) and is considered the leukemia-initiating event. The biologic and clinical significance of microRNA dysregulation associated with AML1/ETO expressed in t(8;21) AML is unknown. Here, we show that AML1/ETO triggers the heterochromatic silencing of microRNA-193a (miR-193a) by binding at AML1-binding sites and recruiting chromatin-remodeling enzymes. Suppression of miR-193a expands the oncogenic activity of the fusion protein AML-ETO, because miR-193a represses the expression of multiple target genes, such as AML1/ETO, DNMT3a, HDAC3, KIT, CCND1, and MDM2 directly, and increases PTEN indirectly. Enhanced miR-193a levels induce G(1) arrest, apoptosis, and restore leukemic cell differentiation. Our study identifies miR-193a and PTEN as targets for AML1/ETO and provides evidence that links the epigenetic silencing of tumor suppressor genes miR-193a and PTEN to differentiation block of myeloid precursors. Our results indicated a feedback circuitry involving miR-193a and AML1/ETO/DNMTs/HDACs, cooperating with the PTEN/PI3K signaling pathway and contributing to leukemogenesis in vitro and in vivo, which can be successfully targeted by pharmacologic disruption of the AML1/ETO/DNMTs/HDACs complex or enhancement of miR-193a in t(8;21)-leukemias.
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Gao
authors.forename: Xufeng
authors.initials: X
authors.lastname: Luo
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Gao
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Junzhong
authors.initials: J
authors.lastname: Sun
authors.forename: Liping
authors.initials: L
authors.lastname: Dou
authors.forename: Jingxin
authors.initials: J
authors.lastname: Li
authors.forename: Chengwang
authors.initials: C
authors.lastname: Xu
authors.forename: Lixin
authors.initials: L
authors.lastname: Wang
authors.forename: Minhang
authors.initials: M
authors.lastname: Zhou
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Jiang
authors.forename: Jihao
authors.initials: J
authors.lastname: Zhou
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Clara
authors.initials: C
authors.lastname: Nervi
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Li
authors.initials: L
authors.lastname: Yu
mesh_terms: D000818:Animals; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D015536:Down-Regulation / Q000502:physiology; D044127:Epigenesis, Genetic / Q000502:physiology; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology; D020868:Gene Silencing / Q000502:physiology; D018922:HL-60 Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D038042:Myelopoiesis / Q000235:genetics; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D015398:Signal Transduction / Q000235:genetics*; D020298:U937 Cells; D000099186:Histone Deacetylase 3
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D019938:Cyclin D1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D006655:Histone Deacetylases; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit; D051736:Proto-Oncogene Proteins c-mdm2; D000075142:RUNX1 Translocation Partner 1 Protein; D000099186:Histone Deacetylase 3; C107844:AML1-ETO fusion protein, human; C530104:CCND1 protein, human; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C546818:MIRN193 microRNA, human; C497206:MDM2 protein, human; C494929:PTEN protein, human