title: Allelic methylation levels of the noncoding VTRNA2-1 located on chromosome 5q31.1 predict outcome in AML.
abstract: Deletions of chromosome 5q are associated with poor outcomes in acute myeloid leukemia (AML) suggesting the presence of tumor suppressor(s) at the locus. However, definitive identification of putative tumor suppressor genes remains controversial. Here we show that a 106-nucleotide noncoding RNA vault RNA2-1 (vtRNA2-1), previously misannotated as miR886, could potentially play a role in the biology and prognosis of AML. vtRNA2-1 is transcribed by polymerase III and is monoallelically methylated in 75% of healthy individuals whereas the remaining 25% of the population have biallelic hypomethylation. AML patients without methylation of VTRNA2-1 have a considerably better outcome than those with monoallelic or biallelic methylation (n = 101, P = .001). We show that methylation is inversely correlated with vtRNA2-1 expression, and that 5-azanucleosides induce vtRNA2-1 and down-regulate the phosphorylated RNA-dependent protein kinase (pPKR), whose activity has been shown to be modulated by vtRNA2-1. Because pPKR promotes cell survival in AML, the data are consistent with vtRNA2-1 being a tumor suppressor in AML. This is the first study to show that vtRNA2-1 might play a significant role in AML, that it is either mono- or biallelically expressed in the blood cells of healthy individuals, and that its methylation state predicts outcome in AML.
authors: Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
authors: Marianne Bach
authors: MB
authors: Treppendahl
authors: Xiangning
authors: X
authors: Qiu
authors: Alexandra
authors: A
authors: Søgaard
authors: Xiaojing
authors: X
authors: Yang
authors: Cecilie
authors: C
authors: Nandrup-Bus
authors: Christoffer
authors: C
authors: Hother
authors: Mette Klarskov
authors: MK
authors: Andersen
authors: Lars
authors: L
authors: Kjeldsen
authors: Lars
authors: L
authors: Möllgård
authors: Lars
authors: L
authors: Möllgaard
authors: Eva
authors: E
authors: Hellström-Lindberg
authors: Johan
authors: J
authors: Jendholm
authors: Bo T
authors: BT
authors: Porse
authors: Peter A
authors: PA
authors: Jones
authors: Gangning
authors: G
authors: Liang
authors: Kirsten
authors: K
authors: Grønbæk
mesh_terms: D000483:Alleles; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012320:RNA Polymerase III; D022661:RNA, Untranslated / Q000235:genetics*; D015996:Survival Rate; D020394:Vault Ribonucleoprotein Particles / Q000235:genetics*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D004273:DNA, Neoplasm; C559060:MIRN886 microRNA, human; D035683:MicroRNAs; D022661:RNA, Untranslated; D020394:Vault Ribonucleoprotein Particles; D019892:eIF-2 Kinase; D012320:RNA Polymerase III