Allelic methylation levels of the noncoding VTRNA2-1 located on chromosome 5q31.1 predict outcome in AML

Marianne Bach Treppendahl; Xiangning Qiu; Alexandra Søgaard; Xiaojing Yang; Cecilie Nandrup-Bus; Christoffer Hother; Mette Klarskov Andersen; Lars Kjeldsen; Lars Möllgård; Lars Möllgaard; Eva Hellström-Lindberg; Lars Johan Jendholm; Bo T Porse; Peter A Jones; Gangning Liang; Kirsten Grønbæk

doi:10.1182/blood-2011-06-362541

Allelic methylation levels of the noncoding VTRNA2-1 located on chromosome 5q31.1 predict outcome in AML

Marianne Bach Treppendahl, Xiangning Qiu, Alexandra Søgaard, Xiaojing Yang, Cecilie Nandrup-Bus, Christoffer Hother, Mette Klarskov Andersen, Lars Kjeldsen, Lars Möllgård, Lars Möllgaard, Eva Hellström-Lindberg, Lars Johan Jendholm, Bo T Porse, Peter A Jones, Gangning Liang, Kirsten Grønbæk

Department of Clinical Medicine

67 Citations (Scopus)

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.

Original language	English
Journal	Blood
Volume	119
Issue number	1
Pages (from-to)	206-16
Number of pages	11
ISSN	0006-4971
DOIs	https://doi.org/10.1182/blood-2011-06-362541
Publication status	Published - 5 Jan 2012

Keywords

Alleles
Base Sequence
Blotting, Northern
Blotting, Western
Case-Control Studies
Cells, Cultured
Chromosomes, Human, Pair 5
DNA Methylation
DNA, Neoplasm
Female
Gene Expression Regulation, Leukemic
Humans
Leukemia, Myeloid, Acute
Male
MicroRNAs
Middle Aged
Molecular Sequence Data
Mutation
Phosphorylation
Polymerase Chain Reaction
Prognosis
Promoter Regions, Genetic
RNA Polymerase III
RNA, Untranslated
Survival Rate
Vault Ribonucleoprotein Particles
eIF-2 Kinase

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10.1182/blood-2011-06-362541

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Treppendahl, M. B., Qiu, X., Søgaard, A., Yang, X., Nandrup-Bus, C., Hother, C., Andersen, M. K., Kjeldsen, L., Möllgård, L., Möllgaard, L., Hellström-Lindberg, E., Jendholm, L. J., Porse, B. T., Jones, P. A., Liang, G., & Grønbæk, K. (2012). Allelic methylation levels of the noncoding VTRNA2-1 located on chromosome 5q31.1 predict outcome in AML. Blood, 119(1), 206-16. https://doi.org/10.1182/blood-2011-06-362541

Treppendahl, MB, Qiu, X, Søgaard, A, Yang, X, Nandrup-Bus, C, Hother, C, Andersen, MK, Kjeldsen, L, Möllgård, L, Möllgaard, L, Hellström-Lindberg, E, Jendholm, LJ, Porse, BT, Jones, PA, Liang, G & Grønbæk, K 2012, 'Allelic methylation levels of the noncoding VTRNA2-1 located on chromosome 5q31.1 predict outcome in AML', Blood, vol. 119, no. 1, pp. 206-16. https://doi.org/10.1182/blood-2011-06-362541

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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.",

keywords = "Alleles, Base Sequence, Blotting, Northern, Blotting, Western, Case-Control Studies, Cells, Cultured, Chromosomes, Human, Pair 5, DNA Methylation, DNA, Neoplasm, Female, Gene Expression Regulation, Leukemic, Humans, Leukemia, Myeloid, Acute, Male, MicroRNAs, Middle Aged, Molecular Sequence Data, Mutation, Phosphorylation, Polymerase Chain Reaction, Prognosis, Promoter Regions, Genetic, RNA Polymerase III, RNA, Untranslated, Survival Rate, Vault Ribonucleoprotein Particles, eIF-2 Kinase",

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doi = "10.1182/blood-2011-06-362541",

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T1 - Allelic methylation levels of the noncoding VTRNA2-1 located on chromosome 5q31.1 predict outcome in AML

AU - Treppendahl, Marianne Bach

AU - Qiu, Xiangning

AU - Søgaard, Alexandra

AU - Yang, Xiaojing

AU - Nandrup-Bus, Cecilie

AU - Hother, Christoffer

AU - Andersen, Mette Klarskov

AU - Kjeldsen, Lars

AU - Möllgård, Lars

AU - Möllgaard, Lars

AU - Hellström-Lindberg, Eva

AU - Jendholm, Lars Johan

AU - Porse, Bo T

AU - Jones, Peter A

AU - Liang, Gangning

AU - Grønbæk, Kirsten

PY - 2012/1/5

Y1 - 2012/1/5

N2 - 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.

AB - 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.

KW - Alleles

KW - Base Sequence

KW - Blotting, Northern

KW - Blotting, Western

KW - Case-Control Studies

KW - Cells, Cultured

KW - Chromosomes, Human, Pair 5

KW - DNA Methylation

KW - DNA, Neoplasm

KW - Female

KW - Gene Expression Regulation, Leukemic

KW - Humans

KW - Leukemia, Myeloid, Acute

KW - Male

KW - MicroRNAs

KW - Middle Aged

KW - Molecular Sequence Data

KW - Mutation

KW - Phosphorylation

KW - Polymerase Chain Reaction

KW - Prognosis

KW - Promoter Regions, Genetic

KW - RNA Polymerase III

KW - RNA, Untranslated

KW - Survival Rate

KW - Vault Ribonucleoprotein Particles

KW - eIF-2 Kinase

U2 - 10.1182/blood-2011-06-362541

DO - 10.1182/blood-2011-06-362541

M3 - Journal article

C2 - 22058117

SN - 0006-4971

VL - 119

SP - 206

EP - 216

JO - Blood

JF - Blood

IS - 1

ER -

Allelic methylation levels of the noncoding VTRNA2-1 located on chromosome 5q31.1 predict outcome in AML

Abstract

Keywords

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