Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a

Staci L. Haney, G. Michael Upchurch, Jana Opavska, David Klinkebiel, Ryan A. Hlady, Abhinav Suresh, Samuel J. Pirruccello, Vipul Shukla, Runqing Lu, Stefan Costinean, Angie Rizzino, Adam R. Karpf, Shantaram Joshi, Patrick Swanson, Rene Opavsky

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

DNA methyltransferase 3a (DNMT3A) catalyzes the formation of 5-methyl-cytosine in mammalian genomic DNA, and it is frequently mutated in human hematologic malignancies. Bi-allelic loss of Dnmt3a in mice results in leukemia and lymphoma, including chronic lymphocytic leukemia (CLL). Here, we investigate whether mono-allelic loss of Dnmt3a is sufficient to induce disease. We show that, by 16 months of age, 65% of Dnmt3a+/- mice develop a CLL-like disease, and 15% of mice develop non-malignant myeloproliferation. Genome-wide methylation analysis reveals that reduced Dnmt3a levels induce promoter hypomethylation at similar loci in Dnmt3a+/- and Dnmt3aδ/δ CLL, suggesting that promoters are particularly sensitive to Dnmt3a levels. Gene expression analysis identified 26 hypomethylated and overexpressed genes common to both Dnmt3a+/- and Dnmt3aδ/δ CLL as putative oncogenic drivers. Our data provide evidence that Dnmt3a is a haplo-insufficient tumor suppressor in CLL and highlights the importance of deregulated molecular events in disease pathogenesis.

Original languageEnglish
Pages (from-to)1190-1201
Number of pages12
JournalCell Reports
Volume15
Issue number6
DOIs
StatePublished - May 10 2016

Fingerprint

B-Cell Chronic Lymphocytic Leukemia
Genes
Loss of Heterozygosity
Methylation
Cytosine
Gene expression
Tumors
Hematologic Neoplasms
DNA
Lymphoma
Leukemia
Genome
Gene Expression
Neoplasms

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Haney, S. L., Upchurch, G. M., Opavska, J., Klinkebiel, D., Hlady, R. A., Suresh, A., ... Opavsky, R. (2016). Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a. Cell Reports, 15(6), 1190-1201. https://doi.org/10.1016/j.celrep.2016.04.004

Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a. / Haney, Staci L.; Upchurch, G. Michael; Opavska, Jana; Klinkebiel, David; Hlady, Ryan A.; Suresh, Abhinav; Pirruccello, Samuel J.; Shukla, Vipul; Lu, Runqing; Costinean, Stefan; Rizzino, Angie; Karpf, Adam R.; Joshi, Shantaram; Swanson, Patrick; Opavsky, Rene.

In: Cell Reports, Vol. 15, No. 6, 10.05.2016, p. 1190-1201.

Research output: Contribution to journalArticle

Haney, SL, Upchurch, GM, Opavska, J, Klinkebiel, D, Hlady, RA, Suresh, A, Pirruccello, SJ, Shukla, V, Lu, R, Costinean, S, Rizzino, A, Karpf, AR, Joshi, S, Swanson, P & Opavsky, R 2016, 'Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a', Cell Reports, vol. 15, no. 6, pp. 1190-1201. https://doi.org/10.1016/j.celrep.2016.04.004
Haney, Staci L. ; Upchurch, G. Michael ; Opavska, Jana ; Klinkebiel, David ; Hlady, Ryan A. ; Suresh, Abhinav ; Pirruccello, Samuel J. ; Shukla, Vipul ; Lu, Runqing ; Costinean, Stefan ; Rizzino, Angie ; Karpf, Adam R. ; Joshi, Shantaram ; Swanson, Patrick ; Opavsky, Rene. / Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a. In: Cell Reports. 2016 ; Vol. 15, No. 6. pp. 1190-1201.
@article{9951217be1d744bdacce3044e957fb78,
title = "Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a",
abstract = "DNA methyltransferase 3a (DNMT3A) catalyzes the formation of 5-methyl-cytosine in mammalian genomic DNA, and it is frequently mutated in human hematologic malignancies. Bi-allelic loss of Dnmt3a in mice results in leukemia and lymphoma, including chronic lymphocytic leukemia (CLL). Here, we investigate whether mono-allelic loss of Dnmt3a is sufficient to induce disease. We show that, by 16 months of age, 65{\%} of Dnmt3a+/- mice develop a CLL-like disease, and 15{\%} of mice develop non-malignant myeloproliferation. Genome-wide methylation analysis reveals that reduced Dnmt3a levels induce promoter hypomethylation at similar loci in Dnmt3a+/- and Dnmt3aδ/δ CLL, suggesting that promoters are particularly sensitive to Dnmt3a levels. Gene expression analysis identified 26 hypomethylated and overexpressed genes common to both Dnmt3a+/- and Dnmt3aδ/δ CLL as putative oncogenic drivers. Our data provide evidence that Dnmt3a is a haplo-insufficient tumor suppressor in CLL and highlights the importance of deregulated molecular events in disease pathogenesis.",
author = "Haney, {Staci L.} and Upchurch, {G. Michael} and Jana Opavska and David Klinkebiel and Hlady, {Ryan A.} and Abhinav Suresh and Pirruccello, {Samuel J.} and Vipul Shukla and Runqing Lu and Stefan Costinean and Angie Rizzino and Karpf, {Adam R.} and Shantaram Joshi and Patrick Swanson and Rene Opavsky",
year = "2016",
month = "5",
day = "10",
doi = "10.1016/j.celrep.2016.04.004",
language = "English",
volume = "15",
pages = "1190--1201",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "6",

}

TY - JOUR

T1 - Promoter Hypomethylation and Expression Is Conserved in Mouse Chronic Lymphocytic Leukemia Induced by Decreased or Inactivated Dnmt3a

AU - Haney, Staci L.

AU - Upchurch, G. Michael

AU - Opavska, Jana

AU - Klinkebiel, David

AU - Hlady, Ryan A.

AU - Suresh, Abhinav

AU - Pirruccello, Samuel J.

AU - Shukla, Vipul

AU - Lu, Runqing

AU - Costinean, Stefan

AU - Rizzino, Angie

AU - Karpf, Adam R.

AU - Joshi, Shantaram

AU - Swanson, Patrick

AU - Opavsky, Rene

PY - 2016/5/10

Y1 - 2016/5/10

N2 - DNA methyltransferase 3a (DNMT3A) catalyzes the formation of 5-methyl-cytosine in mammalian genomic DNA, and it is frequently mutated in human hematologic malignancies. Bi-allelic loss of Dnmt3a in mice results in leukemia and lymphoma, including chronic lymphocytic leukemia (CLL). Here, we investigate whether mono-allelic loss of Dnmt3a is sufficient to induce disease. We show that, by 16 months of age, 65% of Dnmt3a+/- mice develop a CLL-like disease, and 15% of mice develop non-malignant myeloproliferation. Genome-wide methylation analysis reveals that reduced Dnmt3a levels induce promoter hypomethylation at similar loci in Dnmt3a+/- and Dnmt3aδ/δ CLL, suggesting that promoters are particularly sensitive to Dnmt3a levels. Gene expression analysis identified 26 hypomethylated and overexpressed genes common to both Dnmt3a+/- and Dnmt3aδ/δ CLL as putative oncogenic drivers. Our data provide evidence that Dnmt3a is a haplo-insufficient tumor suppressor in CLL and highlights the importance of deregulated molecular events in disease pathogenesis.

AB - DNA methyltransferase 3a (DNMT3A) catalyzes the formation of 5-methyl-cytosine in mammalian genomic DNA, and it is frequently mutated in human hematologic malignancies. Bi-allelic loss of Dnmt3a in mice results in leukemia and lymphoma, including chronic lymphocytic leukemia (CLL). Here, we investigate whether mono-allelic loss of Dnmt3a is sufficient to induce disease. We show that, by 16 months of age, 65% of Dnmt3a+/- mice develop a CLL-like disease, and 15% of mice develop non-malignant myeloproliferation. Genome-wide methylation analysis reveals that reduced Dnmt3a levels induce promoter hypomethylation at similar loci in Dnmt3a+/- and Dnmt3aδ/δ CLL, suggesting that promoters are particularly sensitive to Dnmt3a levels. Gene expression analysis identified 26 hypomethylated and overexpressed genes common to both Dnmt3a+/- and Dnmt3aδ/δ CLL as putative oncogenic drivers. Our data provide evidence that Dnmt3a is a haplo-insufficient tumor suppressor in CLL and highlights the importance of deregulated molecular events in disease pathogenesis.

UR - http://www.scopus.com/inward/record.url?scp=84964635596&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964635596&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2016.04.004

DO - 10.1016/j.celrep.2016.04.004

M3 - Article

VL - 15

SP - 1190

EP - 1201

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 6

ER -