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

doi:10.1016/j.celrep.2016.04.004

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

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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 Dnmt3a^δ/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 Dnmt3a^δ/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 language	English (US)
Pages (from-to)	1190-1201
Number of pages	12
Journal	Cell Reports
Volume	15
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2016.04.004
State	Published - May 10 2016

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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Haney, S. L., Upchurch, G. M., Opavska, J., Klinkebiel, D., Hlady, R. A., Suresh, A., Pirruccello, S. J., Shukla, V., Lu, R., Costinean, S., Rizzino, A., Karpf, A. R., 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, 15(6), 1190-1201. https://doi.org/10.1016/j.celrep.2016.04.004

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

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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.",

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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

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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.

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

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