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Acute Leukemias

Prognostic and biologic significance of DNMT3B expression in older patients with cytogenetically normal primary acute myeloid leukemia

Leukemia volume 29, pages 567–575 (2015)Cite this article

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Abstract

DNMT3B encodes a DNA methyltransferase implicated in aberrant epigenetic changes contributing to leukemogenesis. We tested whether DNMT3B expression, measured by NanoString nCounter assay, associates with outcome, gene and microRNA expression and DNA methylation profiles in 210 older (⩾60 years) adults with primary, cytogenetically normal acute myeloid leukemia (CN-AML). Patients were dichotomized into high versus low expressers using median cut. Outcomes were assessed in the context of known CN-AML prognosticators. Gene and microRNA expression, and DNA methylation profiles were analyzed using microarrays and MethylCap-sequencing, respectively. High DNMT3B expressers had fewer complete remissions (CR; P=0.002) and shorter disease-free (DFS; P=0.02) and overall (OS; P<0.001) survival. In multivariable analyses, high DNMT3B expression remained an independent predictor of lower CR rates (P=0.04) and shorter DFS (P=0.04) and OS (P=0.001). High DNMT3B expression associated with a gene expression profile comprising 363 genes involved in differentiation, proliferation and survival pathways, but with only four differentially expressed microRNAs (miR-133b, miR-148a, miR-122, miR-409-3p) and no differential DNA methylation regions. We conclude that high DNMT3B expression independently associates with adverse outcome in older CN-AML patients. Gene expression analyses suggest that DNMT3B is involved in the modulation of several genes, although the regulatory mechanisms remain to be investigated to devise therapeutic approaches specific for these patients.

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Acknowledgements

The Cancer and Leukemia Group B institutions, and their principal investigators participating in this study are provided in the Supplementary Information. We thank Donna Bucci and the CALGB/Alliance Leukemia Tissue Bank at The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA for sample processing and storage services; Lisa J. Sterling and Chris Finks for data management; and The Ohio State University Comprehensive Cancer Center’s Nucleic Acid and Microarray Shared Resources for technical support. This work was supported in part by the National Cancer Institute (grants CA101140, CA114725, CA140158, CA31946, CA33601, CA16058, CA77658 and CA129657), the Coleman Leukemia Research Foundation, the Pelotonia Fellowship Program (A-KE), the Conquer Cancer Foundation (JHM) and the Deutsche Krebshilfe–Dr Mildred Scheel Cancer Foundation (HB).

Author Contributions

CN, JK, SV, KMr, GM and CDB designed the study, analyzed the data and wrote the manuscript, and all authors agreed on the final version; SPW, KHM, A-KE, PY, DF, HB, SS, JHM, JPC, Y-ZW, and RB carried out laboratory-based research; JK, KMa, SV and DN performed statistical analyses; and AJC, MRB, BLP, JEK, JOM, THC, RAL, RMS, KMr, GM and CDB were involved directly or indirectly in the care of patients and/or sample procurement.

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Author notes

  1. K Mrózek, G Marcucci and C D Bloomfield: These senior authors contributed equally to this work.

Authors and Affiliations

  1. The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA,

    C Niederwieser, J Kohlschmidt, S Volinia, S P Whitman, K H Metzeler, A-K Eisfeld, K Maharry, P Yan, D Frankhouser, H Becker, S Schwind, D Nicolet, J H Mendler, J P Curfman, Y-Z Wu, K Mrózek, G Marcucci & C D Bloomfield

  2. Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN, USA,

    J Kohlschmidt, K Maharry & D Nicolet

  3. Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA,

    A J Carroll

  4. Department of Medicine and Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA,

    M R Baer

  5. Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC, USA,

    B L Powell

  6. Monter Cancer Center, Hofstra North Shore-Long Island Jewish School of Medicine, Lake Success, NY, USA,

    J E Kolitz

  7. Department of Medicine, Duke University Medical Center, Durham, NC, USA,

    J O Moore

  8. Department of Internal Medicine, University of Iowa, Iowa City, IA, USA,

    T H Carter

  9. Departments of Physics and Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA

    R Bundschuh

  10. Department of Medicine, University of Chicago Medical Center, Chicago, IL, USA,

    R A Larson

  11. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA,

    R M Stone

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Correspondence to K Mrózek, G Marcucci or C D Bloomfield.

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Additional information

Presented in part at the 18th Congress of the European Hematology Association, Stockholm, Sweden, 13–;16 June 2013, and published in abstract form: Niederwieser C, Kohlschmidt J, Maharry K, Mrózek K, Metzeler K, Volinia S et al. High expression of DNMT3B negatively impacts on clinical outcome of older patients (pts) with primary cytogenetically normal (CN) acute myeloid leukemia (AML) (CALGB 20202 (Alliance)). Haematologica 2013; 98(suppl 1): 484 (abstract S1168).

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Niederwieser, C., Kohlschmidt, J., Volinia, S. et al. Prognostic and biologic significance of DNMT3B expression in older patients with cytogenetically normal primary acute myeloid leukemia. Leukemia 29, 567–575 (2015). https://doi.org/10.1038/leu.2014.267

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