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Stem Cells

A stem cell-like gene expression signature associates with inferior outcomes and a distinct microRNA expression profile in adults with primary cytogenetically normal acute myeloid leukemia

Leukemia volume 27, pages 2023–2031 (2013)Cite this article

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Abstract

Acute myeloid leukemia (AML) is hypothesized to be sustained by self-renewing leukemia stem cells (LSCs). Recently, gene expression signatures (GES) from functionally defined AML LSC populations were reported, and expression of a ‘core enriched’ (CE) GES, representing 44 genes activated in LCSs, conferred shorter survival in cytogenetically normal (CN) AML. The prognostic impact of the CE GES in the context of other molecular markers, including gene mutations and microRNA (miR) expression alterations, is unknown and its clinical utility is unclear. We studied associations of the CE GES with known molecular prognosticators, miR expression profiles, and outcomes in 364 well-characterized CN-AML patients. A high CE score (CEhigh) associated with FLT3-internal tandem duplication, WT1 and RUNX1 mutations, wild-type CEBPA and TET2, and high ERG, BAALC and miR-155 expression. CEhigh patients had a lower complete remission (CR) rate (P=0.003) and shorter disease-free (DFS, P<0.001) and overall survival (OS, P<0.001) than CElow patients. These associations persisted in multivariable analyses adjusting for other prognosticators (CR, P=0.02; DFS, P<0.001; and OS, P<0.001). CEhigh status was accompanied by a characteristic miR expression signature. Fifteen miRs were upregulated in both younger and older CEhigh patients, including miRs relevant for stem cell function. Our results support the clinical relevance of LSCs and improve risk stratification in AML.

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Acknowledgements

This work was supported in part by the National Cancer Institute (CA101140, CA114725, CA31946, CA33601, CA16058, CA77658, CA129657 and CA140158), The Coleman Leukemia Research Foundation, the Deutsche Krebshilfe-Dr Mildred Scheel Cancer Foundation (HB), the Pelotonia Fellowship Program (A-KE) and the Conquer Cancer Foundation (JHM). The CALGB/Alliance institutions, principal investigators and cytogeneticists participating in this study are listed 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, for sample processing and storage services, and Lisa J Sterling, Christine Finks and Colin G Edwards, PhD, for data management.

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Author notes

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

Authors and Affiliations

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

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

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

    K Maharry, J Kohlschmidt & D Nicolet

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

    B L Powell

  4. University of Iowa, Iowa City, IA, USA

    T H Carter

  5. Roswell Park Cancer Institute, Buffalo, NY, USA

    M Wetzler

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

    J E Kolitz

  7. Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA

    M R Baer

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

    A J Carroll

  9. Dana-Farber Cancer Institute, Boston, MA, USA

    R M Stone

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  1. K H Metzeler
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Correspondence to G Marcucci or C D Bloomfield.

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Metzeler, K., Maharry, K., Kohlschmidt, J. et al. A stem cell-like gene expression signature associates with inferior outcomes and a distinct microRNA expression profile in adults with primary cytogenetically normal acute myeloid leukemia. Leukemia 27, 2023–2031 (2013). https://doi.org/10.1038/leu.2013.181

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