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Prdm14 initiates lymphoblastic leukemia after expanding a population of cells resembling common lymphoid progenitors

Oncogene volume 30, pages 2859–2873 (2011)Cite this article

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Abstract

Understanding the heterogeneous genetic mechanisms of tumor initiation in lymphoid leukemias (LL) will lead to improvements in prognostic classification and treatment regimens. In previous studies of mouse leukemias, we showed that retroviral insertion at the ecotropic viral insertion site 32 locus leads to increased expression of Prdm14, a pluripotency gene implicated in the self-renewal capacity of embryonic stem cells and the early stages of breast cancer. Here, we show that PRDM14 is also overexpressed in ∼25% of human lymphoid neoplasms, with increased frequencies in T-cell acute LL and hyperdiploid precursor B-cell acute LL. To test if Prdm14 overexpression could initiate leukemia, mice were transduced with bone marrow cells transfected with a Prdm14 expression vector. LLs developed in 96% of female mice and 42% of male mice. Before the onset of leukemia, differentiation of transduced cells was biased up to 1000-fold toward cells with features of common lymphoid progenitors (CLPs), and lymphoid differentiation showed a relative block at the pro-B stage. Microarray gene expression analysis of expanded CLP-like cells before the onset of leukemia demonstrated upregulation of genes involved in pluripotency, tumor initiation, early B-lineage commitment, Wnt/Ras signaling and the epithelial-to-mesenchymal transition. Among the dysregulated genes were imprinted genes and non-coding RNAs including Dlk1 and Meg3, which are also key pluripotency mediators. Heightened expression of the estrogen-dependent oncogene, Myb, in tumors suggests a basis for the increased frequency of cancer in female mice. These data provide the first direct evidence for the association of Prdm14 with cancer initiation in an in vivo mouse model and in human lymphoid malignancies, while suggesting mechanisms for Prdm14's mode of action.

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Acknowledgements

The work by MJJ was supported by NIH R01 CA63229, R01 CA15530 and a Baylor College of Medicine Interim funding award. SJS was supported by an NIH National Research Service Award Institutional Training Grant 3 T32 CA115303-04, ‘Pediatric Oncology Research Training Program.’ HCM was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. We thank John Belmont and Molly Bray at the Laboratory for Translational Genomics at BCM for microarray data production; Jill Crowe for excellent technical assistance; and Frank Probst for the critical reading of the paper.

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  1. E J Dettman and S J Simko: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    E J Dettman, B Ayanga, B L Carofino & M J Justice

  2. Department of Pediatrics, Section of Hematology and Oncology, Baylor College of Medicine, Houston, TX, USA

    S J Simko & J F Margolin

  3. Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA

    H C Morse III

  4. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA

    M J Justice

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Dettman, E., Simko, S., Ayanga, B. et al. Prdm14 initiates lymphoblastic leukemia after expanding a population of cells resembling common lymphoid progenitors. Oncogene 30, 2859–2873 (2011). https://doi.org/10.1038/onc.2011.12

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