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

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Oncogene (Impact Factor: 8.46). 02/2011; 30(25):2859-73. DOI: 10.1038/onc.2011.12
Source: PubMed


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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    • "The classic mechanism for metastasis of a solid tumor is EMT, migration, and MET [2]. This process is generally considered to be distinct from the mechanisms of progression in leukemia, though there are elements that are common across these cancer types [34,35]. To test these distinctions, we hypothesized that promoter occupancy would be higher in the solid tumor (MET) model than in the non-cancer model. "
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    ABSTRACT: Mesenchymal to Epithelial Transition (MET) plasticity is critical to cancer progression, and we recently showed that the OVOL transcription factors (TFs) are critical regulators of MET. Results of that work also posed the hypothesis that the OVOLs impact MET in a range of cancers. We now test this hypothesis by developing a model, OVOL Induced MET (OI-MET), and sub-model (OI-MET-TF), to characterize differential gene expression in MET common to prostate cancer (PC) and breast cancer (BC). In the OI-MET model, we identified 739 genes differentially expressed in both the PC and BC models. For this gene set, we found significant enrichment of annotation for BC, PC, cancer, and MET, as well as regulation of gene expression by AP1, STAT1, STAT3, and NFKB1. Focusing on the target genes for these four TFs plus the OVOLs, we produced the OI-MET-TF sub-model, which shows even greater enrichment for these annotations, plus significant evidence of cooperation among these five TFs. Based on known gene/drug interactions, we prioritized targets in the OI-MET-TF network for follow-on analysis, emphasizing the clinical relevance of this work. Reflecting these results back to the OI-MET model, we found that binding motifs for the TF pair AP1/MYC are more frequent than expected and that the AP1/MYC pair is significantly enriched in binding in cancer models, relative to non-cancer models, in these promoters. This effect is seen in both MET models (solid tumors) and in non-MET models (leukemia). These results are consistent with our hypothesis that the OVOLs impact cancer susceptibility by regulating MET, and extend the hypothesis to include mechanisms not specific to MET. We find significant evidence of the OVOL, AP1, STAT1, STAT3, and NFKB1 TFs having important roles in MET, and more broadly in cancer. We prioritize known gene/drug targets for follow-up in the clinic, and we show that the AP1/MYC TF pair is a strong candidate for intervention.
    BMC Systems Biology 03/2014; 8(1):29. DOI:10.1186/1752-0509-8-29 · 2.44 Impact Factor
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    • "Expression of Prdm3 or Prdm16 isoforms that lack the PRDI-BF1-RIZ1 homologous domain during haematopoiesis can lead to acute myeloid leukaemia (Morishita, 2007). Prdm14 is overexpressed in breast cancer (Nishikawa et al., 2007) and causes lymphoid leukaemia (Dettman et al., 2011). Prdm3 is a susceptibility locus in nasopharyngeal carcinoma (Bei et al., 2010) and a variety of other solid tumours (Koos et al., 2011; Sugita et al., 2000). "
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    ABSTRACT: Members of the Prdm family are characterized by an N-terminal PR domain that is related to the SET methyltransferase domain, and multiple zinc fingers that mediate sequence-specific DNA binding and protein-protein interactions. Prdm factors either act as direct histone methyltransferases or recruit a suite of histone-modifying enzymes to target promoters. In this way, they function in many developmental contexts to drive and maintain cell state transitions and to modify the activity of developmental signalling pathways. Here, we provide an overview of the structure and function of Prdm family members and discuss the roles played by these proteins in stem cells and throughout development.
    Development 07/2012; 139(13):2267-82. DOI:10.1242/dev.070110 · 6.46 Impact Factor
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    ABSTRACT: The PRDM family has recently spawned considerable interest as it has been implicated in fundamental aspects of cellular differentiation and exhibits expanding ties to human diseases. The PRDMs belong to the SET domain family of histone methyltransferases, however, enzymatic activity has been determined for only few PRDMs suggesting that they act by recruiting co-factors or, more speculatively, confer methylation of non-histone targets. Several PRDM family members are deregulated in human diseases, most prominently in hematological malignancies and solid cancers, where they can act as both tumor suppressors or drivers of oncogenic processes. The molecular mechanisms have been delineated for only few PRDMs and little is known about functional redundancy within the family. Future studies should identify target genes of PRDM proteins and the protein complexes in which PRDM proteins reside to provide a more comprehensive understanding of the biological and biochemical functions of this important protein family.
    BioEssays 01/2012; 34(1):50-60. DOI:10.1002/bies.201100107 · 4.73 Impact Factor
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