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

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...

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Published in:	Oncogene Vol. 30; no. 25; pp. 2859 - 2873
Main Authors:	Dettman, E J, Simko, S J, Ayanga, B, Carofino, B L, Margolin, J F, Morse, H C, Justice, M J
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 23-06-2011 Nature Publishing Group
Subjects:	692/420/2489/68 692/699/67/1990/283 Acute lymphocytic leukemia Animals Apoptosis Biological and medical sciences Bone marrow Breast cancer Cancer Cell Biology Cell differentiation Cell physiology Cell self-renewal Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Cells DNA microarrays DNA-Binding Proteins Embryo cells Embryonic stem cells Estrogens Female Fundamental and applied biological sciences. Psychology Gene expression Genetic aspects Genetic Predisposition to Disease Genetics Hematologic and hematopoietic diseases Human Genetics Insertion Internal Medicine Leukemia Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Lymphatic leukemia Lymphocytes Lymphocytes B Lymphocytes T Male Medical sciences Medicine Medicine & Public Health Mesenchyme Mice Molecular and cellular biology Oncology original-article Pluripotency Polymerase chain reaction Preadipocyte factor 1 Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology Progenitor cells RNA-Binding Proteins Stem cell transplantation Stem cells Transcription Factors - genetics Transcription Factors - physiology Tumors Wnt protein United States leukemia pluripotency leukemia-initiating cell acute lymphoblastic leukemia common lymphoid progenitor Prdm14 Acute leukemia Malignant hemopathy Prdml4 Carcinogenesis Cell population Lymphoproliferative syndrome Acute lymphocytic leukemia Cancer
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 These authors contributed equally to this manuscript
ISSN:	0950-9232 1476-5594 1476-5594
DOI:	10.1038/onc.2011.12