Abstract
The gene encoding PTPROt (truncated isoform of protein tyrosine phosphatase receptor-type O) is methylated and suppressed in chronic lymphocytic leukemia (CLL). PTPROt exhibits in vitro tumor-suppressor characteristics through the regulation of B-cell receptor (BCR) signaling. Here we generated transgenic (Tg) mice with B-cell-specific expression of PTPROt. Although lymphocyte development is normal in these mice, crossing them with TCL1 Tg mouse model of CLL results in a survival advantage compared with the TCL1 Tg mice. Gene expression profiling of splenic B-lymphocytes before detectable signs of CLL followed by Ingenuity Pathway Analysis revealed that the most prominently regulated functions in TCL1 Tg vs non-transgenic (NTg) and TCL1 Tg vs PTPROt/TCL1 double Tg are the same and also biologically relevant to this study. Further, enhanced expression of the chemokine Ccl3, the oncogenic transcription factor Foxm1 and its targets in TCL1 Tg mice were significantly suppressed in the double Tg mice, suggesting a protective function of PTPROt against leukemogenesis. This study also showed that PTPROt-mediated regulation of Foxm1 involves activation of p53, a transcriptional repressor of Foxm1, which is facilitated through suppression of BCR signaling. These results establish the in vivo tumor-suppressive function of PTPROt and identify p53/Foxm1 axis as a key downstream effect of PTPROt-mediated suppression of BCR signaling.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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B-Lymphocytes / metabolism
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B-Lymphocytes / pathology
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism*
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Blotting, Western
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Cells, Cultured
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Disease Models, Animal*
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Female
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Flow Cytometry
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Forkhead Box Protein M1
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism*
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Gene Expression Profiling
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Gene Expression Regulation, Leukemic
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Humans
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Inflammation / genetics
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Inflammation / pathology
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Inflammation / prevention & control*
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Leukemia, Lymphocytic, Chronic, B-Cell / prevention & control*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Oligonucleotide Array Sequence Analysis
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Phenotype
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-bcr / genetics
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Proto-Oncogene Proteins c-bcr / metabolism
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Receptor-Like Protein Tyrosine Phosphatases, Class 3 / physiology*
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Biomarkers, Tumor
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Forkhead Box Protein M1
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Forkhead Transcription Factors
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Foxm1 protein, mouse
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Proto-Oncogene Proteins
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RNA, Messenger
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TCL1A protein, human
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Tumor Suppressor Protein p53
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Bcr protein, mouse
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Proto-Oncogene Proteins c-bcr
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PTPRO protein, human
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Receptor-Like Protein Tyrosine Phosphatases, Class 3