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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
PTPROt-mediated regulation of p53/Foxm1 suppresses leukemic phenotype in a CLL mouse model
T Motiwala1, H Kutay1, N Zanesi2
1Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA.
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.
Insights
Protein tyrosine phosphatase receptor-type O truncated isoform (PTPROt) suppresses chronic lymphocytic leukemia (CLL) in mice. PTPROt inhibits B-cell receptor signaling and the p53/Foxm1 axis, offering protection against leukemia.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- The gene for PTPROt is epigenetically silenced in chronic lymphocytic leukemia (CLL).
- PTPROt demonstrates in vitro tumor-suppressive properties by modulating B-cell receptor (BCR) signaling.
- Understanding PTPROt's in vivo function is crucial for developing CLL therapies.
Purpose of the Study:
- To investigate the in vivo tumor-suppressive role of PTPROt in a mouse model of CLL.
- To elucidate the molecular mechanisms underlying PTPROt's anti-leukemic effects.
- To identify key signaling pathways regulated by PTPROt in CLL.
Main Methods:
- Generation of B-cell-specific PTPROt transgenic (Tg) mice.
- Crossing PTPROt Tg mice with TCL1 Tg mouse model of CLL.
- Gene expression profiling and Ingenuity Pathway Analysis of splenic B-lymphocytes.
Main Results:
- PTPROt Tg mice crossed with TCL1 Tg mice exhibited a survival advantage compared to TCL1 Tg mice.
- PTPROt significantly suppressed the expression of chemokine Ccl3 and the oncogenic transcription factor Foxm1 in TCL1 Tg mice.
- PTPROt-mediated suppression of Foxm1 involved p53 activation, facilitated by BCR signaling inhibition.
Conclusions:
- PTPROt exhibits significant in vivo tumor-suppressive function against CLL development.
- The p53/Foxm1 axis is a critical downstream mediator of PTPROt's anti-leukemic activity.
- PTPROt's regulation of BCR signaling plays a key role in its protective effects against CLL.
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