PTPROt-mediated regulation of p53/Foxm1 suppresses leukemic phenotype in a CLL mouse model.

Abstract

The gene encoding PTPROt is methylated and suppressed in Chronic Lymphocytc Leukemia. PTPROt exhibits in vitro tumor suppressor characteristics through the regulation of B-cell receptor signaling. Here, we generated transgenic (Tg) mice with B-cell specific expression of PTPROt. While lymphocyte development is normal in these mice, crossing them with TCL1 Tg mouse model of CLL results in a survival advantage compared to 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 B-cell receptor 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.