PPM1D/Wip1 is amplified, overexpressed, and mutated in human Non-Hodgkin Lymphomas

AbstractBackground Wip1, is a p53-dependent Ser/Thr phosphatase involved in the timely termination of DDR. ThePPM1Dgene encoding Wip1 is deregulated and thus gained an oncogene character in common human solid tumors and cell lines. This study assessed the oncogenic potential of thePPM1Dgene in human NHL, the most common hematological malignancy worldwide. Methods and Results FFPE human LH (n = 17) and NHL tumor lymph node samples (n = 65) and human NHL cell lines were used to assess the oncogenic potential of thePPM1Dgene in the present study. Copy number gain and mRNA expression analysis of thePPM1D/Wip1 gene were assessed by qRT-PCR analysis. Mutational analysis of Exon 6 of thePPM1Dgene was performed by PCR amplification and Sanger sequencing. Expressions of Wip1 and p53 proteins were assessed by immunohistochemistry and western blot analysis. Conclusions We found thatPPM1Dgained gene copy number in NHL tumors by 0.7-8 times compared to the control (p < 0.01). IncreasedPPM1D/Wip1 gene copy number was associated with higher mRNA and protein expression in human NHL samples (p < 0.01). Overexpression of Wip1 in NHL tumors and NHL cell lines was associated with amplification level and was unaffected by p53 status. Furthermore, a heterozygous type mutation was detected in exon 6 (c.1553C > A, p.518) of thePPM1Dgene particularly in DLBCL samples. Wip1 may have oncogenic potential, perhaps playing a role in the onset and progression of human NHL. The possible significance of Wip1 overexpression to chemotherapy response in NHL remains an intriguing question that requires more exploration.