PDZ-Binding Kinase (PBK/TOPK), a Serine-Threonine Kinase Known to downmodulate P53 Function, is Frequently Overexpressed In a Variety of Hematological Malignancies

PBK/TOPK (PDZ-binding kinase, T-LAK-cell-originated protein kinase) is a serine-threonine kinase that was originally cloned as an IL-2 inducible gene exclusively expressed in cytotoxic T lymphocytes, and an interaction partner with the human tumor suppressor hdlg. PBK/TOPK mRNA has been found to be expressed in normal testicular and embryonic tissues, proliferating neural progenitor cells and various tumor cell lines. Numerous studies have demonstrated that PBK exerts its proproliferation function by phophorylating and thus activating its substrate proteins p38, ERK2, LGN/GPSM2, and histone H3, which are involved in cell growth, cell cycle progression and chromatin remodeling. Recently, we further reported that PBK could interact with tumor suppressor p53 via its DNA binding domain and impair its function as a transcription factor (Oncogene, 2010). These lines of evidence all point to PBK as a novel multifunctional oncoprotein.

To investigate the frequency of PBK expression in hematological malignancies.

Immunohistochemistry for PBK expression on various tissue microarrays (US Biomax) was performed. Briefly, paraffin-embedded tissue microarrays were treated with xylene and ethanol followed by a protein-blocking reagent. After incubation with 1:50 diluted PBK antibody (Cell Signaling) and HRP-labeled-secondary antibody (US Biomax), the tissue microarrays were stained with substrate DAB. The slides were scored according to the following criteria: 0 (negative), <25% cells were stained; +1, 25–50% cells were stained; +2, 51–75% cells were stained; +3, >75% cells were stained.

In 108 cases of diffuse large B-cell lymphoma, 50% were positive for PBK, among which 27 scored +1, 21 scored +2, and 6 scored +3; in 8 cases of Burkitt lymphoma, 7/8 (87.5%) were positive for PBK with all of them scoring +3; in 58 cases of Hodgkin lymphoma, 67% were positive for PBK with 35 scoring +1 and only 4 scoring +2; in 9 cases of plasma cell myeloma, only 2 were positive for PBK and both scored +1. Three follicular lymphomas and 4 reactive lymph nodes scored 0.

PBK protein was highly expressed in a high proportion of Burkitt lymphoma. PBK was also expressed in a relatively high proportion of diffuse large B-cell lymphoma and Hodgkin lymphoma, suggesting that PBK is implicated in the pathogenesis of hematological malignancies with higher proliferation rates. PBK expression was much less frequent in more indolent hematologic neoplasms such as myeloma and follicular lymphoma. Our lab is now working on the crystal structure of PBK with the long-term goal to identify small molecular inhibitors of PBK function. These new results in combination with our earlier data suggest that inhibition of PBK function may be a rational strategy to sensitize aggressive/highly proliferative hematologic neoplasms to anti-neoplastic therapy.

No relevant conflicts of interest to declare.