The PIM1 Oncogene Accelerates TCL1 Driven Lymphomagenesis in a Double-Transgenic Murine Model.

Abstract

Previously, we identified and validated PIM-1 as a differentially expressed gene in mantle cell lymphoma (MCL) patient samples. Further, we have shown PIM-1 to be a significant prognostic biomarker in MCL. PIM-1 is an oncogenic serine/threonine kinase that is transcriptionally regulated by cytokines, mitogens, and numerous growth factors. It cooperates with other oncogenes in tumorigenesis and has been implicated in the development of leukemias, lymphomas, late progression events, and most recently in prostate cancer. PIM-1 is overexpressed in aggressive lymphomas, such as the blastoid variant of MCL, and the ABC-type of DLBCL. Here we tested the in vivo cooperation of PIM-1 with TCL1 in murine lymphomagenesis by producing double transgenic murine strains. PIM-1 transgenic mice overexpress murine PIM-1 under the control of the immunoglobulin enhancer Eμ. TCL1 transgenic mice (pEμ -B29-TCL1) fail to downregulate TCL1 expression in mature B and T cells and provide a unique model for mature B-cell malignancies, including Burkitt-like lymphoma (BLL), DLBCL, marginal zone lymphoma, and B-cell chronic lymphocytic leukemia. We hypothesized that PIM-1 would either accelerate TCL1-driven lymphomagenesis, result in the development of immature lymphomas, or both. Lymphoid malignancies were examined by immunohistochemistry and flow cytometry and classified according to the mouse models of human cancer consortium (MMHCC) ‘Bethesda’ classification scheme. Forty double transgenic mice (PIM-1/TCL1) have been generated and observed for a median follow-up of 9 months. To date, 8/40 (20 %) of the PIM-1/TCL1 mice developed lymphomas, in contrast to 9/88 (10%) PIM-1 and 11/49 (22%) TCL1 transgenic mice, with a median follow-up of 7 and 15 months, respectively. A Kaplan-Meyer plot demonstrated statistically significant acceleration of lymphomagenesis in the PIM-1/TCL1 transgenic mice when compared with single TCL1 transgenic mice (p=0.037). PIM-1 transgenic mice developed early (< 7 months of age) T-cell lymphoblastic lymphomas and late (> 20 months of age) DLBCL. TCL1 transgenic mice developed DLBCL, with single occurrences of lymphoblastic, lymphocytic and Burkitt lymphomas. PIM-1/TCL1 transgenic mice developed DLBCL, frequently with extranodal involvement (spleen, liver and lung). A single case of follicular lymphoma was seen. In addition, endogenous expression of PIM kinase family members was investigated in a human lymphoma cell line bank (n=40) by quantitative real-time PCR. PIM-1, PIM-2, and also PIM-3 were found to be overexpressed in cell lines derived from human lymphoid malignancies of multiple histologies. In summary, aberrant PIM-1 overexpression in TCL1 transgenic mice accelerated the development of mature B-cell lymphomas. To date, the classification of lymphomas in PIM-1/TCL1 mice revealed similar histologies as in TCL1 single transgenic mice, mainly DLBCL. The expression of all 3 PIM kinase family members in lymphomas implies that pan-PIM kinase inhibitors should be developed as a potential mechanism of resistance to more restricted PIM inhibitors could be compensatory overexpression of the non-targeted family members.