Increased Expression of thehPim-2Gene In Human Chronic lymphocytic Leukemia and Non-Hodgkin Lymphoma

Abstract

Pim-1 and Pim-2 are murine proto-oncogenes implicated in lymphomagenesis. The aim of this study was to investigate whether the human Pim-2 (hPim-2) expression is altered in chronic lymphocytic leukemia (B-CLL) and non-Hodgkin's lymphomas (NHL). We analyzed hPim-2 expression in 48 patients with NHL and CLL by quantitative in-situ hybridization, quantitative RT-PCR and FACS analysis. In-situ hybridization revealed a 5.5 +/- 2.2 times higher expression of hPim-2 in NHL over normal lymphocytes (P < 0.001). Similarly, with quantitative RT-PCR, expression in NHL was 1.5 to 2.6 times higher in involved splenic foci compared to nearby uninvolved regions (n = 3). hPim-2 mRNA was increased 3-folds in B-CLL over normal B-cells (P < 0.006). The increased hPim-2 levels correlated with lymphocyte doubling time (DT), in that mRNA levels were two times greater in patients with rapid DT (P < 0.006). Moreover, a significant correlation was found between hPim-2 expression and the Binet staging system of CLL (P < 0.022). The hPIM-2-protein expression was also upregulated in CLL, as assessed by FACS analysis. Therefore, this report provides direct evidence for a linkage of hPim-2 upregulation to NHL and CLL in man. This relationship between hPim-2 and NHL and CLL raises a number of novel mechanistic options for the genesis and/or progression of some types of human lymphomas.

Gene expression signatures separate B-cell chronic lymphocytic leukaemia prognostic subgroups defined by ZAP-70 and CD38 expression status

“…In line with data published by Cohen et al, 31 our RQ-PCR analysis in PBMCs from 94 CLL patients (and in 45 highly purified CLL samples) revealed significantly higher Pim2 expression levels in B-CLL cells as compared to normal donor-derived PBMCs. Pim2 mRNA concentrations in ZAP-70 þ CD38 þ B-CLL cells were significantly higher as compared to ZAP-70 À CD38 À samples when purified cells were tested.…”

“…27 Acting synergistically with CMYC and NMYC in generating T-and B-cell lymphomas, the precise role of Pim2 in lymphomagenesis remains to be elucidated. [28][29][30][31][32] Thus, based on the data initially reported by Cohen et al 31 and the results presented herein Pim2 could serve as a promising target for the development of a novel treatment strategy in B-CLL.…”

“…Our results are confirmatory of findings in a series of 48 non-Hodgkin's lymphoma and B-CLL cases where a correlation of Pim2 expression levels in B-CLL cells with lymphocyte doubling time and Binet stage was reported and expand these to a larger patient cohort. 31 Pim2 functions as an inhibitor of apoptosis and is transcriptionally regulated by a variety of proliferative signals, promoting cell survival by inducing NF-kB-dependent gene expression. 27 Acting synergistically with CMYC and NMYC in generating T-and B-cell lymphomas, the precise role of Pim2 in lymphomagenesis remains to be elucidated.…”

“…[27][28][29] Deregulation of Pim2 expression has been documented in several human malignancies including leukaemia, lymphoma and also B-CLL. [30][31][32] Pim2 mRNA expression was measured by real-time quantitative reverse transcriptase-PCR (RQ-PCR) in 94 patients using PBMC obtained from healthy individuals as a reference with an expression level of one. Overall, Pim2 was found to be expressed at 12-fold higher levels in B-CLL samples than in normal PBMC with a distribution range from 0.9 to 56.2 (data not shown).…”

PIM Kinases Are Essential for Chronic Lymphocytic Leukemia Cell Survival (PIM2/3) and CXCR4-Mediated Microenvironmental Interactions (PIM1)

“…Overexpression of PIM kinases has been shown in various hematologic malignancies such as diffuse large B-cell lymphoma (27), CLL (PIM2; ref. 28), and FLT3-associated acute myelogenous leukemia (AML; ref. 29) as well as in some solid tumors (30).…”