Postepy Hig Med Dosw. (online), 2013; 67: 553-559
Original Article
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Increased expression of PIM-2 and NF-κB genes in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) is associated with complete remission rate and overall survival
Zwiększona ekspresja genów PIM-2 i NF-κB u chorych z ostrą białaczką szpikową i limfoblastyczną wykazuje związek z remisją całkowitą i przeżyciem
Katarzyna Kapelko-Słowik1  ABDEFG, Donata Urbaniak-Kujda1  BDE, Dariusz Wołowiec1  EF, Bożena Jaźwiec1  BF, Jarosław Dybko1  C, Jacek Jakubaszko2  B, Mirosław Słowik3  BE, Kazimierz Kuliczkowski1  AG
1Department of Hematology, Neoplastic Blood Disorders and Bone Marrow Transplantation Wroclaw Medical University, Wroclaw, Poland
2Department of Cardiosurgery, Wroclaw Medical University, Wroclaw, Poland
3Department of Ophthalmology, Wroclaw Medical University, Wroclaw, Poland
Corresponding author
Katarzyna Kapelko-Słowik, M.D., Ph.D, Wroclaw Medical University, Department of Hematology, 4 Pasteur St., 50-367 Wroclaw, Poland; e-mail:

Authors' Contribution:
A - Study Design, B - Data Collection, C - Statistical Analysis, D - Data Interpretation, E - Manuscript Preparation, F - Literature Search, G - Funds Collection

Received:  2012.12.18
Accepted:  2013.04.08
Published:  2013.06.07

Introduction: PIM-2 is a proto-oncogene that encodes for a serine/threonine kinase that interacts with various signaling molecules. PIM-2 is highly expressed in neoplastic tissues and in leukemic and lymphoma cell lines, which is consistent with its role during oncogenic transformation. The nuclear factor kappa B (NF-κB) pathway appears to be deregulated in a variety of tumors, with sustained activ­ity of NF-κB leading to apoptotic resistance in tumor cells. The aim of this study was to investigate whether expression of PIM-2 and NF-κB is altered in acute myeloid leukemia (AML) and acute lym­phoblastic leukemia (ALL).

Patients and methods: One hundred forty-three patients were included: 91 with AML and 52 with ALL, aged 18-84 (median 46.7). Eighty-three patients (51 AML and 32 ALL) reached complete remission (CR). Bone marrow samples were collected at the time of diagnosis. Control samples were obtained from 24 healthy donors. We analyzed PIM-2 and NF-κB εxpression by RQ-PCR analysis.
Results: Expression of both PIM-2 and NF-κB genes in all leukemic patients and both subgroups AML and ALL was significantly higher than in controls. AML patients who reached CR expressed PIM-2 and NF-κB at significantly lower levels than patients with primary resistance to chemo­therapy who did not reach CR (NCR). Survival analysis revealed that in AML patients, higher expression of PIM-2 was related to significantly shorter patients' overall survival (OS).
Conclusion: Our data indicate that increased expression of PIM-2 and NF-κB genes may be involved in patho­genesis of AML and ALL. Moreover, high PIM-2 expression could be associated with CR rate and OS in AML patients.
Key words: acute myeloid leukemia • acute lymphoblastic leukemia • PIM-2 • NF-kB

Inhibition of apoptosis is one of the most important phenomena inducing accumulation of neoplastic cells in leukemia patients. Despite extensive research, intra­cellular events leading to prolongation of cell life and resistance to pro-apoptotic factors are still not clearly defined. In recent years, the search for such events led to focusing on an anti-apoptotic factor, PIM-2 (Proviral integration of Moloney virus-2). PIM-2, along with PIM-1 and PIM-3, belongs to a serine/threonine kinase fam­ily encoded by proto-oncogenes PIM-2 PIM-1 and PIM-3 [2,7,26]. PIM-2 gene expression is regulated at both the mRNA and protein levels by numerous cytokines (es­pecially IL-3) involved in maturation of hematopoietic cells [13], and as such, kinase PIM-2 plays an important role in growth, differentiation, and survival of these cells. Its action is synergistic with another independent pro-survival pathway, PI3K/AKT/m-TOR. Murine model analyses led to the conclusion that incapacity of one of these pathways may be, at least partially, compensated by activities of the other [16].
The elevated expression of PIM-2 was confirmed in human primary solid tumor cell lines (G361, A-549, SW-480) as well as hematological cell lines (HL-60, K-562, RAIJ) [4,24]. Alterations in PIM-2 gene expression regulation were also shown in cells derived from prostate cancer and in some lymphatic system neoplasms [10,11,27]. Nuclear factor kappa B (NF-κB) is a key regulator of cell survival and differentiation [21]. In the inactive state NF-κB proteins occur as homodimeric or heterodimeric complexes in the cytoplasm bound to IκB proteins. After stimulation IκB is phosphorylated, ubiquitinated and degraded, which allows translocation of NF-κB to the nucleus and tran­scription of NF-κB targeted genes including many genes associated with cell survival: XIAP, and cellular inhibi­tors of apoptosis such as FLIP, A1, BCL-2, and BCL-XL. The NF-κB pathway appears to be deregulated in a variety of tumors, with sustained activity of NF-κB leading to apoptotic resistance in tumor cells [20,22]. There is evi­dence that leukemic transformation of the FL5.12 lym­phoid cells expressing Pim-2 transgene is dependent on NF-κB activation [17]. Similar observation on the PIM-2 dependence on NF-κB activity has been found in human hepatocellular carcinoma cells as well [28]. So far, limited data regarding PIM-2 and NF-κB gene expression in acute leukemias are available. Significant levels of PIM-2 mRNA were seen in primary blasts from patients with acute my­eloid leukemia [25].
The aim in our study was to assess PIM-2 and NF-κB ex­pression in bone marrow samples collected from AML and ALL patients and to determine the correlation with clinical data and the outcome of induction treatment. Our promising preliminary data indicate increased levels of PIM-2 mRNA as well as a relationship between PIM-2 ex­pression and CR rate in patients with AML compared with normal controls [19].
Patients, Cell lines and Methods
One hundred forty-three patients were included: 91 with AML and 52 with ALL, aged 18-84 (median 46.7). Eighty-three patients (51 AML and 32 ALL) reached complete remission (CR). Bone marrow samples were collected at the time of diagnosis. Leukemic bone marrow blasts ac­counted for more than 80% of the total cellularity, espe­cially after Ficoll separation. Control samples were ob­tained from 24 healthy donors.
Clinical characteristics of patients and controls included in this study are given in Table 1. All of the patients un­derwent induction remission treatment according to the PALG (Polish Acute Leukemia Group) program for AML and ALL [14,18]. Patients were included in the study from January 1999 to June 2010, and they were observed dur­ing the period of 1 to 340 months (mean: 18 months). Complete remission was diagnosed according to standard criteria [9]. The control group consisted of 24 hematologi­cally healthy bone marrow donors matching age and sex of the patients.
Human leukemic cell lines K-562, HL-60 and SD-1 were used as positive controls regarding expression of the ex­amined genes.
Real-time PCR (RT-PCR)
Bone marrow was obtained from patients at diagnosis. Bone marrow mononuclear cells (BMNCs) were separated by centrifugation on Gradisol L (AquaMedica, Poland).
Total RNA was isolated from 5-10x106 BMNC using TriRe­agent® Solution (Ambient/Applied Biosystems) according to the manufacturer's protocol. DNA was removed from isolated RNA samples by DNase treatment using DNA-freeTM reagent (Ambient/Applied Biosystems). Two mi­crograms of RNA were reverse transcribed to cDNA with High Capacity cDNA Reverse Transcription Kit (Applied Biosystems) according the manufacturer's protocol. Ex­pression of PIM-2 and NF-κB genes was assessed on a 7500 Real Time PCR System (Applied Biosystems) with Taq­Man real-time reverse transcription-polymerase chain reaction (RT-PCR) assay using inventoried TaqMan Gene Expression Assays Hs00179139_m1 and Hs00231653_m1 from Applied Biosystems. The beta-glucuronidase gene (GUS) was used as an internal control (TaqMan Gene Ex­pression Assay Hs99999908_m1) [5].
The relative gene expression was calculated as the differ­ence between the Ct values of PIM-2 and NF-κB, and GUS control (ΔCt) and expressed as 2-ΔCt for statistical analysis.
Statistical analysis
Statistical analysis was performed using Mann-Whitney U test for independent samples. The correlation between quantitative variables was tested with Spearman's rank correlation test. Survival analysis was performed with Kaplan-Meier test.
Expression of PIM-2 and NF-κB genes
In leukemic patients either considered as a whole group (AML+ALL) or stratified into AML and ALL subgroups, the median expression of both PIM-2 and NF-κB genes was sig­nificantly higher than in controls (Fig. 1, Fig. 2 and Table 1, Table 2). Only in AML patients who obtained CR was the median expression of PIM-2 and NF-κB significantly lower than in patients who did not respond to induction treatment (Fig. 3, Fig. 4 and Table 2). The relationship of both PIM-2 and NF-κB mRNA levels with response to in­duction therapy was not seen in the ALL group. No sig­nificant differences were observed between AML and ALL subgroups (Table 2) and between particular subgroups stratified according to the FAB classification in AML and ALL patients (data not shown).
Figure 1. Comparison of PIM-2 gene expression between AML and ALL patients and control group

Figure 2. Comparison of NF-κB gene expression between AML and ALL patients and control group

Table 1. Clinical data of patients and controls (AML-acute myeloid leukemia, ALL - acute lymphoblastic leukemia, F - females, M - males, CR - complete remission, NCR - no complete remission, HR - high risk group, IR - intermediate risk group, SR - standard risk group, Hb - concentration of hemoglobin, WBC - white blood cells, PLT - platelets, g/dL - gram/deciliter, G/L - Giga/liter, SD - standard deviation, M0 - minimally differentiated acute myeloid leukemia, M1 - acute myeloid leukemia without maturation, M2 - acute myeloid leukemia with maturation, M4 - acute myelomonocytic leukemia, M5a - acute monoblastic leukemia, M5b - acute monocytic leukemia, M6 - erythroleukemia)

Table 2. Median expression of PIM-2 and NF-κB genes in patients and controls (AML - acute myeloid leukemia, ALL - acute lymphoblastic leukemia, CR - complete remission, NCR - no complete remission)

Figure 3. PIM-2 gene expression among AML patients stratified according to treatment response (CR - complete remission, NCR - not complete remission)

Figure 4. NF-κB gene expression among AML patients stratified according to treatment response (CR - complete remission, NCR - not complete remission)

For AML patients, a positive correlation between PIM-2 and patient age (R=0.23, p=0.02) was observed. There was no cor­relation between PIM-2 or NF-κB expression and absolute leu­kemic cell count in peripheral blood, hemoglobin concentra­tion, platelet count or presence of chromosomal aberrations.
PIM-2 and NF-κB expression was additionally assessed in K-562, HL-60, and SD-1 leukemic cell lines, and was found to be significantly higher than in the control group, and was comparable to values obtained in leukemic patients (data not shown).
Survival analysis
In univariate analysis, a difference in overall survival be­tween the AML patients with expression of PIM-2 below and above the median value (estimated at 0.77) was ob­served (p=0.0377) (Fig. 5). Such a difference was not ob­served in AML patients with respect to NF-κB expression.
Figure 5. Cumulative overall survival among AML patients stratified by PIM-2 gene expression. Patients were stratified as above or below the median value of PIM-2 gene expression (0.77)

The analyses of cell lines and some studies carried out on lymphoma cells indicated that increased PIM-2 ex­pression may be involved in the pathogenesis of hemato­logical malignancies. In fact, PIM-2 expression was found to be increased at both the mRNA and protein levels in chronic lymphocytic leukemia, follicular lymphoma, and diffuse large B-cell lymphoma compared to normal cells [10]. Recent data revealed that PIM-2 kinase inhibitor was able to induce apoptosis in CLL and myeloma cells, thus suggesting its anti-apoptotic function [3,8]. There­fore recently, interest in cancer research has focused on PIM-2 serine/threonine kinase, whose expression is regu­lated by hematopoietic cytokines, such as IL-3. Growth factor-induced increase in PIM-2 expression suppress­es apoptosis and promotes cell survival in hematologic malignancies and solid tumors [6,13]. These events are consequences of PIM-2-mediated phosphorylation of the factors involved in apoptosis signaling, thus conferring apoptotic resistance in the neoplastic cells [23,31]. Yet, the influence of PIM-2 activity on cellular proliferation is still controversial.
In addition, a strong interrelation of PIM-2 and NF-κB path­ways in both leukemo- and tumorigenesis has been dem­onstrated. A key role of NF-κB in the PIM-2 pathway has been reported by Hammerman et al. in a mouse model of lymphoma and by Ren et al. in human hepatocellular car­cinoma [17,28]. PIM-2 kinase activates apoptosis inhibitor 5 (API-5), which is a downstream factor for NF-κB. More­over, apoptosis triggered by high PIM-2 expression could be reversed by NF-κB repressor [28]. So far, there are only a few publications regarding the role of these two factors in the development of acute leukemias in humans. A recent report by Adam et al. on hematopoietic cells transformed by FLT3-ITD (FMS-like tyrosine kinase 3-internal tandem duplication) and BCR/ABL mutations, which are frequently expressed in AML and ALL, demonstrated that the sup­pression of PIM-1 and PIM-2 expression led to a significant decrease in cell survival and immortality [1]. Mizuki et al. observed that PIM-2 mRNA was significantly induced in the AML samples [25]. Moreover, Tamburini et al. found that PIM-2 kinase was constitutively expressed in AML blasts, but was barely detectable in normal CD34+ hematopoietic progenitors [30]. Therefore, we performed comparative analysis of PIM-2 and NF-κB gene expression in bone mar­row of AML and ALL patients and in normal hematopoietic cells. We found that levels of PIM-2 and NF-κB transcripts were significantly and similarly higher in bone marrow cells of acute leukemia patients as well as in HL-60, K562, and SD-1 leukemic cell lines compared to normal cells. The current study is in accordance with the previous report conducted on pre-B-derived murine cell line FL5.12, indi­cating that lymphoid cells transfected with Pim-2 kinase demonstrated longer survival [17]. High PIM-2 expression (both at the mRNA and at the protein level) was also dem­onstrated by Gong et al. in human hepatocellular cancer cells (HepG2). After PIM-2 knock-down, the cancer cells lost survival ability in IL-3 starvation medium [15]. On the other hand, Dai JM et al. observed that antisense oligo­nucleotides against PIM-2 induce a significant decrease in the proliferating fraction of the DU-145 human prostate cancer cell line, at least in part, due to the inhibition of cell cycle progression in G1 phase [12]; no signs of apop­tosis of the tumor cells were also seen in this report. In contrast, Zhang et al. observed an increase of the apopto­sis rate after silencing of PIM-2 gene expression by siRNA (small-interfering RNAs) in the human colon cancer cell line SW-480, which proved its anti-apoptotic action [32]. Also, recent data revealed that PIM-2 kinase inhibitor was able to induce apoptosis in CLL and myeloma cells [3,8].
An important observation of our study was that PIM-2 and NF-κB gene expression was found to be lower in pa­tients with AML who reached CR in comparison to the AML group, in which induction treatment was ineffec­tive. Our finding of a PIM-2 relationship with the clinical outcome is in line with a recent report of Rubenstein et al., who observed higher levels of PIM2 mRNA in recur­rent CNS lymphomas refractory to rituximab [29]. Based on the fact that PIM-2 and NF-κB promote cell survival in leukemic hematopoiesis, our observation points to the possibility that their high expression decreases blast cell sensitivity to apoptosis, including cell death induced by cytotoxic drugs. In addition, our results showed that the lower PIM-2 expression in AML blasts corresponded with patients' overall survival, suggesting its possible prog­nostic significance.
In the current study, we found that expression of PIM-2 and NF-κB genes was significantly increased in patients with AML and ALL, confirming their important role in the pathogenesis of acute leukemias. The high expression of the PIM-2 gene was associated with a lower complete remission rate and worse overall survival. Although the latter relationship was revealed in univariate analysis in patients with AML only, it may suggest relevance of PIM- 2 expression as a possible prognostic factor in patients with acute leukemias. Nevertheless, it is possible that the capacity of PIM-2 and NF-κB to protect blast cells against cytostatic drug-driven eradication requires cooperation with other anti-apoptotic intracellular factors, and needs further studies.
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The authors have no potential conflicts of interest to declare.