Gain of chromosome 6p is an infrequent cause of increased PIM1 expression in B-cell non-Hodgkin's lymphomas

Sivertsen, Einar Andreas; Galteland, Eivind; Mu, David; Holte, Harald; Meza‐Zepeda, Leonardo A.; Myklebost, Ola; Patzke, Sebastian; Smeland, Erlend B.; Stokke, Trond

doi:10.1038/sj.leu.2404094

Cited by 13 publications

(9 citation statements)

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“…The DI of the lymphomas and cervical cancers and the tumor cell fraction of the lymphomas were determined by use of flow cytometry, and most of these data have been published earlier [ 14 , 23 , 25 ]. The lymphoma cells were labeled with phycoerythrin-labeled antibodies to the tumor characteristic light chains for identifying the tumor cells and Hoechst 33258 for assessment of DNA content.…”

Section: Methodsmentioning

confidence: 99%

GeneCount: genome-wide calculation of absolute tumor DNA copy numbers from array comparative genomic hybridization data

et al. 2008

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Absolute tumor DNA copy numbers can currently be achieved only on a single gene basis by using fluorescence in situ hybridization (FISH). We present GeneCount, a method for genome-wide calculation of absolute copy numbers from clinical array comparative genomic hybridization data. The tumor cell fraction is reliably estimated in the model. Data consistent with FISH results are achieved. We demonstrate significant improvements over existing methods for exploring gene dosages and intratumor copy number heterogeneity in cancers.

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Section: Methodsmentioning

confidence: 99%

GeneCount: genome-wide calculation of absolute tumor DNA copy numbers from array comparative genomic hybridization data

et al. 2008

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“…PIM1 was identified as a non-immunoglobulin (IG)/BCL6 translocation partner gene and 6p21, its chromosomal locus, was amplified in B-cell lymphomas [10,11]. PIM1 is also known to be a target locus for aberrant somatic hypermutation in some lymphomas [12-15].…”

Section: Introductionmentioning

confidence: 99%

Pim1 promotes human prostate cancer cell tumorigenicity and c-MYC transcriptional activity

2010

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BackgroundThe serine/threonine kinase PIM1 has been implicated as an oncogene in various human cancers including lymphomas, gastric, colorectal and prostate carcinomas. In mouse models, Pim1 is known to cooperate with c-Myc to promote tumorigenicity. However, there has been limited analysis of the tumorigenic potential of Pim1 overexpression in benign and malignant human prostate cancer cells in vivo.MethodsWe overexpressed Pim1 in three human prostate cell lines representing different disease stages including benign (RWPE1), androgen-dependent cancer (LNCaP) and androgen-independent cancer (DU145). We then analyzed in vitro and in vivo tumorigenicity as well as the effect of Pim1 overexpression on c-MYC transcriptional activity by reporter assays and gene expression profiling using an inducible MYC-ER system. To validate that Pim1 induces tumorigenicity and target gene expression by modulating c-MYC transcriptional activity, we inhibited c-MYC using a small molecule inhibitor (10058-F4) or RNA interference.ResultsOverexpression of Pim1 alone was not sufficient to convert the benign RWPE1 cell to malignancy although it enhanced their proliferation rates when grown as xenografts in vivo. However, Pim1 expression enhanced the in vitro and in vivo tumorigenic potentials of the human prostate cancer cell lines LNCaP and DU145. Reporter assays revealed increased c-MYC transcriptional activity in Pim1-expressing cells and mRNA expression profiling demonstrated that a large fraction of c-MYC target genes were also regulated by Pim1 expression. The c-MYC inhibitor 10058-F4 suppressed the tumorigenicity of Pim1-expressing prostate cancer cells. Interestingly, 10058-F4 treatment also led to a reduction of Pim1 protein but not mRNA. Knocking-down c-MYC using short hairpin RNA reversed the effects of Pim1 on Pim1/MYC target genes.ConclusionOur results suggest an in vivo role of Pim1 in promoting prostate tumorigenesis although it displayed distinct oncogenic activities depending on the disease stage of the cell line. Pim1 promotes tumorigenicity at least in part by enhancing c-MYC transcriptional activity. We also made the novel discovery that treatment of cells with the c-MYC inhibitor 10058-F4 leads to a reduction in Pim1 protein levels.

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“…A subgroup of the activated B-cell (ABC) type of DLBCL demonstrated increased PIM1 mRNA levels, which correlated with poor prognosis (Alizadeh et al , 2000; Sivertsen et al , 2006). In addition, PIM2 was reported to be upregulated during the progression of several B-cell malignancies, including chronic lymphocytic leukaemia, DLBCL, mantle-cell lymphoma and plasma-cell myeloma (Cohen et al , 2004).…”

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confidence: 99%

PIM kinases are progression markers and emerging therapeutic targets in diffuse large B-cell lymphoma

et al. 2012

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Background: PIM serine/threonine kinases are often highly expressed in haematological malignancies. We have shown that PIM inhibitors reduced the survival and migration of leukaemic cells. Here, we investigated PIM kinases in diffuse large B-cell lymphoma (DLBCL) biopsy samples and DLBCL cell lines. Methods: Immunohistochemical staining for PIM kinases and CXCR4 was performed on tissue microarrays from a cohort of 101 DLBCL cases, and the effects of PIM inhibitors on the survival and migration of DLBCL cell lines were determined. Results: PIM1 expression significantly correlated with the activation of signal transducer and activator of transcription (STAT) 3 and 5, P-glycoprotein expression, CXCR4-S339 phosphorylation, and cell proliferation. Whereas most cases exhibited cytoplasmic or cytoplasmic and nuclear PIM1 and PIM2 expression, 12 cases (10 of the non-germinal centre DLBCL type) expressed PIM1 predominately in the nucleus. Interestingly, nuclear expression of PIM1 significantly correlated with disease stage. Exposure of DLBCL cell lines to PIM inhibitors modestly impaired cellular proliferation and CXCR4-mediated migration. Conclusion: This work demonstrates that PIM expression in DLBCL is associated with activation of the JAK/STAT signalling pathway and with the proliferative activity. The correlation of nuclear PIM1 expression with disease stage and the modest response to small-molecule inhibitors suggests that PIM kinases are progression markers rather than primary therapeutic targets in DLBCL.

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Gain of chromosome 6p is an infrequent cause of increased PIM1 expression in B-cell non-Hodgkin's lymphomas

Cited by 13 publications

References 8 publications

GeneCount: genome-wide calculation of absolute tumor DNA copy numbers from array comparative genomic hybridization data

GeneCount: genome-wide calculation of absolute tumor DNA copy numbers from array comparative genomic hybridization data

Pim1 promotes human prostate cancer cell tumorigenicity and c-MYC transcriptional activity

PIM kinases are progression markers and emerging therapeutic targets in diffuse large B-cell lymphoma

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