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Harald StenmarkHåvard E. DanielsenKnut Liestøl Ragnhild A. LotheAntoni WiedlochaKirsten SandvigErlend B. Smeland
The transformation of normal cells to cancer cells is closely related to control mechanisms for cell growth and cell death. The understanding of how different factors participate in these processes is therefore of crucial importance. We study the functional role of the BMP/TGF-β pathways in normal and neoplastic B cells. In these studies, we use a broad selection of cell lines representing various subgroups of B cell lymphomas, and we have access to tumour samples and different subsets of normal B cells for comparison.
TGF-β family members are structurally related secreted cytokines, which include TGF-β isoforms, activins and bone morphogenetic proteins (BMPs). They are multi-functional cytokines involved in many aspects of cell function including proliferation, apoptosis, differentiation, and morphogenesis. BMPs signal by activating Smad proteins, which translocate to the nucleus where they regulate transcription of target genes
During the past years epigenetic changes have been increasingly recognised as an important mechanism for altered gene expression in malignant cells, and they have been suggested to be even more common than genetic changes in human cancer. Epigenetics include mechanisms that influence expression of a gene without permanently changing the DNA, and the most studied mechanism is transcriptional inactivation of tumor-suppressor genes due to hypermethylation of promoter regions. Altered DNA methylation patterns may serve as biomarkers for cancer detection, assessment of prognosis, and prediction of response to therapy. Importantly, this is also of therapeutic interest, as methylation is potentially reversible with demethylating agents.
In this project we want to identify methylated genes in lymphomas by comparing data from several lymphoma cell lines and primary biopsies. Changes in methylation status after treatment with demethylation agents will be assayed by microarry studies and correlated to gene expression profiling data from lymphoma subtypes. Our aim is to identify marker genes for early lymphoma development and for the different subtypes of lymphomas in order to start early a suitable treatment.
Follicular lymphoma (FL) is one of the most common types of lymphoma, comprising about one third of adult non-Hodgkin’s lymphomas in Western populations. The clinical course is relatively indolent with a median survival of 7-10 years. FL in advanced stages is currently an incurable disease clinically characterized by waxing and waning lymph node tumors, bone marrow failure and reduced performance status. The patients may go through several treatment regimens with initial effect, but eventually the disease becomes chemoresistant. The course of the disease is strikingly variable indicating that the histologically well-defined FL composes biologically heterogeneous subtypes. In 25-60% of the patients the FL transforms to a more aggressive lymphoma, usually diffuse large B cell lymphoma (DLBCL). However, many patients also experience progressive disease or relapse without transformation to a more aggressive phenotype (see figure). The aims of the study are to i) identify chromosomal aberrations that are associated with progression and relapse of follicular lymphoma, and ii) identify specific chromosomal aberrations that are associated with an indolent or aggressive disease course. We use array comparative genome hybridization (CGH) to examine genomic alterations in serial biopsies from patients with relapsing and progressing FL. The genome-wide analysis is performed on the in-house CGH arrays, which comprise approximately 4.000 BAC/PACs in duplicate and has a high resolution of 1Mb. The genetic aberrations will be correlated to clinical parameters.
In 25-60% of the patients the follicular lymphoma (FL) transforms to a more aggressive lymphoma, usually diffuse large B cell lymphoma (DLBCL), an event that represents the outgrowth of a more malignant subclone (Figure 2). Transformation is usually associated with a rapidly progressive clinical course, refractoriness to treatment, and short survival. Several secondary genetic abnormalities have been associated with this histological transformation of FL, including rearrangements of the MYC gene, mutations of the P53 tumor suppressor gene, of the BCL6 gene and of the translocated BCL2 gene, and inactivation of the P16 and P15 genes by deletion, mutation, and hypermethylation. However, these alterations are each observed in only a subset of transformed lymphomas, suggesting that the process of histological transformation can occur by multiple different mechanisms. The aim of this study is to identify changes in protein expression that are linked to transformation and correlate protein expression with clinical parameters. We will also investigate if the tumour microenvironment is of crucial importance, as previously implicated from gene expression profiling. This study is part of a larger prospective study in transformed lymphomas (chaired by Harald Holte and Jan Delabie), examining the effect of high-dose therapy (HDT) with autologous stem cell support in patients who obtain remission on conventional salvage chemotherapy.
In cooperation with Harald Holte, we are also involved in an ongoing Nordic Lymphoma Group – phase II study on diffuse large B-cell lymphomas (DLBCL) with adverse clinical risk profile (International Prognostic Index score 2 – 3 of 3 possible). The patients are treated with intensified treatment (CHOEP14 plus Rituximab) followed by high dose iv CNS chemo-prophylaxis, and the results will be compared to historical controls from a previous Nordic phase III study.