The Departments of Immunology, Medical Oncology and Pathology have in close cooperation performed high quality lymphoma research for several years (see Doctoral thesis), focusing on:
- Phenotypic studies of B-cell lymphomas
- Regulation of cell cycle activation and progression in normal and neoplastic B-lymphocytes
- Functional studies on hematopoietic stem cell and early B-cell differentiation
- Molecular studies on B-cell lymphomas
- Basic biological studies of lymphoid cells
- Lymphoma pathology: new entities
- Tumor immunology, searching for tumor antigens as targets for vaccine strategies
Phenotypic and functional studies of normal and neoplastic B-lymphoid cells
Already from the late 1970es, lymphoma tissue has been snap frozen and kept in a lymphoma tumour bank for diagnostic and research purposes. In addition, lymphoma cell suspensions were made from the same time period and kept in liquid nitrogen, being the basis for lymphoma biology research leading to several Doctoral theses. The cell suspensions were thawned and different entities of lymphomas were caracterized phenotypically by immunofluorescence and flow cytometry and the findings were correlated to treatment response and patient survival. Furthermore, in vitro studies were performed, caracterizing intracellular signal transduction pathways of cell cycle stimulatory and inhibitory factors. Stimulatory and inhibitory agents studied include interleukins, cytokines, cAMP analogues, retinoids and various monoclonal antibodies against B-cell antigens. Signal transduction pathways studies include protein kinases, Ca++/PI cycle activation and expression of proto-oncogenes and tumor suppressor genes. Novel cell cycle regulators identified in the Dept of Immunology are being characterized as well as novel B-cell antigens.
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. Large-scale analyses will help to identify novel pathways involved in lymphomagenesis and discern distinct subgroups of lymphomas based on a biological understanding of the pathogenesis of distinct subgroups identified by their expression profile. The detailed functional analysis of selected genes identified by interesting expression profiles (i.e. the BMP6 gene product) provide a basic platform for the development of new therapeutic strategy based on this biological insight. This is presently an important area of research in the Depts of Immunology and Pathology.
Hematopoietic stem cell and B-lymphopoietic studies
One of the main research interests for the Dept. of Immunology is hematopoietic stem cell and early B-cell lymphopoiesis. The in vitro purging method with immunomagnetic beads (Dynabeads) was first described at by Smeland, Funderud and Kvalheim. The method has been the basis for characterization of various highly purified progenitor cells subgroups. Specifically, the effects of various cytokines and interleukins on proliferation, differentiation and apoptosis have been studied in detail in several doctoral theses from the Department.
In the late 1980ies the purging methodology using immunomagnetic beads was scaled up and introduced in the clinics in the setting of high dose therapy; the autologous grafts were purged, removing lymphoma cells efficiently before stem cell re-infusion (see also high dose therapy).
In the past two decades, there have been major advances in our understanding of the pathogenesis and biology of lymphoid malignancies. Many molecular abnormalities or markers with significant diagnostic or prognostic importance have been identified, such as the activation of oncogenes through specific translocations and other mechanisms, the inactivation of tumor suppressor genes (TSGs) and abnormalities in the apoptotic pathways. Modern molecular diagnostics, therefore, serve not only as an aid to render a diagnosis, but also should measure parameters that are relevant to the biologic and clinical behaviour of a tumour. Traditionally, the investigation and measurement of these parameters have been performed individually, rather than globally. With the development of DNA-microarray technology for large scale gene expression profiling, it is now possible to obtain a comprehensive genome-wide picture of gene expression alterations associated with normal or disease processes. Recognizing the potential of this technology when coupled with a large tumour/clinical resource, the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) has been created with a consortium of 8 institutions, including the Norwegian Radium Hospital, devoted to the study of lymphoid malignancies. Our goals are to establish a new molecular diagnosis of human lymphoid malignancies using gene expression profiling, to elucidate the oncogenic pathways that result in malignant transformation of normal B lymphocytes, and to relate gene expression to clinical outcome, thereby establishing useful prognostic indicators and identifying potential targets for new therapies.
Important findings so far, being published in highly meritied journals, may be summarized:
- Diffuse Large B-Cell Lymphomas (DLBCL) may be subdivided by gene expression profiling into three signatures with independent prognostic value.
- A subgroup of DLBCL occuring in the anterior mediastinum often in young females, has a characteristic gene expression profile with significant similarity to Hodgkin lymphoma derived cell lines.
- Mantle cell lymphomas, beeing one of the lymphoma entities with the most dismal prognosis, can also be characterized by molecular profiling into groups with different prognosis. Different from the DLBCL, RNA expression of cell cycle related proteins was the only signature with effect on patient prognosis.
- Follicular lymphomas, characterized clinically by an indolent, often spontanously fluctuating course. Interstingly, by molecular profiling, the two signatures with independent prognostic value derived from the reactive cells (one signature from reactive lymphocytes was correlated to a good prognosis, the other from macrophage/monocyte was correlated to a dismal prognosis), not from the tumor cells.
- Potential targets for new therapies have been identified, and preclinical studies are ongoing.
Lymphoma pathology research