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Multiple Myeloma Research

Multiple myeloma (MM) represents a malignant B cell disorder, characterized by an accumulation of monoclonal plasma cells in the bone marrow (BM). It accounts for approximately 1 % of all malignant diseases and represents about 10% of all hematological malignancies. The median age at diagnosis is 65 years and about 3% of patients are younger than 40 years.

The cause of MM is unknown. Environmental exposures that may increase the risk of MM include high doses of ionizing radiation and occupational exposure in the farming and petrochemical industries.

The clinical presentation of MM varies from totally asymptomatic in patients whose disease is discovered incidentally to life-threatening clinical events. The tumor itself, and the host response to it result in organ dysfunction with a variety of symptoms. These include bone pain with or without associated fractures (due to osteolysis), anemia, susceptibility to infections and hypercalcemia, with or without renal failure caused by the precipitation of monoclonal light chains in the collecting tubules.

The hallmark of MM is the detection of an M-protein in blood and/or urine (Bence Jones). Serum protein electrophoresis reveals a band in 80% of patients. The remaining 20% of patients will have either hypogammaglobulenimia or a normal appearing pattern. In this patient population with oligo- or non-secretory MM, the serum free light-chain assay can be useful for monitoring.

The research work in the department of Hematology-Immunology relates to different aspects in the biology and treatment of MM, using both human MM cells and the murine 5TMM model. The latter is a syngenic immunocompetent murine model, which mimics the human disease closely. The research group focuses, in particular on interactions between MM cells and their host microenvironment and studies how specific interactions with endothelial cells, osteoclasts and stromal cells can be targeted for therapeutical intervention, with special emphasis on overcoming drug-resistance.

Bone marrow and peripheral blood stem cell therapy

Stem cells are undifferentiated cells that are capable of self-renewal and differentiation in mature functional cells. They are not only present during embryonic life (embryonic stem cells) but can also be identified in various tissues during adult life (adult stem cells). The adult stem cell type that has been best characterized until now is the haematopoietic stem cell (HSC). Haematopoietic stem cell transplantations (HSCT) are used for more than 20 years as standard therapy for treatment of patients with haematological malignancies or stem cell deficiencies.

For more than two decades, the research unit Hematology-Immunology (HEIM) studies biological features and clinical use of haematopoietic stem cells (HSC) for treatment of patients with malignant blood cell disorders. These research activities are directly linked to a clinical transplantation program UZ Brussel that is internationally accredited by the European Group of Blood and Marrow Transplantation (EBMT) and that includes so far more that 500 transplantation procedures. The HSC preparation, prior to clinical use, is performed in the stem cell laboratory UZ Brussel. This laboratory is equipped for processing and cryopreservation of HSC according to international standards of GLP (Good Laboratory Practice). All technical facilities for clinical scale isolation, freezing and quality control of HSC grafts are available. There is a direct collaboration with the laboratories Hematology-Immunology, HLA-typing and Molecular Haematology, UZ Brussel. Past and ongoing research studies are related to the phenotype of normal and malignant stem cells, identification of predictive parameters for clinical complications associated with allogeneic HSC grafting, in vitro manipulation of HSC grafts, role of NK cell antigens in the outcome of allogeneic HSCT and molecular detection of minimal residual disease.

Although HSC mostly produce mature blood cells, at least a subpopulation expresses the capacity for non-haematopoietic differentiation as well. Indeed, a subset of CD133+ HSC can differentiate in endothelial cells that form blood vessels. This feature, called stem cell plasticity, is also the hallmark of another adult, bone marrow-derived cell type, the mesenchymal stem cell (MSC). MSCs can differentiate in osteoblasts, chondrocytes, myocytes, tendocytes and adipocytes. More recently it was found that MSC can also differentiate into endothelial cells and neural cells. MSC have also the capacity to sustain the growth of HSC by secretion of various haematopoiesis-supporting cytokines.

Based on all these observations it is assumed that bone marrow-derived multipotent adult stem cells can be therapeutically used for various types of tissue-regeneration, induction of blood vessel formation and as target cells for gene therapy in inborn or malignant disorders. Whereas CD133+ stem cells can directly be immuno-selected from bone marrow or from peripheral blood, MSC can be isolated from bone marrow by in vitro culture-expansion. Both techniques allow generating these adult stem cell types at levels sufficient for therapeutical administration. In the stem cell laboratory UZ Brussel, all technical facilities and conditions were established to prepare these multipotent stem cells for (pre-) clinical studies.

For clinical applications with adult multipotent stem cells, intravenous injection seems to be the simplest route of administration. However, the directed migration of intravenously injected stem cells to the targeted tissue implicates that these cells must be equipped with the appropriate mechanisms that allow transendothelial migration and tissue-directed homing. In the research unit HEIM, an ongoing research project aims to identify molecular mechanisms that mediate the extravasation and homing of culture-expanded MSC. In parallel, there is a study ongoing, in collaboration with the department cardiology UZ Brussel, to evaluate the homing properties of in vitro-selected CD133+ stem cells after intracoronary delivery in patients with chronic ischemic heart disease.


Thrombophilia is a group of hereditary and acquired risk factors which induce a hypercoagulable state of the blood and cause a higher tendency to develop venous thromboembolic events. Hereditary thrombophilia can, on the one hand, be caused by deficiencies or dysfunctions of the natural anticoagulants (antithrombin, protein C and protein S) as a result of mutations; on the other hand, mutations in genes coding for clotting factors can result in a hyperfunction of these factors which leads to a higher tendency to thrombosis. One of these mutations is the Factor V Leiden mutation which makes clotting factor V resistant to inhibition by activated protein C (APC). The risk of venous thrombosis is highly dependent of the type of hereditary thrombophilia: deficiencies of the physiological anticoagulants are very rare (prevalence <1%) but are associated with a high thrombotic risk. Aberrant proteins with a gain of function, like Factor V Leiden and prothrombin G20210A, are more prevalent (prevalence ~5%) but the thrombotic risk in carriers of these mutations is lower.

The main research topic of the hemostasis unit (located in the UZ Brussel laboratory for Clinical biology) is inherited antithrombin deficiency. Over the past 20 years, our center has become a reference center for this disorder. Besides phenotypical characterization, we are the only Belgian center performing molecular analysis to unravel the genetic background of inherited AT deficiency. We collaborate with different national and international laboratories and hospitals for the diagnostic work-up of their AT deficient patients.

During the past 10 years, the study of inherited protein C deficiency was added to our research topics. Since molecular analyses of the protein C gene was not offered by any Belgian center, we decided to implement this in the UZ Brussel. Like in inherited antithrombin deficiency, we aim to better understand phenotype-genotype correlation and to identify new pathologic mutations.

Our aim is to provide a more patient-specific counseling (including treatment and prognosis) according to the (sub)classification of the deficiency.