HEMATOTHESIS

Impact of a rare disease on public health today and tomorrow: the case of haemophilia

Summary

Haemophilia is a rare X-linked disease of coagulation, implying a partial or a complete deficiency of circulating factor VIII, in case of haemophilia A, or factor IX, in case of haemophilia B. If untreated, the bleeding tendency in patients with haemophilia may induce spontaneous bleeding episodes leading to serious complications, including premature death. Substitutive treatments consisting of intravenous infusions of clotting factor VIII or IX concentrates, which can be administered in a preventive or curative way, are presently available. To be effective, there is a need to administrate the correct dosing of clotting factors. The optimal substitutive treatment dosing of factor VIII concentrates in haemophilia A is addressed in relation to morphometric variables in the first section of this thesis. However, current treatments for haemophilia have some limitations and the development of new treatments through clinical studies would be beneficial. Factors influencing the motivation of patients to participate in clinical studies to develop new treatments are addressed in the second section of the thesis. Finally, this work was integrated in a general public health perspective by investigating the health and the economic burden of haemophilia in Belgium in the final section. The consumption of coagulation factors needed to treat haemophilia and its associated cost is steadily increasing in Belgium and other developed countries. For the first time the total economic burden of haemophilia in Belgium was estimated. In addition, the disease burden related to haemophilia in Belgium was quantified through Disability-Adjusted Life Year (DALY) calculations.

(BELG J HEMATOL 2016; 7(3):123–6)

Altered gene and miRNA regulation in paediatric acute myeloid leukaemia

Summary

This thesis describes investigations towards altered gene and miRNA regulation in paediatric acute myeloid leukaemia. The first part of the thesis focuses on altered gene regulation. High IGSF4 expression was typical for acute myeloid leukaemia patients with MLL-rearrangements and a FAB-M5 phenotype, and caused by promoter demethylation. RUNX1 mutations were found in 65% of congenital neutropenia patients and found in only 2.8% of de novo acute myeloid leukaemia patients. The second part of the thesis describes investigations towards epigenetic alterations in paediatric acute myeloid leukaemia, largely focusing on miRNA expression profiles and function. Acute myeloid leukaemia with MLL-rearrangements t(15;17), t(8;21) and inv(16) were found to have specific miRNA expression profiles. In addition, miR-9 appeared to be a tumour suppressor only in a t(8;21) acute myeloid leukaemia background. Mutations in epigenetic regulator genes were infrequently found in paediatric acute myeloid leukaemia.

(BELG J HEMATOL 2016;7(2):87–9)

Impact of graft source and composition on outcomes after allogeneic stem cell transplantation

summary

Since many graft-related factors may affect outcomes after allogeneic stem cell transplantation, graft selection is one of the crucial steps of transplant preparation. Optimal graft selection may offer the best chance of successful transplantation. Here, we reviewed the impact of graft-related factors on post transplant outcomes in light of new data that may help to refine the strategy for graft and graft source selection.

(BELG J HEMATOL 2015;6(4): 162–8)

Innate immunity in chronic infectious and inflammatory diseases

Summary

In the first part of this thesis, we analysed modifying genes encoding proteins involved in innate immune lung defence that influence pulmonary disease severity in cystic fibrosis patients. Firstly, we found that cystic fibrosis patients with mannose binding lectin, ficolin 1 and 2 gene polymorphisms are at risk for earlier onset of chronic Pseudomonas aeruginosa (Pa) colonisation.¹ Secondly, we identified the involvement of toll-like receptor 1, 2 and 5 in the modulation of cystic fibrosis lung disease.²

In the second part of the thesis, we explored the innate immune response and genetic defects in patients with chronic inflammatory and infectious disease. We described at first a complete factor I deficiency caused by dysfunctional factor I in a patient with recurrent aseptic meningoencephalitis. Furthermore, we reported a novel mutation in the IL-12receptorβ1 gene and we described c.1623_1624delGCinsTT mutation as the first founder effect on the IL-12Rβ1 gene. A large survey on 141 patients with IL-12Rβ1 deficiency reports a less favourable outcome, especially in patients with environmental mycobacteria.

In the scope of this journal, we will highlight the most important findings of the second part of this thesis.

(BELG J HEMATOL 2015;6(1):37–9)

In vitro generation of AML-specific T-cells from human haematopoietic progenitor cells. A step towards curing acute myeloid leukaemia?

Summary

This dissertation focuses on T-cell-mediated immunotherapeutic strategies for the treatment of acute myeloid leukaemia. Two major key points determine the success of adoptive T-cell therapy: the nature of the target antigen and the characteristics of the infused T-cells. We reviewed potential acute myeloid leukaemia target antigens and performed an in-depth study of the Receptor for Hyaluronic Acid Mediated Motility as a potential leukaemia associated antigen. Subsequently, an alternative immunotherapeutic strategy was studied: the in vitro generation of antigen-specific T-cells starting from T-cell receptor-transduced human haematopoietic progenitor cells.

(BELG J HEMATOL 2014;5(4):154–7)

MicroRNAs: new actors in acute myeloid leukaemia

Summary

Despite their small size, the impact of microRNAs in acute myeloid leukaemia seems to grow with every microRNA-related publication. Aberrant expression of microRNAs and oncogenic and tumour suppressor properties of microRNAs may contribute to the biology of acute myeloid leukaemia. As we performed for miR-29b, a critical step is to identify target genes and pathways deregulated by microRNAs during leukemogenesis. We are just starting to understand the clinical impact of microRNAs in acute myeloid leukaemia and to emphasise future microRNA-targeted therapeutic strategies. These small new actors may become important clinical contributors for the diagnosis, prognosis and treatment of acute myeloid leukaemia.

(BELG J HEMATOL 2014;5(3):110–12)

Biological properties of mesenchymal stem cells in the multiple myeloma tumour microenvironment

Summary

Mesenchymal stem cells are multipotent non-hematopoietic progenitor cells that are capable of differentiating into various mesenchymal tissues and give rise to most bone marrow stromal cells. Several studies have demonstrated that bone marrow derived mesenchymal stem cells from multiple myeloma patients are functionally and genetically abnormal compared to their normal counterparts. However, the direct involvement of mesenchymal stem cells in the pathophysiology of multiple myeloma remains unclear. In our research project we aimed to investigate how mesenchymal stem cells influence multiple myeloma cell growth and whether and at which level the differentiation of mesenchymal stem cells towards osteoblasts is impaired in this disease. Our data provided evidence that mesenchymal stem cells can stimulate tumour growth and disease evolution in multiple myeloma and are involved in the bone disease associated with this malignancy.

(BELG J HEMATOL 2014;5(2):64–7)