BJH - volume 8, issue 6, october 2017
S. Peirs PhD
Patients with T-cell acute lymphoblastic leukaemia are mainly treated with intensive combination chemotherapy. Although this treatment strategy is quite successful in children, refractory or relapsed disease is more difficult to treat. Moreover, the chemotherapeutic agents are associated with substantial toxicity. In order to find more effective and less toxic therapies, the genetic and epigenetic alterations in T-cell acute lymphoblastic leukaemia are studied and molecularly targeted drugs are being developed. In this thesis, two new strategies to treat T-cell acute lymphoblastic leukaemia were identified and evaluated. On the one hand, high expression of the anti-apoptotic factor BCL2 was found as a hallmark of the immature T-cell acute lymphoblastic leukaemia subgroup. The BCL-2 specific inhibitor venetoclax proved to be a promising potential new therapy in T-cell acute lymphoblastic leukaemia and synergized with standard chemotherapeutic agents and BET bromodomain inhibitors. On the other hand, the enzyme KDM1A was identified as an interaction partner of the oncogenic transcription factor ZEB2. Antileukemic effects were demonstrated in several T-cell acute lymphoblastic leukaemia cell lines upon pharmacological inhibition of KDM1A.
(BELG J HEMATOL 2017;8(6):244–6)
Read moreBJH - volume 8, issue 5, september 2017
H. Helsmoortel PhD, T. Lammens PhD, P. Van Vlierberghe PhD, B. De Moerloose MD, PhD
Juvenile myelomonocytic leukaemia is a rare and aggressive blood cancer occurring in early childhood. Research in the past decades mainly focused on identifying aberrations at the DNA level. Although our molecular knowledge about juvenile myelomonocytic leukaemia biology has steadily increased over the last years, haematopoietic stem cell transplantation is currently the only curative option. Unfortunately, the relapse rate after stem cell transplantation remains high and almost half of the children do not survive the disease, indicating that new therapeutic strategies are urgently required. To further elucidate the biology of the disease, we investigated gene expression levels of both coding and non-coding RNA molecules. This led to the identification of LIN28B and its co-regulated genes as central players in juvenile myelomonocytic leukaemia biology and opens the door for the development of new targeted therapeutics.
(BELG J HEMATOL 2017;8(5):198–200)
Read moreBJH - volume 8, issue 3, june 2017
F. Ghazavi PhD, T. Lammens PhD, P. Van Vlierberghe PhD, B. De Moerloose MD, PhD
Paediatric B-cell precursor acute lymphoblastic leukaemia arises from recurrent genetic lesions that block precursor B-cell differentiation and drive aberrant proliferation and cell survival. Risk-adapted intensive chemotherapy has been a major breakthrough in reaching the current survival rates of >90% for this ALL subtype. Recent developments in genome-wide genetic analysis have provided a wide range of chromosomal and genomic abnormalities characterising B-cell precursor acute lymphoblastic leukaemia, several of which are associated with patient outcome. This article summarises the results of several studies performed during the PhD thesis of Dr Farzaneh Ghazavi. This research project has led to the identification of a novel molecular lesion predicting poor outcome, a novel targetable pathway in a subgroup of B-cell precursor acute lymphoblastic leukaemia patients and resulted in the identification of an ETV6/RUNX1-specific long non-coding RNA signature providing novel biological insights into ETV6/RUNX1-mediated leukemogenesis.
(BELG J HEMATOL 2017;8(3):118–21)
Read moreBJH - volume 8, issue 2, march 2017
A.G. Dinmohamed PhD, MSc
The main aim of this thesis was to progress our understanding on different epidemiologic aspects of myelodysplastic syndromes and acute myeloid leukaemia at the population level in the Netherlands. These aspects include surveillance of the cancer burden, guideline adherence concerning diagnostics and therapy, and comparative effectiveness research. Population-based registries are useful instruments to study all patients within a well-defined area, so as to overcome patient selection which is always at hand in clinical intervention studies. The results described in this thesis provided a benchmark for incidence, diagnosis, treatment, trial participation and survival of myelodysplastic syndromes and acute myeloid leukaemia in the Netherlands. Future studies should provide insight whether clinical practice changed following the results described in this thesis.
(BELG J HEMATOL 2017;8(2):83–6)
Read moreBJH - volume 8, issue 2, march 2017
K. Durinck PhD
T-cell acute lymphoblastic leukaemia was originally identified as a highly aggressive blood disorder associated with poor prognosis, but intensified therapy has since led to remarkable improvements in survival. Unfortunately, these treatment regimens (mainly combination chemotherapy) are associated with severe acute and long-term toxicities. Moreover, the prognosis of patients with relapsed and refractory disease remains extremely poor. To shift towards a personalised medicine approach, a profound understanding of the molecular basis of the progression of this leukaemia subtype is required. This thesis discusses an integrative genomics approach to functionally dissect the interplay between established and novel transcriptional regulators that take part in the rewired transcriptional networks that drive malignant transformation of thymocytes to T-ALL lymphoblasts.
(BELG J HEMATOL 2017;8(2):80–2)
Read moreBJH - volume 7, issue 6, december 2016
B. Van Aelst PhD, H.B. Feys PhD, R. Devloo , Prof P. Vandekerckhove PhD, Prof V. Compernolle PhD
Pathogen inactivation technologies are photochemical treatments developed to decrease transfusion transmitted infections. However, the impact of pathogen inactivation technologies on the blood components themselves is not entirely clear. Therefore, we investigated the quality of blood components following pathogen inactivation. First, the impact of three different pathogen inactivation technologies on plasma was compared. The different methods all negatively affected ADAMTS13 activity and antigen level, but to different degrees. The pathogen inactivation technology using riboflavin as a photosensitizer had the largest effect. This effect was caused by reactive oxygen because removal of dissolved molecular oxygen prevented protein damage to occur. Next, we investigated the influence of three different pathogen inactivation technologies on platelet concentrates. For this, platelet function was assessed in microfluidic flow chamber experiments. These indicated a decreased platelet function compared to untreated controls for all pathogen inactivation technologies. Additional experiments showed that the underlying mechanisms of platelet damage were different for every pathogen inactivation technology, but all three resulted in similar thrombus formation deficiencies in flow chambers. We focused on one particular pathogen inactivation technology which combines the photosensitizer amotosalen (a psoralen) and UVA light (PUVA). The data showed a specific inhibition of the phosphatidylinositol 3-kinase signal transduction pathway caused by covalent binding of amotosalen to phospholipids during photoactivation. As the combination of a psoralen with UVA light is clinically used off-label for graft-versus-host disease treatment, phosphatidylinositol 3-kinase signal transduction in T lymphocytes of patient samples was studied and also here inhibition of phosphatidylinositol 3-kinase signal transduction was found. To conclude, research that initiated from the observation that platelet and plasma function is decreased following pathogen inactivation technologies has revealed an overall effect of PUVA on cellular phosphatidylinositol 3-kinase signal transduction by covalent modification of phospholipids.
(BELG J HEMATOL 2016;7(6):240–3)
Read moreBJH - volume 7, issue 5, october 2016
A. Rombout PhD, B. Verhasselt MD, PhD, J. Philippé MD, PhD
A typical hallmark of chronic lymphocytic leukaemia is its clinical heterogeneity, which is reflected by the presence or absence of several prognostic factors, such as cell surface molecules, genetic lesions and microRNAs. Despite having established prognostic value, the functional implications of most of these biomarkers remains poorly defined. The aim of this work was to gain more insight into the role of the B cell receptor and associated prognostic markers ZAP70 and LPL in the biology of chronic lymphocytic leukaemia.
(BELG J HEMATOL 2016;7(5):199–202)
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