HEMATOTHESIS

Anaemia and its association with asymptomatic malaria, iron and zinc deficiencies, and Ferroportin Q248H mutation in children aged under five years in South Kivu, Democratic Republic of Congo

BJH - volume 13, issue 7, november 2022

Y. Lufungulo Bahati MD, PhD, J. Delanghe MD, PhD, G. Bisimwa Balaluka MD, PhD, J. Philippé MD, PhD

SUMMARY

Anaemia is a public health problem affecting one quarter of the global population with significant health consequences as well as an adverse impact on social and economic development. In malaria endemic areas, Plasmodium infection remains the major cause of anaemia. The ferroportin Q248H mutation has been described to protect red blood cells against oxidative stress and malaria infection. The objective of this study was to describe the main mechanisms causing anaemia and the role of ferroportin Q248H mutation in relation with anaemia and malaria in childhood in a Bantu population living in the volcanic region of South Kivu. 1088 healthy children aged under five years were randomly selected in the health zone of Miti Murhesa in South Kivu/Democratic Republic of Congo. Almost 40% of children under five years were anaemic, submicroscopic Plasmodium infection was as high as 22.3%. The prevalence of ferroportin Q248H mutation was 11.4%. No difference was observed in the frequencies of malaria or anaemia between ferroportin mutated compared to ferroportin wild type children. The prevalence of iron deficiency was found to be high (49.1%) when free erythrocyte protoporphyrin (FEP) was used to assess iron status. We found zinc deficiency in 17.6% of children. The prevalence of anaemia in South Kivu remains high, children with low parasitemia detected by loop mediated-isothermal amplification assay (LAMP) but not by microscopy showed a significantly increased prevalence of anaemia. Ferritin, an acute phase protein of infection is less suited to assess iron status in endemic areas of Plasmodium infection.

(BELG J HEMATOL 2022;13(7):281–3)

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Genetic drivers of peripheral T-cell lymphomagenesis

BJH - volume 13, issue 6, october 2022

K. Debackere MD

SUMMARY

Peripheral T-cell lymphomas represent an unmet medical need. The paucity of biological studies impedes the development of new treatment strategies. In this doctoral thesis, I leveraged next-generation sequencing technologies to identify new gene fusions in peripheral T-cell lymphomas. These insights were used to engineer cell systems and mouse models, which closely resemble human peripheral T-cell lymphomas. These models are valuable tools to understand the biology of peripheral T-cell lymphomas and provide a rational for new treatment regimens.

(BELG J HEMATOL 2022;13(6):253–5)

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TCR-based T cell immunotherapy for AML: Multidimensional aids in optimising treatment and patient identification

BJH - volume 13, issue 4, june 2022

S. Bonte PhD, T. Kerre MD, PhD

SUMMARY

Acute myeloid leukaemia (AML) has a dismal outcome, as demonstrated by a 5-year overall survival rate of only 26%. Although a complete remission can be achieved in approximately 50% of the patients with classical chemotherapy, the chances of relapse are high. Current treatment options for relapsed or refractory AML only offer a bridge to allogeneic haematopoietic stem cell transplantation since no other curative option exists. In primary refractory patients, and patients at high risk for relapse, harnessing the power of the immune system with immunotherapy might provide a new treatment option. In this dissertation, we approached AML immunotherapy from two sides: the optimisation of TCR-based immunotherapy for AML, and of the identification of patients eligible for this type of treatment.

(BELG J HEMATOL 2022;13(4):165–7)

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Risk factors, diagnosis and management of (azole-resistant) invasive aspergillosis

BJH - volume 12, issue 8, december 2021

A. Schauwvlieghe MD, PhD

INTRODUCTION

An invasive fungal disease (IFD) is a life-threatening infection that is almost exclusively diagnosed in immunocompromised hosts. The most common invasive mould infection is caused by Aspergillus species and called invasive aspergillosis (IA). Patients with acute myeloid leukaemia who are treated with intensive chemotherapy and hematopoietic stem cell transplant recipients are at highest risk for IA. Incidence rates of IA vary substantially and depend on host and environmental factors but also the modalities of allogeneic stem cell transplantation recipients as well as the use of antifungal prophylaxis. Without prophylaxis the incidence of IA in these populations can be as high as 10–20%.1–3 IA does not only lead to a higher overall mortality and morbidity but also to substantially higher medical costs.4 The case fatality rate of IA is estimated to lie between 20–38%, six to twelve weeks after diagnosis but this as well varies substantially between populations.5 Therefore, optimising the management of IA is key in order to reduce the burden of this devastating complication in the immunocompromised host. For more than fifteen years voriconazole, a drug of the triazole class, has been the recommended treatment for this life-threatening infection after a pivotal randomised trial showed an improved survival with voriconazole compared with amphotericin B deoxycholate. However, also with voriconazole and improved diagnostic tests, the overall 6-week mortality is still unacceptably high at 25–30%.6 A troublesome emerging problem in patients with IA is the increasing incidence of infections with triazole-resistant A. fumigatus. Although limited by numbers, case series have demonstrated that the overall mortality of patients infected with triazole-resistant A. fumigatus is very high (50–88%).7,8 This thesis focuses on risk factors for and the diagnosis of invasive aspergillosis. Additionally, the management of azole-resistant aspergillosis is addressed. The thesis consisted of several chapters. You can read all chapters in the digital version of the thesis. We briefly summarise the most important findings in every chapter.

(BELG J HEMATOL 2021;12(8):353–4)

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Immunity, the Epstein-Barr virus and the microenvironment in lymphoma

BJH - volume 12, issue 6, october 2021

L. Marcelis MD, PhD, R. Snoeck MD, PhD, D. Dierickx MD, PhD, T. Tousseyn MD, PhD

SUMMARY

Immune regulation therapy or ‘immunotherapy’ has been a major evolution in the field of cancer therapy in the last decade. The goal of this thesis was to better characterise multiple rare lymphoproliferative disorders in order to guide therapy development, predictive biomarker discovery and ultimately help ensuring that these novel therapies can get to the patients who stand to benefit from them. Many lymphoma types arise in a context of altered immune system function with potential implications for immunotherapy. One example of lymphoma arising in the context of chronic immune stimulation is Helico bacter Pylori infection, which is known as mucosa associated lymphoid tissue (MALT) lymphoma of the stomach. For this lymphoma we reviewed the literature and described how it is an excellent model to understand lymphomas arising in an immune stimulated context.1 Other lymphomas arise in a context of immunosuppression, of which post-transplant lymphoproliferative disorders (PTLD) are the best characterised. Besides the immune state, the presence of a virus such as the Epstein-Barr virus has major effects on lymphomas and their (immune) microenvironment with potential impact on immunotherapy. A review of EBV-related effects on PTLDs was done.² Lymphoproliferative disorder’s (LPDs) arising in the context of treatment with immunomodulatory (IM)/immunosuppressive (IS) drugs for various auto-immune diseases are lesser-known. These are called immunomodulation related lymphoproliferative disorders (IARLPD). For this thesis, we characterised one of the largest single centre case series of IARLPD.³ Finally, some lymphomas arise in specific ‘immune-privileged’ sites such as the central nervous system (CNS) called Primary central nervous system lymphoma (PCSNL). Digital slide analysis method and the novel MILAN multiplex staining technique were used to study the tumour microenvironment (TME) in PCNSL confirming the relevance of the microenvironment in the clinical behaviour of this lymphomas, highlighting potential relevance of immunotherapy and confirming the usefulness of the mentioned techniques in the study of the TME.4 For the purpose of this dissertation presentation we will focus primarily on this latter work.

(BELG J HEMATOL 2021;12(6):280-2)

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Oncogenic co-operation in T-cell acute lymphoblastic leukaemia: The role of TLX3 and TCF7::SPI1

BJH - volume 13, issue 8, december 2022

Q. Van Thillo MD, PhD

SUMMARY

T-cell acute lymphoblastic leukaemia (T-ALL) is a devastating disease, which mainly occurs in childhood. Despite an improvement of the overall survival, the current treatments have many side effects, and patients with relapsed or refractory disease continue to have a very poor prognosis. T-ALL arises from T-cell progenitors that have acquired multiple genomic lesions, which co-operate to drive leukaemia development. For some genetic alterations, such as the TCF7::SPI1 fusion or ectopic expression of TLX3, their role in driving leukaemia remains largely unknown. Therefore, we first investigated the co-operation between TCF7::SPI1 and NRAS(G12D). Using a mouse model, we were able to show that β-catenin is a crucial coactivator for the oncogenic function of the TCF7::SPI1 fusion protein. In the second part, we demonstrated that TLX3 and FLT3-ITD co-operate in driving leukaemia by activating the SPI1/PU.1 transcriptional program in an ex vivo pro-T-cell model and mouse model. This oncogenic function of TLX3 was shown to be dependent on other cofactors. Together, these two models of oncogenic co-operation in T-ALL demonstrate that the interaction between oncogenic transcription factors and cofactors is paramount for their function. Thus, these data provide a rationale for developing treatments directed at these protein interactions in the future for leukaemia.

(BELG J HEMATOL 2022;13(8):325–7)

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Novel therapeutic targets in juvenile myelomonocytic leukaemia: Are noncoding RNAs valuable treatment options?

BJH - volume 12, issue 4, june 2021

M. Hofmans MD, PhD, T. Lammens PhD, J. Philippé MD, PhD, B. De Moerloose MD, PhD

SUMMARY

Juvenile myelomonocytic leukaemia is a rare and aggressive clonal disease of early childhood for which hematopoietic stem cell transplantation remains the only curative option, albeit with a high relapse rate and many associated toxicities. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) have recently been implicated in a variety of biological processes, including haematopoiesis and receive much research attention as they possess features interesting for treatment, such as tissue specificity, low overall expression and easy targetability with RNAi or gene editing technology. Within this dissertation, we aimed at deciphering the lncRNA and circRNA transcriptome of JMML and use this knowledge to develop novel treatments.

(BELG J HEMATOL 2021;12(4):173-6)

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