B. De Moerloose MD, PhD

Recent advances in the genomic and epigenomic biology of juvenile myelomonocytic leukaemia

SUMMARY

Juvenile myelomonocytic leukaemia is a heterogeneous disease caused by constitutional activation of the Ras signal transduction pathway. The clinical course of the disease is variable and non-specific. In the majority of patients prompt hematopoietic stem cell transplantation is necessary for long-term survival, whereas in a minority the disease will resolve without treatment. In more than 90% of the patients, mutations in one or more of the following genes can be found (somatic NRAS, KRAS and PTPN11, germline NF1 and CBL). However, these canonical mutations are insufficient to explain the phenotypic heterogeneity of this disease. More recently, secondary mutations, non-coding RNA expression, and genomic DNA methylation have led to a better understanding of the pathobiology of the disease, and shown to play a role in the classification and prognostication of this rare disease. In addition, this novel information has been crucial for novel drug development and introduction of novel patient-tailored therapies, which are currently being tested in vitro or in vivo in clinical trials.
(BELG J HEMATOL 2020;11(2):49–55)

Severe neutropenia in an infant after treatment with infliximab during pregnancy

SUMMARY

We describe a 7-month-old girl with severe neutropenia born to a mother treated for ulcerative colitis with infliximab until the 24^th week of pregnancy. Despite the recommendation of using Tumour Necrosis Factor inhibitors (TNFi) only in the first and second trimester of pregnancy, significant levels of TNFi in offspring are possible. Hence, drug-induced neutropenia should be considered in the differential diagnosis of infants with severe neutropenia if these were exposed to TNFi in utero. Moreover, additional information is given on the risk of infection and dysfunctional immune development in these new-borns.

(BELG J HEMATOL 2019;10(7):285–9)

Retrospective study of infant leukaemia in the University Hospitals of Leuven and Ghent

SUMMARY

Infant leukaemia is a rare disease but the 3^rd most frequent malignancy in this age group. Both acute lymphoblastic leukaemia and acute myeloid leukaemia in the first year of life have particular clinical and biological characteristics such as B-cell phenotype with co-expression of myeloid markers in acute lymphoblastic leukaemia, FAB M5 or M7 in acute myeloid leukaemia, the presence of extramedullary symptoms and a high frequency of KMT2A rearrangements. Survival rates for infant acute leukaemia are worse than for older children. In this study, the characteristics and outcome of 50 infants with acute lymphoblastic leukaemia and acute myeloid leukaemia treated at the University Hospitals of Ghent and Leuven between 1989 and 2015 were studied and correlated with literature data. With event-free survival and overall survival rates of 44% and 52% for the entire cohort, the outcome of these patients was comparable to those in published clinical trials. In general, the event-free survival and overall survival was superior in acute myeloid leukaemia compared to acute lymphoblastic leukaemia infants and not influenced by age (< or ≥6 months), white blood cell count at diagnosis or presence of a KMT2A rearrangement. For future trials in infant leukaemia, the high number of early deaths, toxic deaths and relapses remain the most challenging problems.

(BELG J HEMATOL 2018;9(2):57–63.)

The impact of chemotherapy on the host microbiota in the context of oral and gastrointestinal mucositis

SUMMARY

In this PhD thesis, we investigated the impact of chemotherapy on the microbiota in the context of mucositis by using different experimental set-ups. Using bacterial monocultures, we showed that exposure to 5-fluorouracil at physiologically relevant concentrations differentially impacts oral microorganisms. Despite this difference in microbial sensitivity to 5-fluorouracil in pure cultures, we showed that the impact of 5-fluorouracil, as well as irinotecan, towards highly diverse gastrointestinal microbial populations is only marginal. These findings were generated with two different model systems that exclude host cells and this led us to conclude that the host is crucial in the establishment of chemotherapy-induced shifts in microbial composition and functionality. The next step in our research entailed the use of an in vitro wound healing model, where we demonstrated that the presence of microbiota negatively impacts the wound healing capacity of damaged oral epithelial cells. This indicates that microbial presence can delay the recovery from mucositis. Yet, we also found that microbial composition, which is for instance disturbed in patients receiving cancer therapy, is an additional determinant of aggravated wound healing. We further substantiated this conclusion with an in vivo longitudinal monitoring study of paediatric patients treated for haematological malignancies. While shifts in the oral microbial community during and following chemotherapy were mostly patient-specific, clear associations were made with the use of systemic antibiotics and antibacterial mouth rinses, which create microbial dysbiosis. In view of these findings we propose that the preventive use of antimicrobials needs careful consideration given the profound impact on the microbiome and subsequent consequence for the host.

(BELG J HEMATOL 2018;9(2):68–70.)

PP01 Exploring the long non-coding RNA landscape in Juvenile Myelomonocytic Leukemia

Unravelling the biology of juvenile myelomonocytic leukaemia using transcriptomics

SUMMARY

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)

Genetic insights in ETV6/RUNX1-positive B-cell precursor acute lymphoblastic leukaemia

SUMMARY

Acute lymphoblastic leukaemia, a clinically and biologically heterogeneous disease, represents the most common malignant disease in childhood. Approximately 20–25% of B-cell precursor acute lymphoblastic leukaemia in childhood carry the cryptic chromosomal translocation t(12;21)(p13;q22). This translocation combines two transcription factors and essential regulators of normal haematopoiesis, ETV6 and RUNX1, into the fusion oncogene ETV6/RUNX1 (formerly known as TEL/AML1). Recent studies in various animal models have strengthened the view that ETV6/RUNX1-positive cells give rise to pre-leukemic clones with a differentiation block in the pro/pre-B stage of B-cell development that, after acquisition of additional mutations, may transform into full malignancy. Despite the favourable prognostic parameters of this B-cell precursor acute lymphoblastic leukaemia subgroup, relapse and resistance to chemotherapeutics do occur and increased knowledge of the molecular mechanisms underlying ETV6/RUNX1-driven leukaemia is essential to develop novel therapeutic strategies to selectively target ETV6/RUNX1-positive leukaemia. In this manuscript, an overview of the most recent genetic insights in ETV6/RUNX1-positive B-cell precursor acute lymphoblastic leukaemia is given.

(BELG J HEMATOL 2017;8(5):179–84)