T. Lammens 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)

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.)

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

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)

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)

Novel molecular genetic insights in paediatric B-cell precursor acute lymphoblastic leukaemia

SUMMARY

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)

P76 PrimeFlow™ RNA Assay: a novel technique for single-cell expression analysis in heterogeneous cell populations