Understanding the developmental origins of resistant infant leukaemia
Acute lymphoblastic leukaemia (ALL) is a form of blood cancer characterised by over-production of lymphoid cells, including B cell and T cell progenitors, in the bone marrow. ALL is the most common blood cancer in children; fortunately improvements in treatment and supportive care mean that 9 out of 10 children with ALL can now be cured. Unfortunately, the subset of childhood ALL that occurs in infants (up to 1 year of age) remains a thorn-in-the-side of this remarkable success story, with only 5 out of 10 infants surviving. Despite international collaborative efforts, survival outcomes for infant ALL have not improved in the past 20 years.
Mutations that drive childhood ALL often result from chromosomal translocations, whereby a part of a chromosome breaks and a portion of it reattaches to a different chromosome, creating an abnormal fusion gene. In the case of infant ALL, the MLL (KMT2A) gene is translocated in 80% of cases; and usually partners with the AF4 gene to give rise to the MLL-AF4 fusion gene. This invariably occurs in utero, and is almost unique in that this single translocation event seems to be sufficient to give rise to an aggressive B-ALL in infants without the need for cooperating mutations. It is likely that the biology of ALL, including leukaemia initiation, maintenance and progression depends on the developmental stage and type of cell in which it originates. It is also possible that fetal specific characteristics of the target cell make infant ALL particularly difficult to treat, and indeed analysis of infant ALL samples has shown that they retain expression of fetal-specific genes,
Understanding more about the origins of infant ALL may be key to replicating the success seen in the treatment of ALL in older children. Research undertaken by Dr Anindita Roy’s group, Department of Paediatrics, aims to identify and characterise the poorly understood target cell population responsible for in utero initiation of infant and childhood ALL. This group recently defined novel B lymphoid developmental pathways in human fetal life that might answer this question. Current research in the Roy lab involves understanding why fetal-specific progenitors are particularly susceptible to leukaemic transformation by MLL rearrangement and how the leukaemia progresses, especially compared to postnatal progenitors found in paediatric and adult life. This includes studying how haematopoiesis, and in particular B cell development, changes through the human lifetime.
One of the major obstacles in identifying and testing new treatments for infant ALL is that we currently do not have an accurate model of the disease. This has led to gaps in our knowledge about the precise mechanisms by which MLL translocations initiate leukemic transformation in infants. Previous work aimed at making a mouse model of MLL-AF4-driven ALL has often failed to mimic the infant B-ALL phenotype, most likely because of a lack of the appropriate human fetal cell context.
Siobhan Rice set out to create the first faithful model of MLL-AF4-driven infant ALL by targeting human fetal progenitor cells. In order to cause the MLL-AF4 chromosomal translocation, she used CRISPR-Cas9 gene editing technology to create the same breaks in the MLL and AF4 genes that occur in infant ALL patients. She found that by using this approach, human fetal cells could be transformed to give rise to aggressive MLL-AF4+ B-ALL in mice.
Most excitingly, analysis of the phenotypic features as well as the gene expression profile of this leukaemia by Siobhan Rice and Dr Thomas Jackson confirmed that it specifically recapitulated infant ALL. This is the first accurate model of infant ALL using human fetal cells, and the work was recently presented at the annual European Haematology Association meeting.
Work in the Milne lab has also focussed on identifying specific molecular pathways/genes that are disrupted by MLL translocations. MLL-AF4 is thought to promote leukaemogenesis by activating key target genes, mainly by altering the epigenetic profile of the cell. They have recently described aberrant expression of one such gene, PROM1.
The unique infant ALL model developed by the two labs now allows them to dissect the function of MLL-AF4 at target genes, as well as better understand other aberrant molecular details that underpin this disease. This will help identify the key dependencies required for MLL-AF4 leukaemia initiation and progression that can be taken forward to develop new therapies. Future work will focus on identifying gene regulatory networks and protein interactions that are disrupted by MLL-AF4. The pathways that are found to be crucial for leukaemia initiation and/or maintenance will be taken forward for drug development, including immunotherapy.
About the labs
This research is a collaborative effort between the Roy, Milne and Roberts labs at the Department of Paediatrics and Weatherall Institute of Molecular Medicine, Oxford, funded by the Medical Research Council (MRC), Wellcome Trust and Blood Cancer UK.
Dr Anindita Roy is a principle investigator whose lab is focused on the study of prenatal B cell development in order to understand the origins of infant and childhood leukaemia. Dr Thomas Milne is a principle investigator whose lab is focused on understanding how epigenetics affect gene regulation in leukaemia. Prof Irene Roberts’ lab investigates how trisomy 21 impacts prenatal blood cell development and its implications for childhood leukaemia.
Siobhan Rice is a doctoral research student jointly supervised by the Roberts, Roy and Milne labs whose interests include the impact of cell context on ALL biology and the molecular functions of MLL-AF4 that drive leukaemia development.
Dr Thomas Jackson is a postdoctoral research scientist in the Roy lab who is interested in identifying molecular drivers and vulnerabilities of infant ALL, and how these differ from ALL in older children and adults.
Through their collaboration, these labs aim to understand, at the molecular level, why prenatal blood cells are permissive to leukaemic transformation, and to identify new treatment strategies for infant/childhood ALL. The overarching aim of their research is to deliver clinically meaningful improvement in the outcome of treatment resistant childhood ALL.