Acute Myeloid Leukaemia (AML), one of the most aggressive leukaemias, is a clinically and molecularly heterogeneous disease characterised by uncontrolled proliferation, block in differentiation and acquired self-renewal of hematopoietic stem and myeloid progenitor cells. This results in the clonal expansion of myeloid blasts within the bone marrow and peripheral blood. The incidence of AML increases with age, and in childhood, AML accounts for 20% of all leukaemias. The current overall survival rate in children is only 60-70%, and thereafter falls progressively with age to 5-15% in the elderly. Current therapy consists of cytarabine in combination with anthracycline however both children and adults die from a combination of relapse (up to 35% and 99% respectively) and treatment-related mortality during both induction and consolidation therapy.
Whilst there are many clinical and biological similarities between paediatric and adult AML with continuum across the age range, many characteristics of AML are associated with age of disease onset. Paediatric AML, in comparison to adult AML, is characterized by a higher frequency of cytogenetic abnormalities with some occurring almost exclusively in children, and the main genetic driver of AML often dictates disease phenotype and prognosis. Furthermore, the epigenetic landscapes of paediatric and adult AML are vastly different with respect to the incidence and type of mutations in epigenetic modulators. These differences in paediatric and adult AML are important clinically because to date the treatment of paediatric AML has been largely extrapolated from adult regimens. There are opportunities to identify novel therapies that may be more appropriate for either paediatric or adult patients, or both.
Our goal is to develop new strategies that will translate into the clinic to improve overall survival of children and adults with AML and help prevent relapse and refractory disease.
Age-specific Mouse Models
Mouse models featuring specific genetic AML features have shown that paediatric and adult AML are distinct biological entities, depending on the cell of origin and that the transcriptional programming within the cell of origin can explain some of the differences in paediatric and adult disease development. We use a number of models in the lab; xenotransplantation, patient-derived xenotransplantation, retro/lenti-viral transduction and transplantation, and novel transgenic models to study AML with a focus on some genetic subgroups e.g. MLL-AF9, NUP98-HOXA9, TRIB2, AML1-ETO.
Biology-based ‘omics’ technologies have revolutionised our understanding of AML pathogenesis. Distinct genetic and epigenetic alterations constitute the clonal diversity each individual case of AML presents. Transcriptomics followed by pathway analysis is a powerful analytical approach that can provide important insights in AML biological and biochemical features, and potential avenues for novel therapies. This has been especially powerful in defining stem cell populations, chemoresistance and metabolic features of AML cells. Work in our lab aims to use the molecular profile of AML cells to drive development of novel agents that will target and kill chemo-resistant AML cells. The Keeshan labs’ work on paediatric AML (Chaudhury et al., Nat Commun. 2018) showed for the first time using a preclinical in vivo model of AML that the age of the cell-of-origin impacts AML disease, and that distinct molecular properties define paediatric disease using omic analysis (RNA-seq datasets, publically available). Molecular techniques in our centre include total and single cell RNA-seq, CRISPR/Cas9, proteomics and metabolomics.
Being able to identify and specifically kill chemo-resistant clones is the current challenge. Addressing the oncogenic and chemo-resistance properties of adult and paediatric AML, we have focused on the pseudokinase and AML oncogene TRIB2, identified by Dr Keeshan (Keeshan K et al., (2006) Cancer Cell. 10(5):401-11). The lab has authored >20 publications on TRIB proteins in leukaemia and has set the paradigm for TRIB oncogenic function across cancer types, identifying C/EBP as the key target for TRIB-oncogenesis and chemo-resistance via BCL-2 family proteins. Ongoing work in the lab investigates TRIB2 as a biomarker for AML patients who would benefit from novel therapy targeting TRIB2, using novel approaches such as ERBB inhibitors and specific TRIB targeting nanobodies.
Leukaemia stem cells
AML arises from, and is maintained by leukaemia stem cells (LSCs), defined by a number of characteristics but we as yet do not know if these are the same within paediatric and adult AML groups. LSCs are relatively resistant to standard therapies and thought responsible for driving disease relapse, and therefore LSC cell surface markers and molecular profiles are used for minimal residual disease (MRD) detection/monitoring. The question remains whether cells adapt their molecular profiles following exposure to chemotherapy, or whether there are inherent features in a clone of cells, that may or may not be within the therapy-naïve LSC compartment responsible for chemoresistance. Currently the Myechild 01 paediatric AML clinical trial is the only trial initiated in the UK where LSC investigation is being carried out. Through collaboration with Myechild 01 trials team and our clinical colleagues, we are addressing the chemo-resistance and the prognostic value of the molecular profiles.
There are a number of PhD and postdoctoral projects in the lab using mouse models, patient samples, and molecular profiling addressing chemo-resistance, LSCs, and distinguishing features of paediatric and adult AML.