Abstract
Acute myeloid leukaemia (AML) 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. 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. These include chromosomal aberrations, gene mutations and differentiation lineage. Following chemotherapy, AML cells that survive and result in disease relapse exist in an altered chemoresistant state. Molecular profiling currently represents a powerful avenue of experimentation to study AML cells from adults and children pre‐ and postchemotherapy as a means of identifying prognostic biomarkers and targetable molecular vulnerabilities that may be age‐specific. This review highlights recent advances in our knowledge of the molecular profiles with a focus on transcriptomes and metabolomes, leukaemia stem cells and chemoresistant cells in adult and paediatric AML and focus on areas that hold promise for future therapies.
Highlights
Acute myeloid leukaemia (AML) is a haematological malignancy, with incidence rates having grown by 29% since the early 1990s
Mutations acquired over time can lead to clonal enrichment in Abbreviations AML, Acute myeloid leukaemia; APL, acute promyelocytic leukaemia; ATO, arsenic trioxide; all-transretinoic acid (ATRA), all-trans-retinoic acid; CH, clonal haematopoiesis; ES, enrichment score; FAO, fatty acid oxidation; GSEA, Gene Set Enrichment Analysis; HSCs, haematopoietic stem cells; ITD, internal-tandem duplications; LSC, leukaemia stem cell; MDS, myelodysplastic syndromes; MPN, myeloproliferative neoplasms; MRD, minimal residual disease; NGS, next-generation sequencing; pLSC6, paediatric 6 gene LSC score; TARGET, Therapeutically Applicable Research to Generate Effective Treatments; VAF, variant allele frequencies
The cells that remain postchemotherapy are distinct from therapy-na€ıve LSCs; chemoresistant adult AML cells are strongly driven by cellular metabolism displaying a dependence on fatty acid oxidation (FAO) together with elevated reactive oxygen species (ROS) and oxidative phosphorylation (OXPHOS) and a mRNA signature distinct from therapy-na€ıve LSCs (Fig. 4B)
Summary
Acute myeloid leukaemia (AML) is a haematological malignancy, with incidence rates having grown by 29% since the early 1990s (www.cancerresearchuk. org). Accumulation of somatic mutations in haematopoietic stem cells (HSCs) is proportional with age suggesting that the initial mutation for AML occurs stochastically in a cell which goes on to garner a unique combination of other AML-related mutations by chance as an individual grows older [7] In adults, it is possible there already exists haematopoietic cells with leukaemia somatic variants that are thriving as passenger lesions [8]. The features associated with ageing cannot be the explanation for paediatric AML incidence and clonal diversity It seems the pathogenesis of AML in children may differ to that in adults. Transcriptomics using bulk or single-cell RNA sequencing followed by pathway analysis is a powerful analytical approach that can provide important insights in AML biological and biochemical features This has been especially powerful in defining stem cell populations, chemoresistance and metabolic features of AML cells, which will be discussed further below. We will consider the molecular profiles that may be used for developing new therapies in the context of specific populations such as LSCs and chemoresistant cells
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