A guide to epigenetics in leukaemia stem cells

• Published in: Molecular oncology 2023-12, Vol.17 (12), p.2493-2506
• Main Authors: Agrawal‐Singh, Shuchi, Bagri, Jaana, Sakakini, Nathalie, Huntly, Brian J. P.
• Format: Article
• Language: English
• Subjects: Amino acids; Bone marrow; Dehydrogenases; Development and progression; Enzymes; Epigenesis, Genetic; Epigenetic inheritance; epigenetic plasticity; Epigenetics; Evolution; Fatty acids; Hematology; heterogeneity; Humans; Kinases; leukaemia stem cells; Leukemia; Leukemia, Myeloid, Acute - genetics; Malignancy; Metabolism; Metabolites; Mutation; myeloid neoplasms; Neoplastic Stem Cells - pathology; Phenotypic plasticity; single cell studies and multiomics; Stem Cells; targeting LSC; Tumors
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.13544

Leukaemia stem cells (LSCs) are the critical seed for the growth of haematological malignancies, driving the clonal expansion that enables disease initiation, relapse and often resistance. Specifically, they display inherent phenotypic and epigenetic plasticity resulting in complex heterogenic diseases. In this review, we discuss the key principles of deregulation of epigenetic processes that shape this disease evolution. We consider measures to define and quantify clonal heterogeneity, combining information from recent studies assessing mutational, transcriptional and epigenetic landscapes at single cell resolution in myeloid neoplasms (MN). We highlight the importance of integrating epigenetic and genetic information to better understand inter‐ and intra‐patient heterogeneity and discuss how this understanding further informs evolution and progression trajectories and subsequent clinical response in MN. Under this topic, we also discuss efforts to identify mechanisms of resistance, by longitudinal analyses of patient samples. Finally, we highlight how we might target these aberrant epigenetic processes for better therapeutic outcomes and to potentially eradicate LSCs. In leukaemic stem cells (LSCs), aberrant epigenetic mechanisms converge and establish intratumoral heterogeneity, supporting leukaemic growth. These aberrant mechanisms lie directly downstream of epigenetic mutations or indirectly relate to metabolic and cell‐extrinsic signalling. Besides initiating and maintaining the LSC state, these aberrant mechanisms also provide potentially targetable vulnerabilities to help eradicate LSC and cure leukaemias.