Dysregulated haematopoietic stem cell behaviour in myeloid leukaemogenesis

• Published in: Nature reviews. Cancer Vol. 20; no. 7; pp. 365 - 382
• Main Authors: Yamashita, Masayuki, Dellorusso, Paul V., Olson, Oakley C., Passegué, Emmanuelle
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2020; Nature Publishing Group
• Subjects: 631/532/71; 631/67/1990/283; Acute myeloid leukemia; Age; Antineoplastic Agents - pharmacology; Biomedical and Life Sciences; Biomedicine; Blood cells; Cancer Research; Carcinogenesis - drug effects; Carcinogenesis - genetics; Carcinogenesis - pathology; Cell survival; Disease resistance; Diseases; Environmental changes; Epigenetic inheritance; Epigenetics; Gene-Environment Interaction; Genetic transformation; Genomic Instability - drug effects; Genomic Instability - physiology; Hematopoiesis - genetics; Hematopoiesis - physiology; Hematopoietic stem cells; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Hematopoietic Stem Cells - physiology; Homeostasis; Humans; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - physiopathology; Molecular modelling; Mutation - drug effects; Mutation - genetics; Mutation - physiology; Relapse; Review Article; Stem Cell Niche - drug effects; Stem Cell Niche - physiology; Stem cells; Tumor Microenvironment - drug effects; Tumor Microenvironment - physiology
• ISSN: 1474-175X; 1474-1768
• DOI: 10.1038/s41568-020-0260-3

Haematopoiesis is governed by haematopoietic stem cells (HSCs) that produce all lineages of blood and immune cells. The maintenance of blood homeostasis requires a dynamic response of HSCs to stress, and dysregulation of these adaptive–response mechanisms underlies the development of myeloid leukaemia. Leukaemogenesis often occurs in a stepwise manner, with genetic and epigenetic changes accumulating in pre-leukaemic HSCs prior to the emergence of leukaemic stem cells (LSCs) and the development of acute myeloid leukaemia. Clinical data have revealed the existence of age-related clonal haematopoiesis, or the asymptomatic clonal expansion of mutated blood cells in the elderly, and this phenomenon is connected to susceptibility to leukaemic transformation. Here we describe how selection for specific mutations that increase HSC competitive fitness, in conjunction with additional endogenous and environmental changes, drives leukaemic transformation. We review the ways in which LSCs take advantage of normal HSC properties to promote survival and expansion, thus underlying disease recurrence and resistance to conventional therapies, and we detail our current understanding of leukaemic ‘stemness’ regulation. Overall, we link the cellular and molecular mechanisms regulating HSC behaviour with the functional dysregulation of these mechanisms in myeloid leukaemia and discuss opportunities for targeting LSC-specific mechanisms for the prevention or cure of malignant diseases. This Review outlines the ways in which leukaemic stem cells (LSCs) take advantage of normal haematopoietic stem cell properties to promote survival and expansion in myeloid leukaemogenesis. Opportunities for treatment of this disease by targeting LSC-specific mechanisms are also discussed.