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Dysregulated haematopoietic stem cell behaviour in myeloid leukaemogenesis

Nature Reviews Cancer volume 20, pages 365–382 (2020)Cite this article

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Abstract

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.

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Fig. 1: Dynamic and coordinated regulation of HSC activity.
Fig. 2: Dysregulation of HSC properties during LSC emergence and leukaemia development.
Fig. 3: Mechanisms of LSC resistance.

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Acknowledgements

The work of the authors is supported by the fellowships NIH F31HL151140 to P.V.D., and T32HL120826 to O.C.O., and by grant NIH R35HL135763 and a SWCRF award to E.P.

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Authors and Affiliations

  1. Columbia Stem Cell Initiative, Department of Genetics & Development, Columbia University Irving Medical Center, New York, NY, USA

    Masayuki Yamashita, Paul V. Dellorusso, Oakley C. Olson & Emmanuelle Passegué

  2. Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Masayuki Yamashita

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  1. Masayuki Yamashita
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  2. Paul V. Dellorusso
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  3. Oakley C. Olson
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  4. Emmanuelle Passegué
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M.Y., P.V.D. and O.C.O. contributed equally to all aspects of the manuscript. E.P. made a substantial contribution to discussion of the content, and also wrote and reviewed/edited the manuscript before submission.

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Correspondence to Emmanuelle Passegué.

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Glossary

Haematopoietic stem cells

(HSCs). Blood-forming stem cells that possess self-renewal and multilineage differentiation capacity, giving rise to all types of blood cells, including granulocytes, monocytes, dendritic cells, erythrocytes, platelets and lymphocytes.

Acute myeloid leukaemia

(AML). Malignant disease with rapid onset in which haematopoietic progenitors are arrested in an early stage of myeloid differentiation.

Bone marrow

The soft, spongy tissue that fills the inner cavities of most bones; in adult mammals, it is the place where haematopoiesis occurs and where most of the blood cells are produced.

Peripheral blood

Fluid (plasma) and blood cells circulating throughout the body; it contains white blood cells (leukocytes), red blood cells (erythrocytes) and platelets.

HSC transplantation

(HSCT). Transplantation of HSCs from donors matched in human leukocyte antigen to the recipient; HSCs are usually derived from bone marrow, peripheral blood or umbilical cord blood. The therapeutic effect derives from myeloablative conditioning and the graft-versus-tumour effect of the donor immune system.

Measurable residual disease

A small number of leukaemic cells that remain in the body during or after treatment; this is a major cause of leukaemia relapse and is typically detected by PCR or flow cytometry.

Leukaemic stem cells

(LSCs). Subset of leukaemic cells that share many features with HSCs, including self-renewal capacity and resistance to anti-cancer drugs, thereby considered as a major contributor to leukaemia development and relapse.

Multipotent progenitors

(MPPs). Early haematopoietic progenitors generated by HSCs that can differentiate into all types of blood cells, but that do not have self-renewal capacity.

G0 phase

An inactive, non-proliferative state of the cell cycle from which HSCs can reversibly exit to enter the cell cycle in response to physiological stimuli (also referred to as quiescence).

Reactive oxygen species

(ROS). Oxygen-containing compounds that easily react with other molecules. They are generated by many biological processes, including mitochondrial oxidative phosphorylation, and can damage cellular components such as DNA, RNA, proteins and lipids. ROS can also act as signalling molecules.

Oxidative phosphorylation

(OXPHOS). Process by which ATP, a usable form of energy in a cell, is produced through the phosphorylation of ADP as a result of the oxygen-driven electron transfer chain in mitochondria.

Granulocyte–macrophage progenitor

(GMP). A committed myeloid progenitor, generated by HSCs, that can only differentiate to the granulocytic and monocytic lineages.

Pre-leukaemic HSCs

Subset of HSCs that are mutated but still capable of differentiating to all lineages of blood cells. They can be found in patients with leukaemia at diagnosis and in clinical remission.

Age-related clonal haematopoiesis

(ARCH). Asymptomatic, age-associated clonal expansion of blood cells derived from mutated HSCs, associated with increases in the risk of haematological malignancy, cardiovascular disease and all-cause mortality.

Myeloproliferative neoplasms

(MPNs). Clonal haematopoietic disorders characterized by the overproduction of mature cells. They include chronic myeloid leukaemia, polycythemia vera, essential thrombocythemia and primary myelofibrosis. Sometimes these disorders transform to AML.

Myelodysplastic syndromes

(MDSs). Haematological disorders characterized by cytopenia in one or more blood lineages, production of abnormal blood cells and destruction of the bone marrow niche microenvironment. Sometimes these also transform to AML.

TET2

Gene encoding the enzyme that converts 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine in an α-ketoglutarate (αKG) and Fe2+-dependent manner. Essential for DNA demethylation.

DNMT3A

Gene encoding the enzyme that promotes DNA methylation by catalysing the transfer of methyl groups from S-adenosylmethionine to specific CpG sites of DNA, resulting in the conversion of cytosine into 5-mC.

DNA double-strand breaks

(DSBs). Severe form of DNA damage in which both strands of DNA are broken, typically caused by ionizing radiation and replication fork collapse. Its misrepair results in chromosomal aberration.

Non-homologous end joining

(NHEJ). Mutation-prone repair process in which the two DSB ends are directly ligated. Does not require sister-chromatid-like homology repair and can occur throughout the cell cycle, including in G0 phase.

PI3K–AKT–mTORC1 pathway

Intracellular signalling pathway that is critical for metabolic activation and cell cycle entry. Regulates various cellular functions, including nutrient uptake, anabolic reactions, autophagy inhibition, cell growth and survival.

BCL-2

Protein that controls cell survival by blocking the mitochondrial apoptosis pathway. Also involved in non-apoptotic processes such as improving OXPHOS and inhibiting autophagy.

Venetoclax–5-azacitidine

Treatment approach combining a BCL-2 inhibitor and a DNA demethylating agent that effectively targets LSCs in AML. Such treatment might have profound implications for changing the ‘standard of care’ currently used in the clinic to treat patients with AML.

Fatty acid oxidation

(FAO). Process by which fatty acids are broken down in mitochondria by sequential oxidation in order to produce acetyl-CoA and generate ATP via electron transport chain.

Branched-chain amino acid

(BCAA). One of three essential amino acids with branched-chain structures (e.g., valine, leucine and isoleucine) that cannot be synthesized de novo in the body and therefore must be obtained from food.

FOXO transcription factors

Transcription factors involved in cellular metabolism and resistance to oxidative stress. Their activation can promote quiescence, autophagy induction and ROS detoxification. They are directly phosphorylated and inhibited by the PI3K–AKT pathway.

TNF

Inflammatory cytokine that can induce various intracellular signalling pathways upon recognition by its receptors. TNF is also known as a death ligand that causes apoptosis and necroptosis.

NF-κB–p65–cIAP2 axis

Intracellular signalling pathway that promotes cell survival by ubiquitylating RIPK1 and stabilizing pro-survival TNF receptor complex I upon TNF ligation, activation of an NF-κB subunit p65 and transactivation of cIAP2.

FLT3-ITD

A poor prognostic mutation common in AML that leads to constitutive activation of the FLT3 receptor tyrosine kinase.

Regulatory T cells

(Tregs). Subpopulation of T cells that act by suppressing the proliferation and cytokine production of other immune cells; they are essential for preventing autoimmunity.

Human leukocyte antigen

(HLA). A major histocompatibility complex in humans, expressed on the cell surface to present antigenic peptides to the T cell receptor on T cells. It is involved in acquired immunity activation and self-versus-nonself discrimination.

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Yamashita, M., Dellorusso, P.V., Olson, O.C. et al. Dysregulated haematopoietic stem cell behaviour in myeloid leukaemogenesis. Nat Rev Cancer 20, 365–382 (2020). https://doi.org/10.1038/s41568-020-0260-3

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