The concept of leukaemic stem cells in acute myeloid leukaemia 25 years on: hitting a moving target

Abstract

Summary The concept of leukaemic stem cells (LSCs) was experimentally suggested 25 years ago through seminal data from John Dick's group, who showed that a small fraction of cells from acute myeloid leukaemia (AML) patients were able to be adoptively transferred into immunodeficient mice. The initial estimation of the frequency was 1:250 000 leukaemic cells, clearly indicating the difficulties ahead in translating knowledge on LSCs to the clinical setting. However, the field has steadily grown in interest, expanse and importance, concomitantly with the realisation of the molecular background for AML culminating in the sequencing of hundreds of AML genomes. The literature is now ripe with contributions describing how different molecular aberrations are more or less specific for LSCs, as well as reports showing selectivity in targeting LSCs in comparison to normal haematopoietic stem and progenitor cells. However, we argue here that these important data have not yet been fully realised within the clinical setting. In this clinically focused review, we outline the difficulties in identifying and defining LSCs at the individual patient level, with special emphasis on intraclonal heterogeneity. In addition, we suggest areas of future focus in order to realise the concept as real‐time benefit for AML patients.

Effective Drug Concentration and Selectivity Depends on Fraction of Primitive Cells

“…Research of CSCs based on the etiology of AML has the potential to translate into more effective therapies aimed at eliminating the cell stage responsible for the initiation and relapse of the disease [ 87 ]. The hope for achieving a therapeutic breakthrough in AML is associated with a new generation of drugs that selectively target the self-replenishing, most primitive stages of the cancer.…”

Interferon Gamma Secretion of Adaptive and Innate Immune Cells as a Parameter to Describe Leukaemia-Derived Dendritic-Cell-Mediated Immune Responses in Acute Myeloid Leukaemia in vitro

“…Standard therapy for AML consists of chemotherapy with or without allogeneic haematopoietic stem cell transplantation [3,4]. With overall 5-year survival rates of 28.7%, mainly due to infections and relapses initiated by leukaemic stem cells and residual blasts, the outcome though remains unsatisfactory [5][6][7].…”

Systematic molecular profiling of acute leukemia cancer stem cells allows identification of druggable targets

“…However, as different studies have detected different expression levels of these two markers for the detection of AML CSCs, besides several other markers that are being used for this purpose ( Yabushita et al., 2018 ), currently there is no universal marker or combination of markers for the isolation of AML CSCs ( Spyrou and Papapetrou, 2020 ). Having said that, functional validation of marker-based isolated AML CSCs based on xenotransplantation assays is considered as the “gold standard” for the precise separation of AML CSCs ( Hokland et al., 2019 ; Spyrou and Papapetrou, 2020 ). Accordingly, a single microarray dataset (GSE30375) was selected based on a rigorous search and filtration strategy and was obtained from the gene expression omnibus (GEO) repository.…”