Acute Myeloid Leukemia Stem Cells: Origin, Characteristics, and Clinical Implications

Abstract

The stem cells of acute myeloid leukemia (AML) are the malignancy initiating cells whose survival ultimately drives growth of these lethal diseases. Here we review leukemia stem cell (LSC) biology, particularly as it relates to the very heterogeneous nature of AML and to its high disease relapse rate. Leukemia ontogeny is presented, and the defining functional and phenotypic features of LSCs are explored. Surface and metabolic phenotypes of these cells are described, particularly those that allow distinction from features of normal hematopoietic stem cells (HSCs). Opportunities for use of this information for improving therapy for this challenging group of diseases is highlighted, and we explore the clinical needs which may be addressed by emerging LSC data. Finally, we discuss current gaps in the scientific understanding of LSCs.

Keywords: Acute Myeloid Leukemia; Hematopoiesis; Leukemia; Leukemia Stem Cell.

Fig. 1

In normal hematopoiesis (green box), quiescent hematopoietic stem cells (HSCs) with self-renewal capacity give rise to multipotent progenitors (MPPs), which can differentiate towards lymphoid primed multipotent progenitors (LMPPs), common myeloid progenitors (CMPs), common lymphoid progenitors (CLPs), granulocyte–macrophage progenitors (GMPs) and megakaryocyte erythroid progenitors (MEP). The primary/initial mutations in HSCs and progenitor cells give rise to pre leukemic stem cells, that, over time can be further transformed into leukemic stem cells (LSCs). In many cases, this process does not involve a clinically recognized pre-leukemic process, but generally, more than one mutation seems needed to generate frank acute leukemia. A restricted progenitor can be transformed to LSC by secondary mutations that confer self-renewal. Acute Myeloid Leukemia (AML) originates from the transformation of normal HSCs, MPPs, or more committed progenitors, developing in leukemic stem cells (LSCs) that subsequently can give rise to full blown leukemia. While treatment with standard induction chemotherapy results in complete remission in the majority of AML patients, a population of (chemo)therapy-resistant cells (TRCs) constituting AML cells with leukemia-initiating potential survive the treatment. LSCs with leukemia-initiating potential within minimal residual disease (MRD) could initiate a relapse. Instead of (chemo)therapeutic selection of pre-existing subpopulations of LSCs, AML cells might adaptively obtain a transient leukemia regenerating cell (LRC) phenotype upon exposure to treatment allowing for regeneration of the leukemia and clinical relapse.

Fig.2

The comparison between stem cell niche organization during normal and malignant hematopoiesis. The HSCs (left) and LSCs (right) reside in bone marrow (BM) niche consisting of hematopoietic cells, cell populations of stromal origin such as mesenchymal stromal cells (MSC) and perivascular endothelial cells (located in blood vessels sinusoids/arterioles), and Extracellular matrix (ECM). In particular, the nestin and/or leptin receptors positive MSC around endothelial sinusoid/arteriole have high expression of chemokine CXCL12 that act as attractant for CXCR4-expressing HSCs. The CD146 positive mesenchymal progenitors provide factors that facilitate homing, proliferation, transendothelial migration, and differentiation of HSCs/ LSCs. The quiescent HSCs are dormant (G0) cells, whereas active HSCs represent cells that have just exited quiescence or actively cycling or migrating. The relevant stromal cell populations were illustrated here along with their interactions and soluble factors such ascytokines that are secreted to support expansion of stem cells in the niche. The arrows represent the direct effects/factors, whereas dotted arrows indicate indirect effects and thick arrows for showing differentiation process. The hypoxic BM niche is regulated by Hypoxiainducible factors (HIF-1/HIF-2), and proliferation of LSCs leads to the expansion of hypoxic niches during malignancy/leukemias. Not all depicted features of the LSC niche will be found to operate in every case of AML. The figure is intend to simplify and represent some of the best candidate niche cells and molecules that were found to be altered during leukemias. OB, Osteoblast; OC, Osteoclast; Mac, Macrophages; Treg, Regulatory T cells; HSC, hematopoietic stem cell; LSC, leukemia stem/initiating cell; MSC, mesenchymal stromal/ stem cells; ECM, extracellular matrix; nmSC, non-myelinating Schwann cells; NA, noradrenaline; CAR cells (CXCL12-abundant reticular cells); CXCL12, C-X-C motif chemokine 12; G-CSF, granulocyte-colony stimulating factor; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor; TPO, thrombopoietin;CCL3, Chemokine (C–C motif) ligand 3; IL-1β/6/7, interleukin 1β/6/7; SCF, stem cell factor; ANGPT1, angiopoietin 1