The genesis and evolution of acute myeloid leukemia stem cells in the microenvironment: From biology to therapeutic targeting

Abstract

Acute myeloid leukemia (AML) is a hematological malignancy characterized by cytogenetic and genomic alterations. Up to now, combination chemotherapy remains the standard treatment for leukemia. However, many individuals diagnosed with AML develop chemotherapeutic resistance and relapse. Recently, it has been pointed out that leukemic stem cells (LSCs) are the fundamental cause of drug resistance and AML relapse. LSCs only account for a small subpopulation of all leukemic cells, but possess stem cell properties, including a self-renewal capacity and a multi-directional differentiation potential. LSCs reside in a mostly quiescent state and are insensitive to chemotherapeutic agents. When LSCs reside in a bone marrow microenvironment (BMM) favorable to their survival, they engage into a steady, continuous clonal evolution to better adapt to the action of chemotherapy. Most chemotherapeutic drugs can only eliminate LSC-derived clones, reducing the number of leukemic cells in the BM to a normal range in order to achieve complete remission (CR). LSCs hidden in the BM niche can hardly be targeted or eradicated, leading to drug resistance and AML relapse. Understanding the relationship between LSCs, the BMM, and the generation and evolution laws of LSCs can facilitate the development of effective therapeutic targets and increase the efficiency of LSCs elimination in AML.

Fig. 1. ROS exert selective pressure for the clonal evolution in AML.

Different from HSC, which mainly obtains energy through glycolysis, LSC mainly relies on oxidative phosphorylation (OXPHOS) to support cell metabolism and survival, thus producing a relatively high ROS level [94]. Chemotherapeutic drugs and chronic inflammation also promote ROS production [37, 41, 42]. In addition, oncogenes such as FLT3(ITD) and BCR-ABL1 can also facilitate intracellular ROS production through NOX or RAC2-MRC cIII pathway [95, 96]. High levels of ROS not only lead to mutagenic reactions in the DNA, but also inhibit DNA repair enzymes, resulting in genomic instability, which may be an important driver of LSC evolution [97]. Rac Rac GTPase; TCA tricarboxylic acid; MRC-cIII mitochondrial respiratory chain complex III.

Fig. 2. Interaction between LSC and BMM.

LSC interact and adhere to various niche cells (such as MSCs, osteoblasts, adipocytes, and endothelial cells) and various ECM molecules secreted by them. The interaction between LSC and BMM can activate many important signaling pathways, thereby regulating the biological function of LSC and remodeling BMM accordingly. (1) The CXCL12/CXCR4 axis plays a key role in LSC maintenance and can activate multiple signaling pathways, such as PI3K/AKT/mTOR, to regulate the survival and proliferation of LSC [98]; (2) The interaction between VLA4 from LSC cells and fibronectin (FN) from MSCs activates the PI3K/AKT/BCL2 pathway, allowing LSCs to be resistant to cytotoxic drugs [99]; (3) The binding of E-selectin to CD44 activates the Wnt [100] and PI3K/AKT/NF-κB signaling pathway [101], and promotes LSC survival; (4) The binding of Jagged to Notch activates the Notch signaling pathway, and the intracellular domain NICD of Notch is then released and translocated into the nucleus to activate the transcription of related genes [102]; (5) Hypoxia can promote the HIF-1α-VEGF signaling pathway and angiogenesis. In addition, NF-κB can promote the production of MMPs and VEGF, which in turn accelerates angiogenesis [103]; (6) LSC-secreted exosomes can induce the expression of DKK1 in MSCs, a suppressor of normal hematopoiesis and osteogenesis, thereby leading to the loss of osteoblasts [50]. BCL-2 B-cell lymphoma 2; Fn fibronectin; MMPs matrix metalloproteinases; mTOR mammalian target of rapamycin; NF-κB nuclear transcription factor-κB; OPN osteopontin; VLA4 very late antigen 4; Wnt wingless-type protein.