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.

Attenuated cell cycle and DNA damage response transcriptome signatures and overrepresented cell adhesion processes imply accelerated progression in patients with lower‐risk myelodysplastic neoplasms

“…The most characteristic transcriptomic signature of prMDS CD34+ cells distinguishing them from stMDS cells was the expression pattern of quiescent-like or slowly proliferating progenitors with LSC markers, and the signatures of processes that are associated with or regulate non-cycling malignant stem cells: that is, suppressed DDR and dysregulated adhesion pathways. 39 It is likely that the aforementioned changes in the cellular composition of CD34+ subpopulations between prMDS vs stMDS CD34+ cells (ie, their differentiation status) determine to some extent the differences in gene expression signatures. 38 We propose that prMDS CD34+ cells bear cell-autonomous and perhaps also noncellautonomous defects to establish a tumor-suppressing DDR barrier;…”

Deregulated Gene Expression Profiles and Regulatory Networks in Adult and Pediatric RUNX1/RUNX1T1-Positive AML Patients

“…A large number of studies have recently revealed that AML patients have repeated mutations in several important epigenetic mediators [ 82 ]. Mutations in genes involved in DNA methylation, such as DNA methyltransferase 3A (DNMT3A) and isocitrate dehydrogenase 1 and 2 (IDH1/2), are the most common.…”

Crosstalk between autophagy and metabolism: implications for cell survival in acute myeloid leukemia

“…Compared to their healthy counterparts, tumor cells not only consume glucose at an accelerated rate, but they also exhibit significantly increased demand for amino acids to support rapid growth and proliferation [ 64 , 65 ]. Recent studies have reported that Leukemic stem cells (LSCs), including those in AML, heavily rely on amino acid metabolism, crucial for maintaining their stemness.…”