Lingbo Liu

Background: Drug resistance and relapse are still major challenges in acute myeloid leukemia (AML) because of the inability to effectively eradicate leukemia stem cells (LSCs). Senescence induction combined with immune killing may offer promising strategies for LSC eradication. However, whether and how drug-resistant LSCs retain stemness via senescence and immune regulation remains unknown. Methods: The immunoproteasome subunit PSMB10 expression levels were analyzed by single-cell RNA-seq data, along with the bioinformatics analysis of publicly available AML datasets, and quantified using RT-qPCR and flow cytometry (FCM) analysis on clinical samples from AML patients. The cellular senescence was evaluated by the assays of cell proliferation, cell cycle, senescence-associated β-galactosidase activity, and senescence-associated secretory phenotype factors. In vitro T-cell killing assay was played to determine immune escape reprogramming of AML cells. FCM was conducted to estimate intracellular drug concentration and cellular apoptosis rates. Human AML xenografts and PSMB10 knockout syngeneic mouse bone marrow transplantation models were utilized to investigate the function of PSMB10. Various techniques were employed for mechanism studies, including Lentivirus transduction or siRNA transfection, western blotting, co-immunoprecipitation assays, luciferase reporter assays, polysome profiling assays, quantitative proteomics, etc. Results: PSMB10 mRNA was significantly upregulated in the surviving nonsenescent LSCs, exhibiting a 13-fold increase compared to senescent LSCs following chemotherapy. The specific high expression of PSMB10 in post-chemotherapy nonsenescent LSCs predicts a poor AML prognosis. The genetic inactivation of PSMB10 resulted in increased senescence and cytotoxic T lymphocyte (CTL) killing, as well as increased intracellular drug concentrations and drug-induced cellular senescence in different types of human AML cells, which also impeded human and murine leukemia initiation and stemness maintenance in vivo with a 19-fold decrease in the frequency of human LSCs and a 7.6-fold decrease of drug-resistant mouse LSCs, while normal hematopoietic cells remained unaffected. Mechanistically, the downregulation of PSMB10 boosted SLC22A16-mediated drug endocytosis and further induced chemotherapy drug-mediated senescence through the RPL6/RPS6-MDM2-P21 pathway in AML cells. Additionally, downregulating PSMB10 also impeded MHC-I protein degradation-induced escape of CTL killing. Conclusions: PSMB10 is a key candidate molecular target for eradicating drug-resistant LSCs via senescence and immune regulation.

Malignant tumors can evade immune surveillance and elimination through multiple mechanisms, with the induction of immune cell dysfunction serving as a crucial strategy. Mounting evidence indicates that T cell senescence constitutes the primary mechanism underlying T cell dysfunction in acute myeloid leukemia (AML) and represents one of the potential causes of immunotherapy failure. AML usually progresses rapidly and is highly susceptible to drug resistance, thereby resulting in recurrence and patient mortality. Hence, disrupting the immune interface within the bone marrow microenvironment of AML has emerged as a critical objective for synergistically enhancing tumor immunotherapy. In this review, we summarize the general characteristics, distinctive phenotypes, and regulatory signaling networks of senescent T cells and highlight their potential clinical significance in the bone marrow microenvironment of AML. Additionally, we discuss potential therapeutic strategies for alleviating and reversing T cell senescence.

Both the senescence of cancer cells and the maintenance of cancer stem cells seem to be mutually exclusive because senescence is considered a physiological mechanism that effectively suppresses tumor growth. Recent studies have revealed common signaling pathways between cellular senescence and the maintenance of stemness in cancer cells, thus challenging the conventional understanding of this process. Although the links between these processes have not yet been fully elucidated, emerging evidence indicates that senescent cancer cells can undergo reprograming to recover stemness. Herein, we provide a comprehensive overview of the close correlation between senescence and stemness reprograming in cancer cells, with a particular focus on the mechanisms by which senescent cancer cells recover their stemness in various tumor systems.

The fate of leukaemia stem cells (LSCs) is determined by both their inherent mechanisms and crosstalk with their niches. Although LSCs were confirmed to be eradicated by restarting senescence, the specific key regulators of LSC resistance to senescence and remodelling of the niche to obtain a microenvironment suitable for stemness remain unknown. Here, we found that RAB27B, a gene regulating exosome secretion, was overexpressed in LSCs and associated with the poor prognosis of acute myeloid leukaemia (AML) patients. The increased RAB27B in LSCs prevented their senescence and maintained their stemness in vitro and in vivo. Mechanically, the increased RAB27B expression in LSCs selectively promoted the loading and release of exosomes rich in senescence-inducing proteins by direct combination. Furthermore, RAB27B-regulated LSC-derived exosomes remodelled the niche and induced senescence of mesenchymal stem cells (MSCs) with increased RAB27B expression ex vivo and in vivo. The increased RAB27B in the senescent MSCs conversely promoted LSC maintenance ex vivo and in vivo via selective excretion of exosomes rich in stemness-promoting proteins. Therefore, we identified the specifically increased RAB27B in LSCs and their educated senescent MSCs as a hub molecule for LSC resistance to senescence and maintenance through crosstalk with its niche via selective exosome excretion.

Gene-expression regulation involves multiple processes and a range of regulatory factors. In this review, we describe the key factors that regulate gene expression, including transcription factors (TFs), chromatin accessibility, histone modifications, DNA methylation, and RNA modifications. In addition, we also describe methods that can be used to detect these regulatory factors.

Acute myeloid leukemia (AML) is a polyclonal and heterogeneous hematological malignancy. Relapse and refractory after induction chemotherapy are still challenges for curing AML. Leukemia stem cells (LSCs), accepted to originate from hematopoietic stem/precursor cells, are the main root of leukemogenesis and drug resistance. LSCs are dynamic derivations and possess various elusive resistance mechanisms. In this review, we summarized different primary resistance and remolding mechanisms of LSCs after chemotherapy, as well as the indispensable role of the bone marrow microenvironment on LSCs resistance. Through a detailed and comprehensive review of the spectacle of LSCs resistance, it can provide better strategies for future researches on eradicating LSCs and clinical treatment of AML.

Cellular senescence is traditionally considered as stable cell cycle arrest state with other phenotypic alterations including the production of an array of cytokines and growth factors. Cancer cells undergo senescence in response to chemotherapeutic agents, radiotherapy and molecular targeted therapy. This form of senescence is termed therapy-induced senescence (TIS) and represents a desirable target in cancer therapy. Recent studies have shown that cellular senescence is a highly heterogeneous and dynamic process. Apart from being cleared by the immune system, the senescent cancer cells may survive for a long time and escape from senescence state. Notably, these cells even have the potential to regain stem-like state with high aggressiveness that eventually facilitates cancer recurrence. Furthermore, the senescence-associated secretory phenotype (SASP) of senescent cells is not always the same, and could establish immunosuppression and a protumor microenvironment. Given these detrimental effects, senescence-inducing chemotherapy followed by senotherapy (the “one–two punch” approach), has emerged. This combined therapy could mitigate unnecessary side effects of the persistent senescent cells, reduce the toxicity of pro-senescence therapy and prolong the survival of cancer patients, and it has a potential future in the precise treatment of cancer. Herein, we review the complex effects of therapy-induced senescence in cancer and highlight the great promise of two-step strategies in anticancer therapies.