Targeting chemoresistance and mitochondria-dependent metabolic reprogramming in acute myeloid leukemia

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: Sept. 7, 2023

Chemoresistance often complicates the management of cancer, as noted in instance acute myeloid leukemia (AML). Mitochondrial function is considered important for viability AML blasts and appears to also modulate chemoresistance. As mitochondrial metabolism aberrant AML, any distinct pathways could be directly targeted impact both cell Therefore, identifying targeting those precise rogue elements a valid therapeutic strategy leukemia. Here, we review evidence abnormalities mitochondria metabolic processes cells, that likely We further address several approaches isocitrate dehydrogenase 2 (IDH2), CD39, nicotinamide phosphoribosyl transferase (NAMPT), electron transport chain (ETC) complex consider roles mesenchymal stromal cells. propose term "mitotherapy" collectively refer such regimens attempt override mitochondria-mediated reprogramming, used by cancer Mounting suggests mitotherapy provide complementary overcome chemoresistance liquid cancers, well solid tumors.

Language: Английский

---

Bone Marrow Stromal Cells Enhance Differentiation of Acute Myeloid Leukemia Induced by Pyrimidine Synthesis Inhibitors

AJP Cell Physiology, Journal Year: 2024, Volume and Issue: 327(5), P. C1202 - C1218

Published: Sept. 16, 2024

Acute myeloid leukemia (AML) is a heterogeneous group of hematological malignancies characterized by differentiation arrest, high relapse rates, and poor survival. The bone marrow (BM) microenvironment recognized as critical mediator drug resistance primary site responsible for AML relapse. Our previous study reported that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) induces cell inhibiting pyrimidine synthesis activating Checkpoint kinase 1. Although the protective effect BM stroma on cells in response to cytotoxic drugs well-documented, its remains less explored. In this study, we investigated impact stromal lines mesenchymal (MSCs) line triggered AICAr brequinar, known dihydroorotate dehydrogenase (DHODH) inhibitor. findings indicate mouse MS-5 line, cytoprotective effects, does not inhibit induced inhibitors. Interestingly, caused morphological changes growth arrest via an AMP-activated protein (AMPK)-dependent pathway. Human HS-5 HS-27, well MSCs isolated from patient marrow, were superior promoting compared with inhibitors significantly affecting themselves. conclusion, our highlights supportive role human enhancing effects cells, suggesting treatment strategies focusing rather than killing may be successful clinical settings.

Language: Английский

---

Dissecting L-glutamine metabolism in acute myeloid leukemia: single-cell insights and therapeutic implications

Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: Nov. 6, 2024

Acute myeloid leukemia (AML) is a rapidly progressing blood cancer. The prognosis of AML can be challenging, emphasizing the need for ongoing research and innovative approaches to improve outcomes in individuals affected by this formidable hematologic malignancy. In study, we used single-cell RNA sequencing (scRNA-seq) from patients investigate impact L-glutamine metabolism-related genes on disease progression. Our analysis revealed increased glutamine-related activity CD34 + pre-B cells, suggesting potential regulatory role tumorigenesis Furthermore, intercellular communication significant signaling pathway involving macrophage migration inhibitory factor through CD74 CD44 within which transmit signals pre-dendritic cells monocytes. Ligands were predominantly expressed stromal naïve T cells. CD74, pertinent receptor, was detected variety cellular components, including plasmacytoid dendritic hematopoietic progenitors. study's results provide insights into possible interplay among these cell types their collective contribution pathogenesis AML. Moreover, identified 10 associated with prognosis, CCL5, CD52, CFD, FABP5, LGALS1, NUCB2, PSAP, S100A4, SPINK2, VCAN. Among these, CCL5 CD52 have been implicated progression are therapeutic targets. This thorough examination biology significantly deepens our grasp presents pivotal information that could guide creation treatment strategies patients.

Language: Английский

---

Endocan in Acute Leukemia: Current Knowledge and Future Perspectives

Biomolecules, Journal Year: 2022, Volume and Issue: 12(4), P. 492 - 492

Published: March 24, 2022

Endocan is a soluble dermatan sulfate proteoglycan expressed by endothelial cells and detected in serum/plasma. Its expression increased tumors/tumor vessels several human malignancies, high (high serum/plasma levels or tumor levels) has an adverse prognostic impact malignancies. The p14 endocan degradation product can also be serum/plasma, but previous clinical studies as well previously unpublished results presented this review suggest that fragment reflect different biological characteristics, the seem to disease heterogeneity acute leukemia better than levels. Furthermore, decreased systemic immunocompetent sepsis patients are associated with later severe respiratory complications, it not known whether true for immunocompromised patients. Finally, early nonrelapse mortality (acute leukemia) receiving allogeneic stem cell transplantation, seems independent of excessive fluid overload. Systemic may become important predict cytokine release syndrome after immunotherapy/haploidentical long-term follow-up survivors regard cardiovascular risk. Therapeutic targeting now possible, possible role should further investigated clarify therapeutic strategy considered.

Language: Английский

---

Tackling the tumor microenvironment – how can complex tumor models in vitro aid oncology drug development?

Expert Opinion on Drug Discovery, Journal Year: 2023, Volume and Issue: 18(7), P. 753 - 768

Published: May 23, 2023

Introduction Identifying effective cancer drugs remains an inefficient process. Drug efficacy in traditional preclinical models translates poorly into therapy the clinic. Implementation of that incorporate tumor microenvironment (TME) is needed to improve selection active prior clinical trials.Areas covered Progression results from behavior cells concert with host's histopathological background. Nonetheless, complex a relevant have yet become integral part drug development. This review discusses existing and provides synopsis areas development where implementation would be value. Their contribution finding therapeutics immune oncology, angiogenesis, regulated cell death targeting fibroblasts as well optimization delivery, combination therapy, biomarkers considered.Expert opinion Complex vitro (CTMIVs) mimic organotypic architecture neoplastic tumors boosted research TME influence on cytoreductive chemotherapy detection specific targets. Despite advances technical prowess, CTMIVs can only address aspects pathophysiology.

Language: Английский

---

In Vitro Insights Into the Influence of Marrow Mesodermal/Mesenchymal Progenitor Cells on Acute Myelogenous Leukemia and Myelodysplastic Syndromes

Stem Cells, Journal Year: 2023, Volume and Issue: 41(9), P. 823 - 836

Published: June 22, 2023

The study of marrow-resident mesodermal progenitors can provide important insight into their role in influencing normal and aberrant hematopoiesis as occurs acute myelogenous leukemia (AML) myelodysplastic syndromes (MDS). In addition, the chemokine competency these cells provides links to inflammatory milieu marrow microenvironment with additional implications for malignant hematopoiesis. While vivo studies have elucidated structure function niche murine genetic models, corollary human not been feasible, thus use culture-adapted has provided insights rare endogenous play physiologic, malignant, states. This review focuses on mesenchymal stem/stromal (MSCs) they utilized understanding influence AML MDS well chemokine-mediated responses myeloid malignancies, injury, inflammation. Such intrinsic limitations but mechanistic clues regarding novel druggable targets.

Language: Английский

---

Bone marrow stromal cells reduce low-dose cytarabine-induced differentiation of acute myeloid leukemia

Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14

Published: Oct. 26, 2023

Low-dose cytarabine (LDAC) is a standard therapy for elderly acute myeloid leukemia (AML) patients unfit intensive chemotherapy. While high doses of induce cytotoxicity, the precise mechanism action LDAC in AML remains elusive. In vitro studies have demonstrated LDAC-induced differentiation; however, such differentiation seldom observed vivo . We hypothesize that this discrepancy may be attributed to influence bone marrow (BM) stromal cells on cells. Thus, study aimed investigate impact BM cell lines and primary samples. Our results demonstrate presence MS-5 prevented cycle arrest, DNA damage signaling U937 MOLM-13 lines. Although transcriptomic analysis revealed stroma reduces expression genes involved cytokine oxidative stress, data obtained with pharmacological inhibitors neutralizing antibodies did not support role CXCL12, TGF-β1 or reactive oxygen species. The samples from AML-M4 myelodysplastic syndrome/AML patients. conclusion, our demonstrates induced by LDAC. These findings provide insights into limited occurrence terminal patients, suggest potential explanation observation.

Language: Английский

---

DNA damage to bone marrow stromal cells by antileukemia drugs induces chemoresistance in acute myeloid leukemia via paracrine FGF10–FGFR2 signaling

Journal of Biological Chemistry, Journal Year: 2022, Volume and Issue: 299(1), P. 102787 - 102787

Published: Dec. 9, 2022

Language: Английский

---

Deciphering the Role of the MST1/2-YAP Axis in Irisin-Treated Aplastic Anemia: Implications for Mesenchymal Stem Cell Function

Published: May 2, 2024

Aplastic anemia (AA) is a debilitating hematological disorder characterized by bone marrow failure. Recent advancements in mesenchymal stem cell (MSC) research have highlighted potential therapeutic avenues, particularly through the modulation of cellular pathways influenced novel agents like Irisin. This study investigates Irisin's effects on MSCs context AA using advanced techniques such as single-cell sequencing and spatial transcriptomics. Irisin administration model mice significantly altered gene expression MSCs, affecting 935 genes associated with Hippo signaling pathway, notably MST1/2-YAP axis. These changes were linked to decreased adipogenic differentiation enhanced mitochondrial membrane system homeostasis. In vitro experiments supported these findings, showing capability inhibit pathway suppress adipogenesis cells (BMSCs). Corresponding vivo studies demonstrated that treatment not only downregulated Mst1 Mst2 but also upregulated Yap expression. Importantly, molecular alterations led reduced adiposity improved hematopoietic function mice, showcasing an effective option. The underscores critical role mediating effects, suggesting promising strategies for management targeted MSC modulation.

Language: Английский

---

Senescent T Cells: The Silent Culprit in Acute Myeloid Leukemia Progression?

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(23), P. 12550 - 12550

Published: Nov. 22, 2024

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

Language: Английский

---