Profiling of Metabolic Differences between Hematopoietic Stem Cells and Acute/Chronic Myeloid Leukemia

Song, Byung Hoo; Son, Su Young; Kim, Hyun Kyu; Ha, Tae Won; Im, Jeong Suk; Ryu, Aeli; Jeon, Han Yong; Chung, Hee Yong; Oh, Jae Sang; Lee, Choong Hwan; Lee, Man Ryul

doi:10.3390/metabo10110427

Cited by 7 publications

(7 citation statements)

References 33 publications

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“…Therefore, additional in vivo experiments are required to verify the regulatory mechanisms in the present study. Second, K562 and HEL cells, which are acute myeloid leukemia-like cell line and human erythroleukemia cell line, and hematopoietic stem cells have certain similarities regarding erythropoietic development, but there are still some differences between the two cell types ( Deezagi, 2014 ; Song et al, 2020 ). Finally, the function of the EPAS1-IRS2 axis in K562 cell erythroid development has been researched here, but its precise molecular mechanism has not been completely investigated.…”

Section: Discussionmentioning

confidence: 99%

Regulation of erythroid differentiation in K562 cells by the EPAS1-IRS2 axis under hypoxic conditions

Gao

et al. 2023

Front. Cell Dev. Biol.

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Red blood cells (RBCs) produced in vitro have the potential to alleviate the worldwide demand for blood transfusion. Hematopoietic cell differentiation and proliferation are triggered by numerous cellular physiological processes, including low oxygen concentration (<5%). In addition, hypoxia inducible factor 2α (HIF-2α) and insulin receptor substrate 2 (IRS2) were found to be involved in the progression of erythroid differentiation. However, the function of the HIF-2α-IRS2 axis in the progression of erythropoiesis is not yet fully understood. Therefore, we used an in vitro model of erythropoiesis generated from K562 cells transduced with shEPAS1 at 5% O2 in the presence or absence of the IRS2 inhibitor NT157. We observed that erythroid differentiation was accelerated in K562 cells by hypoxia. Conversely, knockdown of EPAS1 expression reduced IRS2 expression and erythroid differentiation. Intriguingly, inhibition of IRS2 could impair the progression of hypoxia-induced erythropoiesis without affecting EPAS1 expression. These findings indicated that the EPAS1-IRS2 axis may be a crucial pathway that regulates erythropoiesis and that drugs targeting this pathway may become promising agents for promoting erythroid differentiation.

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Section: Discussionmentioning

confidence: 99%

Regulation of erythroid differentiation in K562 cells by the EPAS1-IRS2 axis under hypoxic conditions

Gao

et al. 2023

Front. Cell Dev. Biol.

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“…However, an increasing body of evidence suggests that both glycolysis and mitochondrial metabolism are upregulated in some cancers [ 14 ]. It was found that both glycolysis- and OXPHOS-related signaling pathways are activated in leukemia cells, such as THP-1, U937, KG-1, and K562, as well as cluster of differentiation 34 (CD34)-positive hematopoietic stem cells (HSCs), as a result of an enhanced need for energy metabolism [ 15 ]. It has become clear that TKI-resistant AML and CML, and leukemic stem cells (LSCs) are accompanied by increased OXPHOS, regardless of the presence or absence of genetic mutations; hence, interest has grown in developing clinically applicable OXPHOS inhibitors [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

8-Hydroxydaidzein Downregulates JAK/STAT, MMP, Oxidative Phosphorylation, and PI3K/AKT Pathways in K562 Cells

Wang

Chen

et al. 2021

Biomedicines

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A metabolite isolated from fermented soybean, 8-hydroxydaidzein (8-OHD, 7,8,4′-trihydroxyisoflavone, NSC-678112), is widely used in ethnopharmacological research due to its anti-proliferative and anti-inflammatory effects. We reported previously that 8-OHD provoked reactive oxygen species (ROS) overproduction, and induced autophagy, apoptosis, breakpoint cluster region-Abelson murine leukemia viral oncogene (BCR-ABL) degradation, and differentiation in K562 human chronic myeloid leukemia (CML) cells. However, how 8-OHD regulates metabolism, the extracellular matrix during invasion and metastasis, and survival signaling pathways in CML remains largely unexplored. High-throughput technologies have been widely used to discover the therapeutic targets and pathways of drugs. Bioinformatics analysis of 8-OHD-downregulated differentially expressed genes (DEGs) revealed that Janus kinase/signal transducer and activator of transcription (JAK/STAT), matrix metalloproteinases (MMPs), c-Myc, phosphoinositide 3-kinase (PI3K)/AKT, and oxidative phosphorylation (OXPHOS) metabolic pathways were significantly altered by 8-OHD treatment. Western blot analyses validated that 8-OHD significantly downregulated cytosolic JAK2 and the expression and phosphorylation of STAT3 dose- and time-dependently in K562 cells. Zymography and transwell assays also confirmed that K562-secreted MMP9 and invasion activities were dose-dependently inhibited by 8-OHD after 24 h of treatment. RT-qPCR analyses verified that 8-OHD repressed metastasis and OXPHOS-related genes. In combination with DisGeNET, it was found that 8-OHD’s downregulation of PI3K/AKT is crucial for controlling CML development. A STRING protein–protein interaction analysis further revealed that AKT and MYC are hub proteins for cancer progression. Western blotting revealed that AKT phosphorylation and nuclear MYC expression were significantly inhibited by 8-OHD. Collectively, this systematic investigation revealed that 8-OHD exerts anti-CML effects by downregulating JAK/STAT, PI3K/AKT, MMP, and OXPHOS pathways, and MYC expression. These results could shed new light on the development of 8-OHD for CML therapy.

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“…Each cell contains different types of metabolites because of the presence of individualized metabolic mechanism based on the fate of the cell. Thus, metabolic profiling has attracted considerable attention as an approach that can immediately detect dynamic cell changes and conditions, as well as early development [ 10 ]. Oncogenic mutations recurrently found in AML drive metabolic dysregulation, and dysregulated metabolism is closely linked to oncogenic addiction and thus potential therapeutic targets for AML.…”

Section: Introductionmentioning

confidence: 99%

“…Oncogenic mutations recurrently found in AML drive metabolic dysregulation, and dysregulated metabolism is closely linked to oncogenic addiction and thus potential therapeutic targets for AML. For example, mutation in the most common oncogene in AML, i.e., FLT3 , is known to be associated with glycolysis [ 10 ]. Other oncogenic driver mutations, such as those in MYC and RAS , have been studied to drive metabolic reprogramming, including increased glycolysis, glutaminolysis, lipid synthesis, and mitochondrial biogenesis, which are important for AML cell proliferation and survival [ 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, AML cells can hinder glucose uptake by normal tissues through desensitization to insulin by increasing the levels of serum insulin-like growth factor binding protein 1 [ 14 ]. Oxidative phosphorylation is activated in AML cells as compared to normal hematopoietic stem/progenitor cells [ 10 ]. Thus, AML cells have metabolic vulnerabilities depending on specific bioenergy sources [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Metabolic Profiling during Acute Myeloid Leukemia Progression Using Paired Clinical Bone Marrow Serum Samples

Kim

Son

et al. 2021

Metabolites

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Cellular metabolic changes reflect the characteristics of patients with acute myeloid leukemia (AML) caused by genetic variations, which are important in establishing AML treatment. However, little is known about the metabolic profile of patients with genetic variation-induced AML. Furthermore, the metabolites differ with disease progression. Here, metabolites in the bone marrow serum of ten patients with AML and healthy individuals were analyzed using gas chromatography–mass spectrometry. Compared with that in healthy individuals, expression of most metabolites decreased in patients with AML; hydroxylamine, 2-hydroxybutyric acid, monomethylphosphate, and ethylphosphate expression was unusually increased in the patients. We further examined serial metabolite changes across the initial diagnosis, postremission, and relapse phases. Patients with relapse showed increased metabolite expression compared with those in the diagnostic phase, confirming that patients with AML had aggressively modified leukemic cells. However, a clear difference in metabolite distribution was not observed between the diagnosis and complete remission phases, suggesting that the metabolic microenvironment did not change significantly despite complete remission. Interestingly, metabolite profiles differed with genetic variations in leukemic cells. Our results, which were obtained using paired samples collected during AML progression, provide valuable insights for identifying vulnerable targets in the AML metabolome and developing new treatment strategies.

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Profiling of Metabolic Differences between Hematopoietic Stem Cells and Acute/Chronic Myeloid Leukemia

Cited by 7 publications

References 33 publications

Regulation of erythroid differentiation in K562 cells by the EPAS1-IRS2 axis under hypoxic conditions

Regulation of erythroid differentiation in K562 cells by the EPAS1-IRS2 axis under hypoxic conditions

8-Hydroxydaidzein Downregulates JAK/STAT, MMP, Oxidative Phosphorylation, and PI3K/AKT Pathways in K562 Cells

Metabolic Profiling during Acute Myeloid Leukemia Progression Using Paired Clinical Bone Marrow Serum Samples

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