scholarly journals Human mesenchymal stem cells derived exosomes inhibit the growth of acute myeloid leukemia cells via regulating miR-23b-5p/TRIM14 pathway

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Hui Cheng ◽  
Jie Ding ◽  
Gusheng Tang ◽  
Aijie Huang ◽  
Lei Gao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Mesenchymal Stem Cells ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Human Mesenchymal Stem Cells ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Akt Pathway ◽  
Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) is a malignancy commonly seen in adults. Previous studies indicated that TRIM14 played a tumorigenic role in various types of cancer and miR-23b-5p was down-regulated in human mesenchymal stem cell-derived exosomes (HMSC-exos) of AML patients. However, their roles in AML remains unclear. Our study aims to investigate the role of TRIM14 and miR-23b-5p in the pathogenesis of AML. Materials and methods The blood specimen was collected from de novo AML patients and healthy donators. Exosomes were extracted from the culture medium of human mesenchymal stem cells under ultracentrifugation. Then exosomes were co-cultured with AML cells to determine the effect of their contents. The cell proliferation was detected by cell counting kit-8 assay, whereas the cell apoptosis was detected by flow cytometry. The expression of miR-23b-5p and TRIM14 was silenced or overexpressed to explore their biological functions in AML. Luciferase reporter assay was conducted to validate the interaction between miR-23b-5p and TRIM14. Gene expression was determined by quantitative real-time PCR and immunoblots. Results TRIM14 was significantly increased in AML patients and cell lines. The inhibition of TRIM14 significantly reduced the proliferation and induced the apoptosis of AML cells via activating PI3K/AKT pathway, whereas its overexpression exhibited reversed effects. HMSC-exos could suppress the proliferation of AML cells through the delivery of miR-23b-5p. Moreover, miR-23b-5p inhibited the transcription of TRIM14 by binding on its 3’UTR region. Overexpression of TRIM14 exhibited reversed effect against the function of miR-23b-5p mimic. Conclusion TRIM14 could promote the proliferation of AML cells via activating PI3K/AKT pathway, which was reversed by HMSC-exos through delivering miR-23b-5p. These findings indicated that miR-23b-5p and TRIM14 could be applied as potential targets for the treatment of AML.

scholarly journals Human Mesenchymal Stem Cells Derived Exosomes Inhibit the Growth of Acute Myeloid Leukemia Cells via Regulating miR-23b-5p/TRIM14 Pathway

2021 ◽  
Author(s):  
hui cheng ◽  
Jie Ding ◽  
Gusheng Tang ◽  
Aijie Huang ◽  
Lei Gao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Mesenchymal Stem Cells ◽  
Myeloid Leukemia ◽  
Human Mesenchymal Stem Cells ◽  
Human Mesenchymal Stem Cell ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Akt Pathway ◽  
Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is a malignancy commonly seen in adults. Previous studies indicated that TRIM14 played a tumorigenic role in various types of cancer and miR-23b-5p was down-regulated in human mesenchymal stem cell-derived exosomes (HMSC-exos) of AML patients. However, their roles in AML remains unclear. Our study aims to investigate the role of TRIM14 and miR-23b-5p in the pathogenesis of AML.Materials and methods: The blood specimen was collected from AML patients and healthy donators. Exosomes were extracted from the culture medium of human mesenchymal stem cells under ultracentrifugation. Then exosomes were co-cultured with AML cells to determine the effect of their contents. The cell proliferation was detected by cell counting kit-8 assay, whereas the cell apoptosis was detected by flow cytometry. The expression of miR-23b-5p and TRIM14 was silenced or overexpressed to explore their biological functions in AML. Luciferase reporter assay was conducted to validate the interaction between miR-23b-5p and TRIM14. Gene expression was determined by quantitative real-time PCR and immunoblots.Results: TRIM14 was significantly increased in AML patients and cell lines. The inhibition of TRIM14 significantly reduced the proliferation and induced the apoptosis of AML cells via activating PI3K/AKT pathway, whereas its overexpression exhibited reversed effects. HMSC-exos could suppress the proliferation of AML cells through the delivery of miR-23b-5p. Moreover, miR-23b-5p inhibited the transcription of TRIM14 by binding on its 3’UTR region. Overexpression of TRIM14 exhibited reversed effect against the function of miR-23b-5p mimic.Conclusion: TRIM14 could promote the proliferation of AML cells via activating PI3K/AKT pathway, which was reversed by HMSC-exos through delivering miR-23b-5p. These findings indicated that miR-23b-5p and TRIM14 could be applied as potential targets for the treatment of AML.

scholarly journals Evidence for malignant transformation in acute myeloid leukemia at the level of early hematopoietic stem cells by cytogenetic analysis of CD34+ subpopulations

Blood ◽  
1995 ◽  
Vol 86 (8) ◽  
pp. 2906-2912 ◽  
Author(s):  
D Haase ◽  
M Feuring-Buske ◽  
S Konemann ◽  
C Fonatsch ◽  
C Troff ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Hematopoietic Stem Cells ◽  
Malignant Transformation ◽  
Cell Sorting ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Leukemic Cells ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a heterogenous disease according to morphology, immunophenotype, and genetics. The retained capacity of differentiation is the basis for the phenotypic classification of the bulk population of leukemic blasts and the identification of distinct subpopulations. Within the hierarchy of hematopoietic development and differentiation it is still unknown at which stage the malignant transformation occurs. It was our aim to analyze the potential involvement of cells with the immunophenotype of pluripotent stem cells in the leukemic process by the use of cytogenetic and cell sorting techniques. Cytogenetic analyses of bone marrow aspirates were performed in 13 patients with AML (11 de novo and 2 secondary) and showed karyotype abnormalities in 10 cases [2q+, +4, 6p, t(6:9), 7, +8 in 1 patient each and inv(16) in 4 patients each]. Aliquots of the samples were fractionated by fluorescence-activated cell sorting of CD34+ cells. Two subpopulations, CD34+/CD38-(early hematopoietic stem cells) and CD34+/CD38+ (more mature progenitor cells), were screened for karyotype aberations as a marker for leukemic cells. Clonal abnormalities and evaluable metaphases were found in 8 highly purified CD34+/CD38-populations and in 9 of the CD34+/CD38-specimens, respectively. In the majority of cases (CD34+/CD38-, 6 of 8 informative samples; CD34+/CD38+, 5 of 9 informative samples), the highly purified CD34+ specimens also contained cytogenetically normal cells. Secondary, progression-associated chromosomal changes (+8, 12) were identified in the CD34+/CD38-cells of 2 patients. We conclude that clonal karyotypic abnormalities are frequently found in the stem cell-like (CD34+/CD38-) and more mature (CD34+/CD38+) populations of patients with AML, irrespective of the phenotype of the bulk population of leukemic blasts and of the primary or secondary character of the leukemia. Our data suggest that, in AML, malignant transformation as well as disease progression may occur at the level of CD34+/CD38-cells with multilineage potential.

scholarly journals Patient Heterogeneity in Acute Myeloid Leukemia: Leukemic Cell Communication by Release of Soluble Mediators and Its Effects on Mesenchymal Stem Cells

Diseases ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 74
Author(s):  
Elise Aasebø ◽  
Annette K. Brenner ◽  
Maria Hernandez-Valladares ◽  
Even Birkeland ◽  
Olav Mjaavatten ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Extracellular Matrix ◽  
Acute Myeloid Leukemia ◽  
Mesenchymal Stem Cells ◽  
Conditioned Medium ◽  
Untreated Control ◽  
Myeloid Leukemia ◽  
Control Mscs ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is an aggressive bone marrow malignancy, and non-leukemic stromal cells (including mesenchymal stem cells, MSCs) are involved in leukemogenesis and show AML-supporting effects. We investigated how constitutive extracellular mediator release by primary human AML cells alters proteomic profiles of normal bone marrow MSCs. An average of 6814 proteins (range 6493−6918 proteins) were quantified for 41 MSC cultures supplemented with AML-cell conditioned medium, whereas an average of 6715 proteins (range 6703−6722) were quantified for untreated control MSCs. The AML effect on global MSC proteomic profiles varied between patients. Hierarchical clustering analysis identified 10 patients (5/10 secondary AML) showing more extensive AML-effects on the MSC proteome, whereas the other 31 patients clustered together with the untreated control MSCs and showed less extensive AML-induced effects. These two patient subsets differed especially with regard to MSC levels of extracellular matrix and mitochondrial/metabolic regulatory proteins. Less than 10% of MSC proteins were significantly altered by the exposure to AML-conditioned media; 301 proteins could only be quantified after exposure to conditioned medium and 201 additional proteins were significantly altered compared with the levels in control samples (153 increased, 48 decreased). The AML-modulated MSC proteins formed several interacting networks mainly reflecting intracellular organellar structure/trafficking but also extracellular matrix/cytokine signaling, and a single small network reflecting altered DNA replication. Our results suggest that targeting of intracellular trafficking and/or intercellular communication is a possible therapeutic strategy in AML.

scholarly journals Mesenchymal Stem Cells (MSCs) Intensify the Impact of KIR Ligand-Mismatching on Acute Graft-Versus-Host Disease Post HSCT in Patients with Acute Myeloid Leukemia but Not with Acute Lymphocytic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-42
Author(s):  
Yu Zhang ◽  
Shaozhen Chen ◽  
Jinhua Ren ◽  
Xiaofeng Luo ◽  
Zhizhe Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Myeloid Leukemia ◽  
Acute Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Acute Myeloid

Objectives: Mesenchymal stem cells (MSCs) and killer cell immunoglobulin-like receptor (KIR) ligand-mismatch, which can trigger the alloreactivity of natural killer (NK) cells, have been shown to be protective for severe acute and chronic graft-versus-host disease (aGVHD, cGVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there are no prospective or retrospective studies exploring their relationship. Here, we investigated the potential influence of KIR matching, MSCs and their coaction on GVHD prophylaxis, overall survival (OS) and relapse rate (RR) of allo-HSCT. Methods: Data from 154 patients with acute myeloid and lymphocytic leukemia treated with allo-HSCT between May 2015 and May 2020 in the transplantation unit of the Fujian Medical University Union Hospital were retrospectively analyzed. The cohort included 93 male patients (60.3%) and 61 female (39.7%), with a median age of 24 years (1-59 years), 104 cases of acute myeloid leukemia (AML; 67.5%) and 50 cases with acute lymphocytic leukemia (ALL; 32.5%). Eighty-one patients (52.6%) underwent MSCs infusion on day+1. The sources of MSCs were human placenta or human bone marrow. MSCs infusion dose ranged from 0.5 to 3x106/kg of recipient weight. KIR genotyping was performed by the PCR-SSO method. The amplicons were quantified on the Luminex 200 flow analyzer and analyzed using the Quick-Type for Lifecodes software for generating KIR data. Cox proportional hazards model and Kaplan-Meier survival curves were used for analysis. Results: At the time of transplantation, 65 cases (42.2%) were in remission, while 89 (57.8%) had active disease. aGVHD occurred in 31 patients (20.1%) and recurrence arose in 21 patients (13.6%), but no significant cGVHD was observed. After adjusting for age, disease-risk, HLA-match, donor gender, conditioning regimen intensity and type of post-grafting GVHD prophylaxis, Cox regression analysis revealed that KIR ligand-matching was associated with an increased risk of aGVHD compared to KIR ligand-mismatching (p=0.023) in AML patients, but KIR ligand-mismatching had no significant effect on aGVHD in ALL patients, and on OS and RR in both AML and ALL patients. MSCs was associated with much lower recurrence rate (RR) (p=0.049), even when the recipients were not in remission at the time of HSCT. Furthermore, MSCs reduced the incidence of aGVHD in both AML and ALL patients, although it did not reach statistical significance (p=0.19). The combination of KIR ligand-mismatching and MSCs infusion significantly suppressed aGVHD occurrence in AML patients (p=0.033). More importantly, MSCs infusion intensified the suppression effect of KIR ligand-mismatching on aGVHD in AML patients (p=0.047). In the KIR ligand-mismatch group, the incidence of aGVHD was 10.3% when patients received MSCs, compared to 25.6% in those who did not. However, combining KIR ligand-mismatch and MSCs injection had no significant effect on aGVHD in ALL patients, or on OS and RR in both AML and ALL patients. Conclusions: KIR ligand-mismatch, MSCs infusion and their combination significantly reduced the risk of aGVHD after allo-HSCT in AML patients. It confirms the relationship between MSCs injection and lower RR. These data provide a clinically applicable strategy where co-transplantation with MSCs and triggering of allo-NK cells by KIR ligand-mismatching can ameliorate aGVHD, thus improving allo-HSCT outcome in AML patients. Disclosures No relevant conflicts of interest to declare.

ATG5 regulates mesenchymal stem cells differentiation and mediates chemosensitivity in acute myeloid leukemia

2020 ◽  
Vol 525 (2) ◽  
pp. 398-405 ◽  
Author(s):  
Ying Li ◽  
Yajing Jiang ◽  
Jingying Cheng ◽  
Jiao Ma ◽  
Qinghua Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Mesenchymal Stem Cells ◽  
Myeloid Leukemia ◽  
Acute Myeloid

scholarly journals Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy

2020 ◽  
Vol 32 (5) ◽  
pp. 829-843.e9 ◽  
Author(s):  
Dorian Forte ◽  
María García-Fernández ◽  
Abel Sánchez-Aguilera ◽  
Vaia Stavropoulou ◽  
Claire Fielding ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Mesenchymal Stem Cells ◽  
Myeloid Leukemia ◽  
Antioxidant Defense ◽  
Marrow Mesenchymal Stem Cells ◽  
Acute Myeloid

scholarly journals A New Entity of Acute Myeloid Leukemia Driven By Epigenetic and Somatic Dis-Regulation of Uncx, a Novel Homeobox Transcription Factor Gene

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1356-1356
Author(s):  
Giulia Daniele ◽  
Clelia Tiziana Storlazzi ◽  
Cristina Papayannidis ◽  
Ilaria Iacobucci ◽  
Angelo Lonoce ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Ectopic Expression ◽  
Response To Therapy ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract We describe a new AML entity, occurring in 30% of de novo acute myeloid leukemia, due to structural and epigenetic deregulation of the UNCX homeobox (HB) gene. By molecular approaches, we identified a M5 AML patient with a t(7;10)(p22;p14) translocation as the sole cytogenetic anomaly and showing ectopic expression of UNCX (7p22.3), which encode for a transcription factor involved in somitogenesis and neurogenesis. Since UNCX was never reported in association with cancer but only with common myeloid cell proliferation and regulation of cell differentiation, we decided to investigate its contribution to leukemogenesis. We observed UNCX ectopic expression in 32.3% (20/62) and in 8% (6/75) of acute myeloid leukemia (AML) patients and cell lines, respectively. Notably, retroviral-mediated UNCX transfer in CD34+ HSCs induced a slow-down in their proliferation and differentiation and transduced cells showed a lower growth rate but a higher percentage of CD34+ stem cells in liquid culture than controls. Additionally, UNCX infected cells displayed a decrease of MAP2K1 proliferation marker but increase of KLF4, HOXA10, and CCNA1, associated with impaired differentiation and pluripotency. Similarly, UNCX-positive patients revealed alteration of gene pathways involved in proliferation, cell cycle control and hematopoiesis. Since HB genes encode for transcription factors showing a crucial role in normal hematopoiesis and in leukemogenesis, we focused our attention on the role of altered UNCX expression level. Of note, its murine ortholog, (Uncx) was previously described as embedded within a low-methylated regions (≤ 10%) called "canyon" and dysregulated in murine hematopoietic stem cells (HSCs) as a consequence of altered methylation at canyons edges (borders) due to Dnmt3a inactivation. In our hands, UNCX activation was accompanied by methylation changes at both its canyon borders, clearly indicating an epigenetic regulation of this gene, although not induced by DNMT3A mutations. Clinical parameters and correlation with response to therapy will be presented. Taken together, our results indicate that more than 30% of de novo AML have a novel entity with a putative leukemogenic role of UNCX, whose activation may be ascribed to epigenetic regulators. Acknowledgments: MG, CP, GS, and AP(2) and this work was supported by ELN, AIL, AIRC, progetto Regione-Università 2010-12 (L. Bolondi), Fondazione del Monte di Bologna e Ravenna, FP7 NGS-PTL project. CTS, GD and AL are supported by Associazione Italiana Ricerca sul Cancro (AIRC) funding. Disclosures Nadarajah: MLL Munich Leukemia Laboratory: Employment. Martinelli:MSD: Consultancy; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; AMGEN: Consultancy; ROCHE: Consultancy.

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