Bacitracin and Rutin Regulate Tissue Factor Production in Inflammatory Monocytes and Acute Myeloid Leukemia Blasts

Aberrant expression of tissue factor (TF) by transformed myeloblasts and inflammatory monocytes drives coagulation activation in acute myeloid leukemia (AML). Although regulation of TF procoagulant activity (PCA) involves thiol-disulfide exchange reactions, the specific role of protein disulfide isomerase (PDI) and other thiol isomerases in AML-associated TF biology is unclear. THP1 cells and peripheral blood mononuclear cells (PBMCs) from healthy controls or AML patients were analyzed for thiol isomerase-dependent TF production under various experimental conditions. Total cellular and membrane TF antigen, TF PCA and TF mRNA were analyzed by ELISA, flow cytometry, clotting or Xa generation assay and qPCR, respectively. PBMCs and THP1 cells showed significant insulin reductase activity, which was inhibited by bacitracin or rutin. Co-incubation with these thiol isomerase inhibitors prevented LPS-induced TF production by CD14-positive monocytes and constitutive TF expression by THP1 cells and AML blasts. Downregulation of the TF antigen was mainly restricted to the cryptic pool of TF, efficiently preventing phosphatidylserine-dependent TF activation by daunorubicin, and at least partially regulated on the mRNA level in LPS-stimulated monocytes. Our study thus delineates a complex role of thiol isomerases in the regulation of myeloid TF PCA, with PDI being a promising therapeutic target in the management of AML-associated coagulopathies.

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Noncoding RNAs in Acute Myeloid Leukemia: From Key Regulators to Clinical Players

Scientifica ◽

10.6064/2012/925758 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Alessandro Fatica

Keyword(s):

Acute Myeloid Leukemia ◽

Tumor Suppressor Genes ◽

Myeloid Leukemia ◽

Hematological Malignancies ◽

Aberrant Expression ◽

Genetic Abnormalities ◽

Non Coding Rnas ◽

Recent Demonstration ◽

Acute Myeloid

Recent analyses have shown that human cells transcribe almost their entire genomes, implying the existence of a huge mass of ncRNAs. At the present, microRNAs are the most investigated regulative non-coding RNAs. Several studies have demonstrated that microRNAs play a crucial role in hematopoietic differentiation and hematological malignancies, including acute myeloid leukemia (AML). Aberrant expression of microRNAs has been associated with specific genetic abnormalities and clinical outcome of patients with AML. In addition, since microRNAs can function as either oncogenes or tumor suppressor genes, the potential of using these molecules as therapeutic targets opens up new opportunities in the future of AML therapy. The recent demonstration that other regulatory ncRNAs, in addition to microRNAs, are involved in hematopoietic cell differentiation and diseases, suggests that they may also have a biological relevance in AML. This paper will describe the role of ncRNAs in AML and discuss the expectations for the use of ncRNAs in diagnosis, prognosis, and therapy of AML.

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Role of FLT3 gene mutations in acute myeloid leukemia: effect on course of disease and results of therapy

Genes and Cells ◽

10.23868/201903007 ◽

2019 ◽

Vol XIV (1) ◽

Author(s):

A.M. Radzhabova ◽

S.V. Voloshin ◽

I.S. Martynkevich ◽

A.A. Kuzyaeva ◽

V.A. Shuvaev ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Gene Mutations ◽

Course Of Disease ◽

Acute Myeloid

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Faculty Opinions recommendation of Role of altered growth factor receptor-mediated JAK2 signaling in growth and maintenance of human acute myeloid leukemia stem cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718326593.793493199 ◽

2014 ◽

Author(s):

Xiaoyan Jiang ◽

Katharina Rothe

Keyword(s):

Stem Cells ◽

Acute Myeloid Leukemia ◽

Growth Factor ◽

Myeloid Leukemia ◽

Growth Factor Receptor ◽

Leukemia Stem Cells ◽

Human Acute Myeloid Leukemia ◽

Acute Myeloid

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Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development

Experimental Hematology and Oncology ◽

10.1186/s40164-021-00233-2 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Yiyi Yao ◽

Fenglin Li ◽

Jiansong Huang ◽

Jie Jin ◽

Huafeng Wang

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chemotherapy Resistance ◽

Bone Marrow Microenvironment ◽

Cytotoxic Effects ◽

High Relapse Rate ◽

Underlying Mechanisms ◽

Acute Myeloid

AbstractDespite the advances in intensive chemotherapy regimens and targeted therapies, overall survival (OS) of acute myeloid leukemia (AML) remains unfavorable due to inevitable chemotherapy resistance and high relapse rate, which mainly caused by the persistence existence of leukemia stem cells (LSCs). Bone marrow microenvironment (BMM), the home of hematopoiesis, has been considered to play a crucial role in both hematopoiesis and leukemogenesis. When interrupted by the AML cells, a malignant BMM formed and thus provided a refuge for LSCs and protecting them from the cytotoxic effects of chemotherapy. In this review, we summarized the alterations in the bidirectional interplay between hematopoietic cells and BMM in the normal/AML hematopoietic environment, and pointed out the key role of these alterations in pathogenesis and chemotherapy resistance of AML. Finally, we focused on the current potential BMM-targeted strategies together with future prospects and challenges. Accordingly, while further research is necessary to elucidate the underlying mechanisms behind LSC–BMM interaction, targeting the interaction is perceived as a potential therapeutic strategy to eradicate LSCs and ultimately improve the outcome of AML.

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Role of CD19 and specific KIT‐D816 on risk stratification refinement in t(8;21) acute myeloid leukemia induced with different cytarabine intensities

Cancer Medicine ◽

10.1002/cam4.3705 ◽

2020 ◽

Author(s):

Biao Wang ◽

Bin Yang ◽

Yun Ling ◽

Jihong Zhang ◽

Xiaoying Hua ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Risk Stratification ◽

Myeloid Leukemia ◽

Acute Myeloid

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High HSPA8 expression predicts adverse outcomes of acute myeloid leukemia

BMC Cancer ◽

10.1186/s12885-021-08193-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jun Li ◽

Zheng Ge

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Prognostic Factor ◽

Myeloid Leukemia ◽

Cell Function ◽

Adverse Outcomes ◽

High Expression ◽

Micro Rnas ◽

Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) remains one of the most common hematological malignancies, posing a serious challenge to human health. HSPA8 is a chaperone protein that facilitates proper protein folding. It contributes to various activities of cell function and also is associated with various types of cancers. To date, the role of HSPA8 in AML is still undetermined. Methods In this study, public datasets available from the TCGA (Cancer Genome Atlas) and GEO (Gene Expression Omnibus) were mined to discover the association between the expression of HSPA8 and clinical phenotypes of CN-AML. A series of bioinformatics analysis methods, including functional annotation and miRNA-mRNA regulation network analysis, were employed to investigate the role of HSPA8 in CN-AML. Results HSPA8 was highly expressed in the AML patients compared to the healthy controls. The high HSPA8 expression had lower overall survival (OS) rate than those with low HSPA8 expression. High expression of HSPA8 was also an independent prognostic factor for overall survival (OS) of CN-AML patients by multivariate analysis. The differential expressed genes (DEGs) associated with HSPA8 high expression were identified, and they were enriched PI3k-Akt signaling, cAMP signaling, calcium signaling pathway. HSPA8 high expression was also positively associated with micro-RNAs (hsa-mir-1269a, hsa-mir-508-3p, hsa-mir-203a), the micro-RNAs targeted genes (VSTM4, RHOB, HOBX7) and key known oncogenes (KLF5, RAN, and IDH1), and negatively associated with tumor suppressors (KLF12, PRKG1, TRPS1, NOTCH1, RORA). Conclusions Our research revealed HSPA8 as a novel potential prognostic factor to predict the survival of CN-AML patients. Our data also revealed the possible carcinogenic mechanism and the complicated microRNA-mRNA network associated with the HSPA8 high expression in AML.

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