<i>In Vitro</i> Characterization of Valproic Acid, ATRA, and Cytarabine Used for Disease-Stabilization in Human Acute Myeloid Leukemia:
Antiproliferative Effects of Drugs on Endothelial and Osteoblastic Cells and Altered Release of Angioregulatory Mediators by Endothelial Cells

Kvestad, Hilde; Evensen, Lasse; Lorens, James B.; Bruserud, Øystein; Hatfield, Kimberley Joanne

doi:10.1155/2014/143479

Cited by 9 publications

(8 citation statements)

References 54 publications

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“…Similarly treated Kasumi-1 cells were cultured in 100 uM cytarabine (AraC), a conventional chemotherapy agent used at a level comparable to serum concentrations in patients undergoing high-dose therapy [35]. Prior studies have shown that b-Catenin and Wnt signaling activity are associated with chemotherapy resistance in various cancer models, including colon, breast, and pancreatic cancer [36–38].…”

Section: Resultsmentioning

confidence: 99%

TLE4 regulation of wnt-mediated inflammation underlies its role as a tumor suppressor in myeloid leukemia

Shin¹,

Brynczka

Dayyani

et al. 2016

Leukemia Research

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The presence of AML1-ETO (RUNX1-CBF2T1), a fusion oncoprotein resulting from a t(8;21) chromosomal translocation, has been implicated as a necessary but insufficient event in the development of a subset of acute myeloid leukemias (AML). While AML1-ETO prolongs survival and inhibits differentiation of hematopoietic stem cells (HSC), other contributory events are needed for cell proliferation and leuke-mogenesis. We have postulated that specific tumor suppressor genes keep the leukemic potential of AML1-ETO in check. In studying del(9q), one of the most common concomitant chromosomal abnormalities with t(8;21), we identified the loss of an apparent tumor suppressor, TLE4, that appears to cooperate with AML1-ETO to confer a leukemic phenotype. This study sought to identify the molecular basis of this cooperation. We show that the loss of TLE4 confers proliferative advantage to leukemic cells, simultaneous with an upregulation of a pro-inflammatory signature mediated through aberrant increases in Wnt signaling activity. We further demonstrate that inhibition of cyclooxygenase (COX) activity partly reverses the pro-leukemic phenotype due to TLE4 knockdown, pointing towards a novel therapeutic approach for myeloid leukemia.

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Section: Resultsmentioning

confidence: 99%

TLE4 regulation of wnt-mediated inflammation underlies its role as a tumor suppressor in myeloid leukemia

Shin¹,

Brynczka

Dayyani

et al. 2016

Leukemia Research

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“…Both conventional intensive chemotherapy and new AML-targeting therapy will probably alter the protein release by the leukemic cells. Previous studies have shown that conventional cytotoxic drugs will also influence various stromal cells (osteoblasts, endothelial cells, immunocompetent cells), including their release of soluble mediators [ 83 , 84 ]. Future studies should therefore try to characterize the effects of various therapeutic strategies on the constitutive protein release by non-leukemic stromal cells.…”

Section: Discussionmentioning

confidence: 99%

The Constitutive Extracellular Protein Release by Acute Myeloid Leukemia Cells—A Proteomic Study of Patient Heterogeneity and Its Modulation by Mesenchymal Stromal Cells

Aasebø

Brenner

Birkeland

et al. 2021

Cancers

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Extracellular protein release is important both for the formation of extracellular matrix and for communication between cells. We investigated the extracellular protein release by in vitro cultured normal mesenchymal stem cells (MSCs) and by primary human acute myeloid leukemia (AML) cells derived from 40 consecutive patients. We observed quantifiable levels of 3082 proteins in our study; for the MSCs, we detected 1446 proteins, whereas the number of released proteins for the AML cells showed wide variation between patients (average number 1699, range 557–2380). The proteins were derived from various cellular compartments (e.g., cell membrane, nucleus, and cytoplasms), several organelles (e.g., cytoskeleton, endoplasmatic reticulum, Golgi apparatus, and mitochondria) and had various functions (e.g., extracellular matrix and exosomal proteins, cytokines, soluble adhesion molecules, protein synthesis, post-transcriptional modulation, RNA binding, and ribonuclear proteins). Thus, AML patients were very heterogeneous both regarding the number of proteins and the nature of their extracellularly released proteins. The protein release profiles of MSCs and primary AML cells show a considerable overlap, but a minority of the proteins are released only or mainly by the MSC, including several extracellular matrix molecules. Taken together, our observations suggest that the protein profile of the extracellular bone marrow microenvironment differs between AML patients, these differences are mainly caused by the protein release by the leukemic cells but this leukemia-associated heterogeneity of the overall extracellular protein profile is modulated by the constitutive protein release by normal MSCs.

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“…The presence of bleeding despite maintenance of a platelet count of >10 9 10 9 /l is indicative of concomitant other factors. The global endothelial dysfunction in this population may reflect damage by chemotherapy (de Vos et al, 2004;Kvestad et al, 2014). Similarly, inflammation and infection can cause haemorrhage to become manifest in thrombocytopenia (Goerge et al, 2008;Ho-Tin-No e et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

The association between haemorrhage and markers of endothelial insufficiency and inflammation in patients with hypoproliferative thrombocytopenia: a cohort study

et al. 2019

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Summary In daily haematological practice, predicting bleeding in thrombocytopenic patients is difficult, and clinicians adhere to transfusion triggers to guide patients through the aplastic phase of chemotherapy. Platelet count is not the only determinant of bleeding and additional mechanisms for impending haemostasis are likely. Beside clot formation, platelets are essential for the maintenance of integrity of vascular beds. We therefore prospectively investigated associations between biomarkers for endothelial damage (urine albumin excretion) and inflammation (C‐reactive protein) and bleeding (WHO grading) in 88 patients with 116 on‐protocol episodes. We found an increase in grade 2 bleeding with a higher urine albumin/creatinine ratio one day after the measurement [odds ratio (OR) 1·24 for every doubling of the ratio, 95% CI 1·05–1·46, P‐value 0·01] and a 29% increase in the odds of grade 2 bleeding for every doubling of serum C‐reactive protein (CRP) (95% CI 1·04–1·60, P‐value 0·02) after correction for morning platelet count. The 24 h post‐transfusion corrected count increment (CCI24) showed a significant association with these biomarkers: increasing urine albumin/creatinine ratio and CRP were associated with lower CCI24. We report two inexpensive and easy‐to‐apply biomarkers that could be useful in designing a prediction model for bleeding risk in thrombocytopenic patients.

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In Vitro Characterization of Valproic Acid, ATRA, and Cytarabine Used for Disease-Stabilization in Human Acute Myeloid Leukemia: Antiproliferative Effects of Drugs on Endothelial and Osteoblastic Cells and Altered Release of Angioregulatory Mediators by Endothelial Cells

Cited by 9 publications

References 54 publications

TLE4 regulation of wnt-mediated inflammation underlies its role as a tumor suppressor in myeloid leukemia

TLE4 regulation of wnt-mediated inflammation underlies its role as a tumor suppressor in myeloid leukemia

The Constitutive Extracellular Protein Release by Acute Myeloid Leukemia Cells—A Proteomic Study of Patient Heterogeneity and Its Modulation by Mesenchymal Stromal Cells

The association between haemorrhage and markers of endothelial insufficiency and inflammation in patients with hypoproliferative thrombocytopenia: a cohort study

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