Association of immunophenotype with expression of topoisomerase II α and β in adult acute myeloid leukemia

Michelson, Andrew P.; McDonough, Shannon; Willman, Cheryl L.; Koegle, Eric R.; Godwin, John; Petersdorf, Stephen H.; List, Alan F.; Othus, Megan; Appelbaum, Frederick R.; Radich, Jerald P.; Ganapathi, Mahrukh K.; Advani, Anjali S.; Ganapathi, Ram

doi:10.1038/s41598-020-62345-9

Cited by 4 publications

(2 citation statements)

References 32 publications

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“…Another gene of interest is topoisomerase II α (TOP2A), which was found to be downregulated 2.2-fold in the 3D BM niche-like AML culture model. Consistently, a recent study has identified a significantly lower expression of TOP2A compared to TOP2B in adult AML patients [ 91 ]. Furthermore, in different cancer types [ 92 , 93 ], the downregulation of TOP2A was found to be related to the inhibition of cell proliferation, which is in agreement with our findings of cell proliferation in the 3D BM niche-like AML model (CFSE data) (Fig.…”

Section: Resultssupporting

confidence: 73%

Fabrication of a three-dimensional bone marrow niche-like acute myeloid Leukemia disease model by an automated and controlled process using a robotic multicellular bioprinting system

Alhattab,

Isaioglou,

Alshehri

et al. 2023

Biomater Res

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Background Acute myeloid leukemia (AML) is a hematological malignancy that remains a therapeutic challenge due to the high incidence of disease relapse. To better understand resistance mechanisms and identify novel therapies, robust preclinical models mimicking the bone marrow (BM) microenvironment are needed. This study aimed to achieve an automated fabrication process of a three-dimensional (3D) AML disease model that recapitulates the 3D spatial structure of the BM microenvironment and applies to drug screening and investigational studies. Methods To build this model, we investigated a unique class of tetramer peptides with an innate ability to self-assemble into stable hydrogel. An automated robotic bioprinting process was established to fabricate a 3D BM (niche-like) multicellular AML disease model comprised of leukemia cells and the BM’s stromal and endothelial cellular fractions. In addition, monoculture and dual-culture models were also fabricated. Leukemia cell compatibility, functionalities (in vitro and in vivo), and drug assessment studies using our model were performed. In addition, RNAseq and gene expression analysis using TaqMan arrays were also performed on 3D cultured stromal cells and primary leukemia cells. Results The selected peptide hydrogel formed a highly porous network of nanofibers with mechanical properties similar to the BM extracellular matrix. The robotic bioprinter and the novel quadruple coaxial nozzle enabled the automated fabrication of a 3D BM niche-like AML disease model with controlled deposition of multiple cell types into the model. This model supported the viability and growth of primary leukemic, endothelial, and stromal cells and recapitulated cell-cell and cell-ECM interactions. In addition, AML cells in our model possessed quiescent characteristics with improved chemoresistance attributes, resembling more the native conditions as indicated by our in vivo results. Moreover, the whole transcriptome data demonstrated the effect of 3D culture on enhancing BM niche cell characteristics. We identified molecular pathways upregulated in AML cells in our 3D model that might contribute to AML drug resistance and disease relapse. Conclusions Our results demonstrate the importance of developing 3D biomimicry models that closely recapitulate the in vivo conditions to gain deeper insights into drug resistance mechanisms and novel therapy development. These models can also improve personalized medicine by testing patient-specific treatments. Graphical Abstract

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Section: Resultssupporting

confidence: 73%

Fabrication of a three-dimensional bone marrow niche-like acute myeloid Leukemia disease model by an automated and controlled process using a robotic multicellular bioprinting system

Alhattab,

Isaioglou,

Alshehri

et al. 2023

Biomater Res

View full text Add to dashboard Cite

show abstract

“…First, the increased levels of several CCL/CXCL chemokines can be important for the interactions between MSCs and other non-leukemic stromal cells in the bone marrow microenvironment, especially for AML-induced angiogenesis [ 36 , 37 ]. Second, the altered expression of collagens as well as soluble integrins and other adhesion molecules (e.g., VCAM, ICAM) may be important for the direct contact between MSCs and neighboring cells and/or extracellular matrix molecules [ 38 , 39 , 40 ]. Third, several MSC molecules involved in intracellular signaling (e.g., GTPases, Src kinases) seem to be important also in AML cells [ 38 , 41 , 42 , 43 ], and therapeutic targeting of such molecules may therefore represent combined direct and indirect therapeutic targeting of AML cells.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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Targeting TOP2B as a vulnerability in aging and aging-related diseases

Zhu,

Li,

Zheng

et al. 2024

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Association of immunophenotype with expression of topoisomerase II α and β in adult acute myeloid leukemia

Cited by 4 publications

References 32 publications

Fabrication of a three-dimensional bone marrow niche-like acute myeloid Leukemia disease model by an automated and controlled process using a robotic multicellular bioprinting system

Fabrication of a three-dimensional bone marrow niche-like acute myeloid Leukemia disease model by an automated and controlled process using a robotic multicellular bioprinting system

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

Targeting TOP2B as a vulnerability in aging and aging-related diseases

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