Characteristics of live parameters of the HS‐5 human bone marrow stromal cell line cocultured with the leukemia cells in hypoxia, for the studies of leukemia–stroma cross‐talk

Podszywałow-Bartnicka, Paulina; Kominek, Agata; Wolczyk, Magdalena; Kolba, Marta D.; Swatler, Julian; Piwocka, Katarzyna

doi:10.1002/cyto.a.23580

Cited by 9 publications

(3 citation statements)

References 38 publications

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“…Although OP9 cells are excellent at supporting BCP-ALL cell proliferation and survival, some applications may need to utilize human MSC stromal support. We therefore tested the human MSC cell line HS-5, which has a similar pattern of gene expression to primary bone marrow MSC [ 29 ] and is widely used to support survival of malignant human hematopoietic cells [ 30 , 31 ]. As shown in Fig 7A , mitotically inactivated HS-5 cells plated alone have attached to the electrodes, causing an increase in cell index values over time.…”

Section: Resultsmentioning

confidence: 99%

Analysis of acute lymphoblastic leukemia drug sensitivity by changes in impedance via stromal cell adherence

et al. 2021

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The bone marrow is a frequent location of primary relapse after conventional cytotoxic drug treatment of human B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Because stromal cells have a major role in promoting chemotherapy resistance, they should be included to more realistically model in vitro drug treatment. Here we validated a novel application of the xCELLigence system as a continuous co-culture to assess long-term effects of drug treatment on BCP-ALL cells. We found that bone marrow OP9 stromal cells adhere to the electrodes but are progressively displaced by dividing patient-derived BCP-ALL cells, resulting in reduction of impedance over time. Death of BCP-ALL cells due to drug treatment results in re-adherence of the stromal cells to the electrodes, increasing impedance. Importantly, vincristine inhibited proliferation of sensitive BCP-ALL cells in a dose-dependent manner, correlating with increased impedance. This system was able to discriminate sensitivity of two relapsed Philadelphia chromosome (Ph) positive ALLs to four different targeted kinase inhibitors. Moreover, differences in sensitivity of two CRLF2-drivenBCP-ALL cell lines to ruxolitinib were also seen. These results show that impedance can be used as a novel approach to monitor drug treatment and sensitivity of primary BCP-ALL cells in the presence of protective microenvironmental cells.

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Section: Resultsmentioning

confidence: 99%

Analysis of acute lymphoblastic leukemia drug sensitivity by changes in impedance via stromal cell adherence

et al. 2021

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“…Early relapse may arise when treatments are effective at eradicating leukemic cells in the peripheral blood but not in the bone marrow, where leukemic cells are sheltered. Thus, novel biological systems are currently established that enable the investigation of leukemia–stroma cross-talk and verification of novel therapies’ effectiveness under such bone marrow niche-mimicking conditions [ 27 ]. In our study, we employed a simple co-culture system with the HS-5 stroma cell line to grow AML cells in a bone-marrow niche environment.…”

Section: Discussionmentioning

confidence: 99%

Rationale for a Combination Therapy with the STAT5 Inhibitor AC-4-130 and the MCL1 Inhibitor S63845 in the Treatment of FLT3-Mutated or TET2-Mutated Acute Myeloid Leukemia

Seipel

Graber

Flückiger

et al. 2021

IJMS

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The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in one-third of patients with de novo acute myeloid leukemia (AML). Mutated FLT3 variants are constitutively active kinases signaling via AKT kinase, MAP kinases, and STAT5. FLT3 inhibitors have been approved for the treatment of FLT3-mutated AML. However, treatment response to FLT3 inhibitors may be short-lived, and resistance may emerge. Compounds targeting STAT5 may enhance and prolong effects of FLT3 inhibitors in this subset of patients with FLT3-mutated AML. Here STAT5-inhibitor AC-4-130, FLT3 inhibitor midostaurin (PKC412), BMI-1 inhibitor PTC596, MEK-inhibitor trametinib, MCL1-inhibitor S63845, and BCL-2 inhibitor venetoclax were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells grown in the absence or presence of bone marrow stroma. Synergistic effects on cell viability were detected in both FLT3-mutated and FLT3-wild-type AML cells treated with AC-4-130 in combination with the MCL1 inhibitor S63845. AML patient samples with a strong response to AC-4-130 and S63845 combination treatment were characterized by mutated FLT3 or mutated TET2 genes. Susceptibility of AML cells to AC-4-130, PTC596, trametinib, PKC412, and venetoclax was altered in the presence of HS-5 stroma. Only the MCL1 inhibitor S63845 induced cell death with equal efficacy in the absence or presence of bone marrow stroma. The combination of the STAT5-inhibitor AC-4-130 and the MCL1 inhibitor S63845 may be an effective treatment targeting FLT3-mutated or TET2-mutated AML.

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“…Stromal cells were previously reported to provide chemoprotection to CML cells via secreted factors and direct cell-cell communication (Kolba et al, 2019;Kumar et al, 2017;Podszywalow-Bartnicka et al, 2018;Weisberg et al, 2008;Wolczyk et al, 2023). Various factors secreted by stromal cells, including inflammatory cytokines like IL-6 and IL-8, or TGFβ can protect CML cells from BCR-ABL1 kinase inhibition by kinase inhibitors such as imatinib (Civini et al, 2013;Le et al, 2020).…”

Section: Impact Of the Microenvironment On Imatinib Resistance In Leu...mentioning

confidence: 99%

High-throughput formulation of reproducible 3D cancer microenvironments for drug testing in myelogenous leukemia

Rudzinska-Radecka,

Turos-Korgul,

Mukherjee

et al. 2024

Preprint

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Targeting cancer microenvironment is currently one of the major directions in drug development and preclinical studies in leukemia. Despite the variety of available chronic myelogenous leukemia 3D culture models, the reproducible generation of miniaturized leukemia microenvironments, suitable for high-throughput drug testing, has remained a challenge. Here, we use microfluidics to generate over ten thousand highly monodisperse leukemic-bone marrow hydrogel microbeads per minute. We employ gelatin methacrylate (GelMA) as a model extracellular matrix (ECM) and tune the concentration of the biopolymer, as well as other possible components of the ECM (fibrin, hyaluronic acid), cell concentration and the ratio of leukemic cells to bone marrow cells within the microbeads. This allows to achieve optimal cell viability and the propensity of the encapsulated cells to microtissue formation, while also warranting long-term stability of the microbeads in culture. We administer model kinase inhibitor, imatinib, at various concentrations to the microbeads and, via comparing mono- and co-culture conditions (cancer alone vs cancer-stroma), we find that the stroma-leukemia crosstalk systematically protects the encapsulated cells against the drug-induced cytotoxicity, confirming therefore that our system mimics the physiological stroma-dependent protection. We finally discuss applicability of our model to (i) studying the role of direct- or close-contact interactions between leukemia and bone marrow cells embedded in 3D ECM on the stroma-mediated protection, and (ii) high-throughput screening of anti-cancer therapeutics in personalized therapies.

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Characteristics of live parameters of the HS‐5 human bone marrow stromal cell line cocultured with the leukemia cells in hypoxia, for the studies of leukemia–stroma cross‐talk

Cited by 9 publications

References 38 publications

Analysis of acute lymphoblastic leukemia drug sensitivity by changes in impedance via stromal cell adherence

Analysis of acute lymphoblastic leukemia drug sensitivity by changes in impedance via stromal cell adherence

Rationale for a Combination Therapy with the STAT5 Inhibitor AC-4-130 and the MCL1 Inhibitor S63845 in the Treatment of FLT3-Mutated or TET2-Mutated Acute Myeloid Leukemia

High-throughput formulation of reproducible 3D cancer microenvironments for drug testing in myelogenous leukemia

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