A Subset of Patients with Acute Myeloid Leukemia Has Leukemia Cells Characterized by Chemokine Responsiveness and Altered Expression of Transcriptional as well as Angiogenic Regulators

Brenner, Annette K.; Reikvam, Håkon; Bruserud, Øystein

doi:10.3389/fimmu.2016.00205

Cited by 26 publications

(21 citation statements)

References 58 publications

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“…Moreover in coculture experiments, AML patient-derived BMMSCs were found to be ubiquitously responsive to AML-derived MIF, which resulted in an increase in IL8 expression by the BMMSCs. This is in keeping with similar reports on other cytokine pathways, which have shown that BM-MSCs can constitutively express various chemokines (32), and AML cells are able to respond to these chemokines (32,33). In this study, we also examined the genotype of six BM-MSCs used for the experiments and found three of six to be normal and in other three, the genotyping failed (Supplementary Table S2).…”

Section: Discussionsupporting

confidence: 89%

MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia

et al. 2017

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Acute myeloid leukemia (AML) cells exhibit a high level of spontaneous apoptosis when cultured in vitro but have a prolonged survival time in vivo, indicating that tissue microenvironment plays a critical role in promoting AML cell survival. In vitro studies have shown that bone marrow mesenchymal stromal cells (BM-MSC) protect AML blasts from spontaneous and chemotherapy-induced apoptosis. Here, we report a novel interaction between AML blasts and BM-MSCs, which benefits AML proliferation and survival. We initially examined the cytokine profile in cultured human AML compared with AML cultured with BM-MSCs and found that macrophage migration inhibitory factor (MIF) was highly expressed by primary AML, and that IL8 was increased in AML/BM-MSC cocultures. Recombinant MIF increased IL8 expression in BMMSCs via its receptor CD74. Moreover, the MIF inhibitor ISO-1 inhibited AML-induced IL8 expression by BM-MSCs as well as BM-MSC-induced AML survival. Protein kinase C b (PKCb) regulated MIF-induced IL8 in BM-MSCs. Finally, targeted IL8 shRNA inhibited BM-MSC-induced AML survival. These results describe a novel, bidirectional, prosurvival mechanism between AML blasts and BM-MSCs. Furthermore, they provide biologic rationale for therapeutic strategies in AML targeting the microenvironment, specifically MIF and IL8.

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Section: Discussionsupporting

confidence: 89%

MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia

et al. 2017

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“…It appears that other mechanisms for chemotherapy resistance may be involved including normal cells, like macrophages, as shown by recent evidence. However, multiple mechanisms involving not only the CCL2/CCR2 axis but as Brenner et al suggested [38], the chemokine milieu is important in AML biology. To targetone or several chemokines may affect AML susceptibility to chemotherapy and help develop new therapies for AML in the future.…”

Section: Discussionmentioning

confidence: 99%

The CCL2/CCR2 Axis Affects Transmigration and Proliferation but Not Resistance to Chemotherapy of Acute Myeloid Leukemia Cells

et al. 2017

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Acute myeloid leukemia (AML) has a high mortality rate despite chemotherapy and transplantation. Both CXCR4/SDF-1 and VLA-4/VCAM1 axes are involved in leukemia protection but little is known about the role of CCL2/CCR2 in AML biology and protection against chemotherapy. We measured CCR2 expression in AML cell lines and primary AML cells by flow cytometry (FCM), real time PCR (RT-PCR) and western blot (WB). CCL2 production was quantified by solid phase ELISA in peripheral blood (PB) and bone marrow (BM) serum. We measured chemotaxis in a transwell system with different concentrations of CCL2/CCR2 blockers; cell cycle with BrDU and propidium iodide and proliferation with yellow tetrazolium MTT. We determined synergy in in vitro cell apoptosis combining chemotherapy and CCL2/CCR2 blockade. Finally, we performed chemoprotection studies in an in vivo mouse model. Of 35 patients, 23 (65%) expressed CCR2 by FCM in PB. Two cell lines expressed high levels of CCR2 (THP-1 and murine AML). RT-PCR and WB confirmed CCR2 production. CCL2 solid phase ELISA showed significantly lower levels of CCL2 in PB and BM compared to normal controls. Chemotaxis experiments confirmed a dose-dependent migration in AML primary cells expressing CCR2 and THP-1 cells. A significant inhibition of transmigration was seen after CCL2/CCR2 blockade. Proliferation of CCR2+ AML cell lines was slightly increased (1.4-fold) after axis stimulation. We observed a non-significant increase in phase S THP-1 cells exposed to CCL2 and a concomitant decrease of cells in G1. The chemotherapy studies did not show a protective effect of CCL2 on cytarabine-induced apoptosis or synergy with chemotherapy after CCL2/CCR2 blockade both in vitro and in vivo. In conclusion, CCL2/CCR2 axis is expressed in the majority of monocytoid AML blasts. The axis is involved in cell trafficking and proliferation but no in vitro and in vivo chemotherapy protective effect was seen.

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“…Chemokines play a central role in the recruitment of cells involved in the induction of an immune-response (Brenner et al 2017;Brenner and Reikvam 2016;Karin and Wildbaum 2015). In cancer, chemokines are secreted by tumor cells, immune cells and stromal cells in the tumor microenvironment (Nagarsheth et al 2017).…”

Section: Role Of Chemokines In Tumor Immunology and In Immunotherapymentioning

confidence: 99%

Serum Chemokine-release Profiles in AML-patients Might Contribute to Predict the Clinical Course of the Disease

Merle

Fischbacher

Liepert

et al. 2019

Immunological Investigations

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In cancer or hematologic disorders, chemokines act as growth-or survival factors, regulating hematopoiesis and angiogenesis, determining metastatic spread and controlling leukocyte infiltration into tumors to inhibit antitumor immune responses. The aim was to quantify the release of CXCL8, −9, −10, CCL2, −5, and IL-12 in AML/ MDS-pts' serum by cytometric bead array and to correlate data with clinical subtypes and courses. Minimal differences in serum-levels subdivided into various groups (e.g. age groups, FAB-types, blastproportions, cytogenetic-risk-groups) were seen, but higher release of CXCL8, −9, −10 and lower release of CCL2 and −5 tendentially correlated with more favorable subtypes (<50 years of age, <80% blasts in PB). Comparing different stages of the disease higher CCL5-release in persisting disease and a significantly higher CCL2release at relapse were found compared to first diagnosispointing to a change of 'disease activity' on a chemokine level. Correlations with later on achieved response to immunotherapy and occurrence of GVHD were seen: Higher values of CXCL8, −9, −10 and CCL2 and lower CCL5-values correlated with achieved response to immunotherapy. Predictive cut-off-values were evaluated separating the groups in 'responders' and 'non-responders'. Higher levels of CCL2 and −5 but lower levels of CXCL8, −9, −10 correlated with occurrence of GVHD. We conclude, that in AML-pts' serum higher values of CXCL8, −9, −10 and lower values of CCL5 and in part of CCL2 correlate with more favorable subtypes and improved antitumor'-reactive function. This knowledge can contribute to develop immune-modifying strategies that promote antileukemic adaptive immune responses.

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A Subset of Patients with Acute Myeloid Leukemia Has Leukemia Cells Characterized by Chemokine Responsiveness and Altered Expression of Transcriptional as well as Angiogenic Regulators

Cited by 26 publications

References 58 publications

MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia

MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia

The CCL2/CCR2 Axis Affects Transmigration and Proliferation but Not Resistance to Chemotherapy of Acute Myeloid Leukemia Cells

Serum Chemokine-release Profiles in AML-patients Might Contribute to Predict the Clinical Course of the Disease

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