IL-8 as mediator in the microenvironment-leukaemia network in acute myeloid leukaemia

Kuett, Alexander; Rieger, Christina; Perathoner, Deborah; Herold, Tobias; Wagner, Michaela; Sironi, Silvia; Sotlar, Karl; Horny, Hans‐Peter; Deniffel, Christian; Drolle, Heidrun; Fiegl, Michael

doi:10.1038/srep18411

Cited by 55 publications

(58 citation statements)

References 36 publications

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“…We observed attenuation of CXCL-1 and IL8 secretions upon the molecular targeting of TIFA coherent with delayed leukemic cell growth and reduced chemoresistance (Fig. 6A and B), which supports previously suggested tumorigenic function of the two inflammatory factors (48,49).…”

Section: Discussionsupporting

confidence: 75%

Aurora A and NF-κB Survival Pathway Drive Chemoresistance in Acute Myeloid Leukemia via the TRAF-Interacting Protein TIFA

Wei

et al. 2017

Cancer Research

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Aurora A-dependent NF-kB signaling portends poor prognosis in acute myeloid leukemia (AML) and other cancers, but the functional basis underlying this association is unclear. Here, we report that Aurora A is essential for Thr9 phosphorylation of the TRAF-interacting protein TIFA, triggering activation of the NF-kB survival pathway in AML. TIFA protein was overexpressed concurrently with Aurora A and NF-kB signaling factors in patients with de novo AML relative to healthy individuals and also correlated with poor prognosis. Silencing TIFA in AML lines and primary patient cells decreased leukemic cell growth and chemoresistance via downregulation of prosurvival factors Bcl-2 and Bcl-X L that support NF-kB-dependent antiapoptotic events. Inhibiting TIFA perturbed leukemic cytokine secretion and reduced the IC 50 of chemotherapeutic drug treatments in AML cells. Furthermore, in vivo delivery of TIFA-inhibitory fragments potentiated the clearance of myeloblasts in the bone marrow of xenograft-recipient mice via enhanced chemotoxicity. Collectively, our results showed that TIFA supports AML progression and that its targeting can enhance the efficacy of AML treatments.Cancer Res; 77(2); 494-508. Ó2016 AACR.

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Section: Discussionsupporting

confidence: 75%

Aurora A and NF-κB Survival Pathway Drive Chemoresistance in Acute Myeloid Leukemia via the TRAF-Interacting Protein TIFA

Wei

et al. 2017

Cancer Research

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“…CXCL8-expression differed between subgroups with significantly lower expression in acute promyelocytic leukemia (APL) and highest expression in non-APL-AML patients with FLT3-internal tandem duplication (Kuett et al 2015). For CXCL9, CXCL10, and IL-12, no association with any AML-subtype was described until now.…”

Section: Chemokine-release In Serum Correlates With Clinical Featuresmentioning

confidence: 97%

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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“…Interleukin-1β, which is produced by malignant HSCs in myeloproliferative neoplasia due to the Jak2V617F mutation, causes damage to MSCs and neurons in the BMM (Arranz et al, 2014). IL-8 acts as a hypoxia-induced cytokine and increases the number of MSCs and their migration in the AML niche (Kuett et al, 2015). In AML, high expression of CXCR4 correlates with poor prognosis (Konoplev et al, 2007;Rombouts et al, 2004).…”

Section: Role Of the Bmm In Chemoresistancementioning

confidence: 99%

The bone marrow microenvironment in health and disease at a glance

Kumar

Godavarthy

Krause

2018

Journal of Cell Science

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The bone marrow microenvironment (BMM) is the 'domicile' of hematopoietic stem cells, as well as of malignant processes that can develop there. Multiple and complex interactions with the BMM influence hematopoietic stem cell (HSC) physiology, but also the pathophysiology of hematological malignancies. Reciprocally, hematological malignancies alter the BMM, in order to render it more hospitable for malignant progression. In this Cell Science at a Glance article and accompanying poster, we highlight concepts of the normal and malignant hematopoietic stem cell niches. We present the intricacies of the BMM in malignancy and provide approaches for targeting the interactions between malignant cells and their BMM. This is done in an effort to augment existing treatment strategies in the future.

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IL-8 as mediator in the microenvironment-leukaemia network in acute myeloid leukaemia

Cited by 55 publications

References 36 publications

Aurora A and NF-κB Survival Pathway Drive Chemoresistance in Acute Myeloid Leukemia via the TRAF-Interacting Protein TIFA

Aurora A and NF-κB Survival Pathway Drive Chemoresistance in Acute Myeloid Leukemia via the TRAF-Interacting Protein TIFA

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

The bone marrow microenvironment in health and disease at a glance

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