Autocrine stimulation of interleukin 1 beta in acute myelogenous leukemia cells.

Sakai, Kenji; Hattori, Toshio; Matsuoka, Masao; Asou, Norio; Yamamoto, Setsu; Sagawa, Kimitaka; Takatsuki, Kiyoshi

doi:10.1084/jem.166.5.1597

Cited by 67 publications

(25 citation statements)

References 16 publications

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“…To explore the effects of IL-1 signaling inhibition by an IL1RAP-targeting antibody, we instead performed in vitro investigations on primary cells harvested from AML patients. In agreement with previous reports using anti-IL-1 antibodies or the IL-1 receptor antagonist IL1RA (15,(17)(18)(19)(20)22), blocking IL-1 signaling with the IL1RAP-targeting antibody mAb3F8 significantly suppressed the proliferation of primary AML cells responsive to IL-1. The importance of IL-1 signaling in AML cells has recently obtained further support by a study that used a combined cytokine and siRNA screen against cell-surface receptors and identified IL-1 signaling inhibition as having the most dramatic effect on regulating growth of AML cells (38).…”

Section: Discussionsupporting

confidence: 81%

“…Multiple studies have shown that interference with IL-1 signaling by anti-IL-1 antibodies or an IL1R1 antagonist (IL1RA) suppress proliferation of leukemic cells from a majority of AML patients (15)(16)(17)(18)(19)(20)(21)(22)(23). We therefore investigated the ability of the developed antibodies to inhibit IL-1 signaling.…”

Section: Murine Effector Cells Mediate the Therapeutic Effect In The mentioning

confidence: 99%

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Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia

Ågerstam

Karlsson

Hansen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

102

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Acute myeloid leukemia (AML) is associated with a poor survival rate, and there is an urgent need for novel and more efficient therapies, ideally targeting AML stem cells that are essential for maintaining the disease. The interleukin 1 receptor accessory protein (IL1RAP; IL1R3) is expressed on candidate leukemic stem cells in the majority of AML patients, but not on normal hematopoietic stem cells. We show here that monoclonal antibodies targeting IL1RAP have strong antileukemic effects in xenograft models of human AML. We demonstrate that effector-cell-mediated killing is essential for the observed therapeutic effects and that natural killer cells constitute a critical human effector cell type. Because IL-1 signaling is important for the growth of AML cells, we generated an IL1RAP-targeting antibody capable of blocking IL-1 signaling and show that this antibody suppresses the proliferation of primary human AML cells. Hence, IL1RAP can be efficiently targeted with an anti-IL1RAP antibody capable of both achieving antibody-dependent cellular cytotoxicity and blocking of IL-1 signaling as modes of action. Collectively, these results provide important evidence in support of IL1RAP as a target for antibody-based treatment of AML.A cute myeloid leukemia (AML) is a genetically heterogeneous disease characterized by clonal expansion of leukemic cells. Despite an increased understanding of the underlying disease biology in AML, the standard treatment with cytotoxic chemotherapy has remained largely unchanged over the last decades and the overall 5-y survival remains poor, being <30% (1, 2). Hence, there is a pressing need for novel therapies with increased efficacy and decreased toxicity, ideally targeting the AML stem cells because these cells are believed to be critical in the pathogenesis of AML, and their inadequate eradication by standard therapy is thought to contribute to the high incidence of relapse (3, 4). Although therapeutic antibodies directed at cell-surface molecules have proven effective for the treatment of malignant disorders such as lymphomas and acute lymphoblastic leukemia, as well as solid tumors (5, 6), no antibody-based therapy is currently approved for AML.The interleukin 1 receptor accessory protein (IL1RAP), also called IL1R3, is a coreceptor of type 1 interleukin 1 receptor (IL1R1) and is indispensable for transmission of IL-1 signaling (7). We have previously reported that IL1RAP is a biomarker for putative chronic myeloid leukemia stem cells (8). In a recent study, we showed that IL1RAP is expressed on the cell surface in ∼80% of AML patients and that candidate CD34 + CD38 − AML stem cells can be selectively killed in vitro by antibody-dependent cellular cytotoxicity (ADCC) (9). Furthermore, IL1RAP is upregulated on immature cells in high-risk AML with chromosome 7 aberrations, and increased IL1RAP expression correlates with poor prognosis (10). These findings could suggest IL1RAP as a novel and specific target for an antibody-based therapy in AML; however, in vivo evidences for therapeuti...

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Section: Discussionsupporting

confidence: 81%

Section: Murine Effector Cells Mediate the Therapeutic Effect In The mentioning

confidence: 99%

Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia

Ågerstam

Karlsson

Hansen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

102

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“…It therefore remains possible that other cytokines and/or growth factors are involved. HS-5 stromal cells also secrete IL-1h that can contribute to autocrine and paracrine growth loops in multiple myeloma (27,28) and AML (29,30). However, we previously reported that an FTI inhibits the expression of IL-1h in leukemic cell lines (17), implying that IL-1h is not the protective cytokine in our models.…”

Section: Discussionmentioning

confidence: 61%

Tipifarnib and Bortezomib Are Synergistic and Overcome Cell Adhesion–Mediated Drug Resistance in Multiple Myeloma and Acute Myeloid Leukemia

Yanamandra

Colaco

Parquet

et al. 2006

Clinical Cancer Research

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It has been established in preclinical models of multiple myeloma and acute myeloid leukemia (AML) that the bone marrow microenvironment provides protection from chemotherapy-and death receptor^mediated apoptosis. This form of resistance, termed de novo drug resistance, occurs independent of chronic exposure to cancer-related therapies and likely promotes the development of multidrug resistance. Consequently, it is of major interest to identify compounds or drug combinations that can overcome environment-mediated resistance. In this study, we investigated the activity of tipifarnib (Zarnestra, formerly R115777) combined with bortezomib (Velcade, formerly PS-341) in microenvironment models of multiple myeloma and AML. The combination proved to be synergistic in multiple myeloma and AML cell lines treated in suspension culture. Even in tumor cells relatively resistant to tipifarnib, combined activity was maintained. Tipifarnib and bortezomib were also effective when multiple myeloma and AML cells were adhered to fibronectin, providing evidence that the combination overcomes cell adhesion^mediated drug resistance (CAM-DR). Of importance, activation of the endoplasmic reticulum stress response was enhanced and correlated with apoptosis and reversal of CAM-DR. Multiple myeloma and AML cells cocultured with bone marrow stromal cells also remained sensitive, although stromal-adhered tumor cells were partially protected (relative to cells in suspension or fibronectin adhered). Evaluation of the combination using a transwell apparatus revealed that stromal cells produce a protective soluble factor. Investigations are under way to identify the cytokines and/or growth factors involved. In summary, our study provides the preclinical rationale for trials testing the tipifarnib and bortezomib combination in patients with multiple myeloma and AML.

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“…28,[39][40][41]42 Previous studies have shown increased IL1␤ production in patients with AML. 43,44 IL1␤ is produced as an autocrine factor in AML and confers apoptosis resistance to AML blast cells. 45 Interestingly, IL1R antagonist (IL1Ra) was previously shown to have an inhibitory effect on the growth of AML blasts, 46 and it is available as a drug (anakinra) with promising safety data.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS

Barreyro¹,

Will²,

Bartholdy³

et al. 2012

Blood

176

182

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IntroductionAcute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs) are heterogeneous neoplastic diseases, and most subtypes have poor clinical outcomes. Despite the established use of poly-chemotherapy and the development of new agents that transiently reduce the tumor burden, relapse or failure to achieve durable remission continues to be the most common causes of death in most subtypes of AML and MDS. Recent experimental evidence suggests that AML arises from transformed immature hematopoietic cells after the accumulation of multiple stepwise genetic and epigenetic changes in hematopoietic stem cells (HSCs) and committed progenitors. 1 The series of transforming events are thought to initially give rise to preleukemia stem cells (pre-LSCs), preceding the formation of fully transformed LSCs. Defining the characteristics of LSCs, and also of pre-LSCs, is critical to understanding the genesis of leukemia and to developing strategies by which these cells can be eradicated. AML is characterized by a cellular heterogeneous tumor bulk, with LSCs at the top of the hierarchy and a differentiation block at various stages during myeloid maturation. 2 To address the problem of cellular heterogeneity within the tumor and to identify relevant molecular pathways effective in LSCs and pre-LSCs, novel experimental approaches other than the examination of bulk tumor cells need to be established. Recent findings have suggested that human LSCs are contained within different phenotypic compartments and at relatively low frequencies. [3][4][5] Several surface molecules were reported to permit enrichment of LSCs in AML. 4,[6][7][8][9][10][11] However, reliable markers for human LSCs at the single-cell level have yet to be identified; and because of the challenges associated with the use of xenograft models, the search for such markers remains difficult. Moreover, although there is clear evidence for the involvement of HSCs in AML pathogenesis, studies from murine models suggest that fully transformed and transplantable LSCs may reside at a committed progenitor stage. 12-15 Here we applied a novel approach of parallel transcriptional analysis of multiple, highly fractionated stem and progenitor populations in individual patients. We isolated phenotypic long-term HSCs (LT-HSCs), short-term HSCs (ST-HSCs), The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 11, 2018. by guest www.bloodjournal.org From and committed granulocyte-monocyte progenitors (GMP) from individual patients with AML, and compared gene expression profiles of each population with their phenotypic counterparts from age-matched healthy controls (HCs). Subsequent intersection of differentially expressed genes in the different cellular compartments allowed us to identify candidate genes that are consistently...

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Autocrine stimulation of interleukin 1 beta in acute myelogenous leukemia cells.

Cited by 67 publications

References 16 publications

Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia

Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia

Tipifarnib and Bortezomib Are Synergistic and Overcome Cell Adhesion–Mediated Drug Resistance in Multiple Myeloma and Acute Myeloid Leukemia

Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS

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