Interleukin 1 as an autocrine growth factor for acute myeloid leukemia cells.

Cozzolino, Federico; Rubartelli, Anna; Aldinucci, Donatella; Sitia, Roberto; Torcia, M; Shaw, Alan; Guglielmo, R Di

doi:10.1073/pnas.86.7.2369

Cited by 125 publications

(56 citation statements)

References 29 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.

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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.

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“…43 Sensitivity of blast cells to GM-CSF in vitro appeared to be inversely related with early treatment response which may be explained by the autocrine production of hematopoietic growth factors in AML blasts. [44][45][46][47] These results were confirmed by Tsuzuki and coworkers, 48 showing that patients whose leukemic cells had a positive proliferative response to growth factors had a poorer outcome.…”

Section: Introductionsupporting

confidence: 76%

Cytogenetic subgroups in acute myeloid leukemia differ in proliferative activity and response to GM-CSF

et al. 2001

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The current study was undertaken to search for differences in the biology of cytogenetic subgroups in patients with de novo acute myeloid leukemia (AML). In addition, factors influencing the metabolism of cytosine arabinoside (araC) as the key agent of antileukemic activity were assessed. Bone marrow aspirates from 91 patients with newly diagnosed AML in whom karyotypes were successfully obtained were analyzed: (1) for spontaneous proliferative activity by 3 H-thymidine ( 3 H-TdR) incorporation; (2) proliferative response to GM-CSF by in vitro incubation of blasts for 48 h with or without GM-CSF (100 U/ml) followed by an additional 4-h exposure to 3 H-TdR (0.5 Ci/ml); and (

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“…In one case the leukaemic cells may produce factors that stimulate the neighboring cells to make growth factors to which the leukemic cells can then respond. For example some human leukaemic cells have been found to produce IL-I which may then induce stromal cells to produce high levels of GM-CSF, G-CSF, and M-CSF (48); these are all factors required for the growth of some leukaemic cells (7,9,(49)(50)(51)(52)(53)(54)(55)(56). This model requires that the leukaemic cells aberrantly express a cytokine and express a receptor for the induced growth factor.…”

Section: Discussionmentioning

confidence: 99%