IL1RAP potentiates multiple oncogenic signaling pathways in AML

Mitchell, Kelly; Barreyro, Laura; Todorova, Tihomira I.; Taylor, Samuel J.; Antony-Debré, Iléana; Narayanagari, Swathi Rao; Carvajal, Luis A.; Leite, Joana; Piperdi, Zubair; Pendurti, Gopichand; Mantzaris, Ioannis; Paietta, Elisabeth; Verma, Amit; Gritsman, Kira; Steidl, Ulrich

doi:10.1084/jem.20180147

Cited by 70 publications

(69 citation statements)

References 70 publications

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“…The elevated responsiveness of IL-1b-sensitive AML bone marrow cells appeared to correlate with a significantly increased expression of IL-1R1 and IL-1RacP compared to IL-1b non-sensitive AML samples, consistent with other findings demonstrating that expression of IL-1RAcP is a prognostic marker of AML [91][92][93]. In addition to relaying growth signals from IL-1 cytokines, a recent study suggested a broader role for IL-1RAcP in AML by amplifying oncogenic AML pathways through recruitment of the tyrosine kinases FLT3 and c-KIT in AML cells [92]. This suggests that therapeutic neutralization of IL-1RacP may permit to simultaneously target multiple oncogenic pathways in AML.…”

Section: Anti-tumorigenic Role Of Il-1b In Solid Tumourssupporting

confidence: 88%

The emerging roles of inflammasome‐dependent cytokines in cancer development

Gorp

Lamkanfi

2019

EMBO Reports

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In addition to the genomic alterations that occur in malignant cells, the immune system is increasingly appreciated as a critical axis that regulates the rise of neoplasms and the development of primary tumours and metastases. The interaction between inflammatory cell infiltrates and stromal cells in the tumour microenvironment is complex, with inflammation playing both pro‐ and anti‐tumorigenic roles. Inflammasomes are intracellular multi‐protein complexes that act as key signalling hubs of the innate immune system. They respond to cellular stress and trauma by promoting activation of caspase‐1, a protease that induces a pro‐inflammatory cell death mode termed pyroptosis along with the maturation and secretion of the pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐18. Here, we will briefly introduce inflammasome biology with a focus on the dual roles of inflammasome‐produced cytokines in cancer development. Despite emerging insight that inflammasomes may promote and suppress cancer development according to the tumour stage and the tumour microenvironment, much remains to be uncovered. Further exploration of inflammasome biology in tumorigenesis should enable the development of novel immunotherapies for cancer patients.

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Section: Anti-tumorigenic Role Of Il-1b In Solid Tumourssupporting

confidence: 88%

The emerging roles of inflammasome‐dependent cytokines in cancer development

Gorp

Lamkanfi

2019

EMBO Reports

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“…Inflammation is frequently detectable in tumorigenic microenvironment, which exerts a fueling or restraining effect on tumorigenesis and therapeutic agent sensitivity (9,10). Recent studies indicate that, compared with normal hematopoietic counterparts, the leukemia cells in certain AML cases are highly proinflammatory (11,12), such as those characterized by the highly increased signaling activity of IL-1 superfamily members (13)(14)(15), which contributes to the modulation of the leukemic propagation in a context-dependent manner. In this regard, the IL-17 family represents a group of proinflammatory cytokines that play a pivotal role in numerous types of inflammatory diseases and cancers (16)(17)(18)(19).…”

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confidence: 99%

Leukemic IL‐17RB signaling regulates leukemic survival and chemoresistance

et al. 2019

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Secreted proteins provide crucial signals that have been implicated in the development of acute myeloid leukemia (AML) in the bone marrow microenvironment. Here we identify aberrant expressions of inflammatory IL‐17B and its receptor (IL‐17RB) in human and mouse mixed lineage leukemia–rearranged AML cells, which were further increased after exposure to chemotherapy. Interestingly, silencing of IL‐17B or IL‐17RB led to significant suppression of leukemic cell survival and disease progression in vivo. Moreover, the IL‐17B–IL‐17RB axis protected leukemic cells from chemotherapeutic agent–induced apoptotic effects. Mechanistic studies revealed that IL‐17B promoted AML cell survival by enhancing ERK, NF‐κB phosphorylation, and the expression of antiapoptotic protein B‐cell lymphoma 2, which were reversed by small‐molecule inhibitors. Thus, the inhibition of the IL‐17B–IL‐17RB axis may be a valid strategy to enhance sensitivity and therapeutic benefit of AML chemotherapy.—Guo, H.‐Z., Niu, L.‐T., Qiang, W.‐T., Chen, J., Wang, J., Yang, H., Zhang, W., Zhu, J., Yu, S.‐H. Leukemic IL‐17RB signaling regulates leukemic survival and chemoresistance. FASEB J. 33, 9565–9576 (2019). http://www.fasebj.org

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“…Aberrant signaling via IL-1 and the downstream IRAK/TRAF pathway shared by IL-1R and Toll-like receptors has been implicated as a driver of survival and/or expansion of MDS and myeloid leukemia stem cells (LSC) (Agerstam et al, 2016;Askmyr et al, 2013;Barreyro et al, 2012;Carey et al, 2017;Muto et al, 2020;Smith et al, 2019;Zhang et al, 2016). Indeed, blockade of these pathways can limit and/or reverse disease progression (Carey et al, 2017;Mitchell et al, 2018;Rhyasen et al, 2013;Zhang et al, 2016). However, the mechanism(s) by which inflammatory signaling initiates expansion of oncogenically mutated HSC remain obscure.…”

Section: Discussionmentioning

confidence: 99%

PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress

Rabe

Loeffler

Higa

et al. 2020

Preprint

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Loss of hematopoietic stem cell (HSC) quiescence and resulting clonal expansion are common initiating events in the development of hematological malignancy. Likewise, chronic inflammation related to aging, disease and/or tissue damage is associated with leukemia progression, though its role in oncogenesis is not clearly defined. Here, we show that PU.1-dependent repression of protein synthesis and cell cycle genes in HSC enforces homeostatic protein synthesis levels and HSC quiescence in response to IL-1 stimulation. These genes are constitutively de-repressed in PU.1-deficient HSC, leading to activation of protein synthesis, loss of quiescence and aberrant expansion of HSC. Taken together, our data identify a mechanism whereby HSC regulate their cell cycle activity and pool size in response to chronic inflammatory stress.

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IL1RAP potentiates multiple oncogenic signaling pathways in AML

Abstract: IL1RAP is an emerging target for AML therapy. Studying its cell-intrinsic function revealed that IL1RAP interacts with and amplifies signaling through c-KIT and FLT3 in AML cells. This novel promiscuous role of IL1RAP in AML has implications for therapeutic targeting.

Cited by 70 publications

References 70 publications

The emerging roles of inflammasome‐dependent cytokines in cancer development

The emerging roles of inflammasome‐dependent cytokines in cancer development

Leukemic IL‐17RB signaling regulates leukemic survival and chemoresistance

PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress

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