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Targeting IRAK1 as a therapeutic approach for Myelodysplastic Syndrome

ABSTRACT: Myelodysplastic Syndromes (MDS) result from expansion of defective hematopoietic stem/progenitor clones. There is an urgent need to develop targeted therapies capable of eliminating the defective MDS clones. We identified that IRAK1, an immune modulating kinase, is overexpressed and hyperactivated in MDS. MDS-propagating clones treated with a small-molecule IRAK1 inhibitor (IRAK1/4-Inh) exhibited impaired expansion and increased apoptosis, which coincided with TRAF6/NF-κB inhibition. Suppression of IRAK1, either by RNAi or with IRAK1/4-Inh, is selectively detrimental to MDS clones as normal CD34+ cells are preserved. Based on conclusions derived from an integrative gene expression analysis, we combined IRAK1 and BCL2 inhibitors and found that co-treatment collaboratively and selectively eliminated MDS clones. In summary, these findings implicate IRAK1 as a drugable target in MDS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE46346 | GEO | 2013/04/25

SECONDARY ACCESSION(S): PRJNA198793

REPOSITORIES: GEO

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Targeting IRAK1 as a therapeutic approach for Myelodysplastic Syndrome

Project description:Myelodysplastic Syndromes (MDS) result from expansion of defective hematopoietic stem/progenitor clones. There is an urgent need to develop targeted therapies capable of eliminating the defective MDS clones. We identified that IRAK1, an immune modulating kinase, is overexpressed and hyperactivated in MDS. MDS-propagating clones treated with a small-molecule IRAK1 inhibitor (IRAK1/4-Inh) exhibited impaired expansion and increased apoptosis, which coincided with TRAF6/NF-M-NM-:B inhibition. Suppression of IRAK1, either by RNAi or with IRAK1/4-Inh, is selectively detrimental to MDS clones as normal CD34+ cells are preserved. Based on conclusions derived from an integrative gene expression analysis, we combined IRAK1 and BCL2 inhibitors and found that co-treatment collaboratively and selectively eliminated MDS clones. In summary, these findings implicate IRAK1 as a drugable target in MDS. MDSL cells were transduced with lentivirus encoding shRNA targeting human IRAK1 and a negative control (pLKO) for 2.5 days. GFP positive cells were sorted for RNA extraction, labeling, and hybridization. A total of four samples were included, and two groups are assigned. Two replicates are for each group. Comparison comprises mRNA expression profile of TRAF6 knockdown (shT6) v.s. control vector (pLKO). Additionally, MDSL cells were treated with either DMSO or IRAK inhibitor for 24hrs. Cells were subjected to RNA extraction, labeling, and hybridization. A total of four samples were included, and two groups are assigned.

2013-04-25 | E-GEOD-46346 | biostudies-arrayexpress

IRAK1 drives intestinal inflammation by promoting the generation of effector Th cells with optimal gut homing capacity

Project description:Interleukin-1 receptor associated kinase 1 (IRAK1) is an important component of the IL-1R and TLR signaling pathways, which influence Th cell differentiation. Here, we show that IRAK1 promotes Th17 development by mediating IL-1β induced upregulation of IL-23R and subsequent STAT3 phosphorylation, thus enabling sustained IL-17 production. Moreover, we show that IRAK1 signaling fosters Th1 differentiation by mediating T-bet induction and counteracts Treg generation. Cotransfer experiments revealed that Irak1-deficient CD4+ T cells have a cell-intrinsic defect in generating Th1 and Th17 cells under inflammatory conditions in spleen, mesenteric lymph nodes and colon tissue. Furthermore, IRAK1 expression in T cells was shown to be essential for T cell accumulation in the inflamed intestine and mLNs. Transcriptome analysis ex vivo revealed that IRAK1 promotes T cell activation and induction of gut-homing molecules in a cell-intrinsic manner. Accordingly, Irak1-deficient T cells failed to upregulate surface expression of α4β7 integrin after transfer into Rag1-/- mice and their ability to induce colitis was greatly impaired. Lack of IRAK1 in recipient mice provided additional protection from colitis. Therefore, IRAK1 plays an important role in intestinal inflammation by mediating T cell activation, differentiation and their accumulation in the gut. Thus, IRAK1 is a promising novel target for therapy of inflammatory bowel diseases.

2015-11-13 | GSE73875 | GEO

Targeting IRAK1-S100A9 Axis Overcomes the Resistance to Paclitaxel in Nasopharyngeal Carcinoma

Project description:Resistance to chemotherapy is one of the main causes of mortality in late-stage nasopharyngeal carcinoma (NPC) with dismal prognosis and limited therapeutic options. Therefore, there is an urgent need to exploit new therapeutic targets to improve current clinical outcome. In this study, we identified pacritinib, a late stage clinical drug targeting IRAK1, as a sensitizer to resistance of paclitaxel in NPC. Through analysis of both chemoresistant cellular models and clinical samples of relapse and metastasis, we have shown that aberrant IRAK1-S100A9 deregulation is correlated with chemoresistance and prognosticates poor clinical outcome. Further functional studies demonstrated that genetic and pharmacological inhibition of IRAK1-S100A9 axis overcomes the resistance to paclitaxel and combination of pacritinib with paclitaxel exhibited superior anti-tumor effect in both in vivo and in vitro models.

2023-06-24 | GSE153125 | GEO

S100A14 Suppresses Metastasis of Nasopharyngeal Carcinoma by Inhibition of NF-kB Signaling through Degradation of IRAK1

Project description:Nasopharyngeal carcinoma (NPC) is a unique head and neck cancer with highly aggressive and metastatic potential, and distant metastasis is the main reason for treatment failure. The underlying molecular mechanisms of NPC metastasis remains poorly understood. Here, we have identified S100 calcium binding protein A14 (S100A14) as a functional regulator suppressed NPC metastasis via inhibiting NF-kB signaling and reversing epithelial-mesenchymal transition (EMT). S100A14 was downregulated in highly metastatic NPC cells and NPC tissues. Analyzing 202 NPC samples by immunohistochemical staining revealed that lower S100A14 expression significantly correlated with shorter patient overall survival (OS) and distant metastasis-free survival (DMFS), serving as an independent unfavorable prognostic factor. Gain- and loss-of-function studies confirmed that S100A14 suppressed NPC cellular motility in vitro and in vivo. Mechanically, S100A14 promoted ubiquitin-proteasome-mediated degradation of interleukin-1 receptor-associated kinase 1 (IRAK1) to suppress NPC cellular migration. Moreover, S100A14 and IRAK1 established a feedback loop, which can be disrupted by the IRAK1 inhibitor T2457. Overall, our study uncovers the S100A14-IRAK1 feedback loop is a theranostic target for NPC metastasis.

2021-03-01 | GSE148481 | GEO

Gene expression changes caused by the IRAK1/IRAK4 inhibitor R191 in cell lines of Waldenström’s macroglobulinemia

Project description:The L265P mutation in MYD88 is very frequent in tumor cells of Waldenström’s macroglobulinemia (WM), and activates NF-kappaB through IRAK1 and IRAK4. We examined the effect of the IRAK1/4 inhibitor R191 on two cell lines of WM. Gene expression profiling suggested that R191 reduced activity of AKT and mTOR signaling, consistent with other assays and functional studies. Other changes suggested reduced proliferation and MYC activity, and an ER stress response.

2019-11-01 | GSE106409 | GEO

IRAK1/4 and BET bromodomain inhibitions converge on NF-κB blockade and display synergistic antitumor activity in ABC-DLBCL with MYD88L265P mutation

Project description:Diffuse large B cell lymphoma cell lines of the activated B cell subtype (ABC-DLBCL) were treated for 6h with IRAK1/4 inhibitor (50µM) followed or not by a 18h exposure to 500 nM CPI203 We used microarrays to uncover the mechanisms underlying IRAKi+BETi activity in ABC-DLBCL

2020-10-24 | GSE159915 | GEO

Physiologic expression of Sf3b1K700E causes impaired erythropoieses, aberrant splicing, and sensitivity to pharmacologic spliceosome modulation

Project description:Over 80% of patients with the refractory anemia with ring sideroblasts subtype of myelodysplastic syndrome (MDS) have mutations in Splicing Factor 3B, Subunit 1 (SF3B1). We generated a conditional knock-in mouse model of the most common SF3B1 mutation, Sf3b1K700E. Sf3b1K700E mice develop macrocytic anemia due to a terminal erythroid maturation defect, erythroid dysplasia, and long-term hematopoietic stem cell (LT-HSC) expansion. Sf3b1K700E myeloid progenitors and SF3B1-mutant MDS patient samples demonstrate aberrant 3' splice-site selection associated with increased nonsense-mediated decay. Tet2 loss cooperates with Sf3b1K700E to cause a more severe erythroid and LT-HSC phenotype. Furthermore, the spliceosome modulator, E7017, selectively kills Sf3b1K700E-expressing cells. Thus, Sf3b1K700E expression reflects the phenotype of the mutation in MDS and may be a therapeutic target in MDS.

2016-08-17 | GSE85712 | GEO

Differential response to Lenalidomide from WT and RUNX1-KO MDS-L del(5q) cells

Project description:We used CRISPR/Cas9 system to generate WT Control and RUNX1-KO MDS-L cells isolated as single clones from the parental MDS-L cell line. We have observed that RUNX1-KO MDS-L cells are resistant to Lenalidomide-induced cell death compared to WT Control MDS-L cells We have treated WT and RUNX1-KO MDS-L cells with 1µM Lenalidomide for 24h or 72h and performed expression analysis

2020-01-28 | GSE126265 | GEO

Stage-specific human induced pluripotent stem cells map the progression of myeloid transformation to transplantable leukemia

Project description:Comparison of disease stage transitions between a panel of iPSC clones derived from different MDS patients

2017-02-16 | GSE92494 | GEO

Next-generation sequencing analysis to compare expression pattern of relapse and baseline "GMP pattern" MDS samples

Project description:Transcriptional changes occurring in the expanding LMPP population of "GMP pattern" MDS patients with blast expansion post-HMA failure were compared with the transcriptional profile of untreated (baseline) "GMP pattern" MDS patients.

2022-01-03 | GSE136812 | GEO

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