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Therapeutic targeting of the NOTCH1 and neddylation pathways in T cell acute lymphoblastic leukemia

ABSTRACT: Gamma Secretase Inhibitors (GSIs) effectively block the activation of oncogenic protein Notch homolog-1 (NOTCH1), a frequent event in T-cell Acute Lymphoblastic Leukemia (T-ALL). However, their clinical application is hampered by severe gastrointestinal toxicity due to the inhibition of NOTCH1 signaling and subsequent increase in goblet cell differentiation in the gut. Genome-wide CRISPR loss-of-function (LOF) screen in the colon cancer cell line LS174T identified the neddylation pathway as a main regulator of goblet cell differentiation upon NOTCH1 inhibition. Consistently, genetic deletion or pharmacologic inhibition of the neddylation pathway with the small molecule inhibitor MLN4924 rescued GSI-induced differentiation and cell death in LS174T cells. Mechanistically, neddylation inhibition by MLN4924 increases the protein stability of Hairy and enhancer of split-1 (HES1), a known NOTCH1 target and a regulator of absorptive and secretory cell fate decisions. Combined treatment with GSI and MLN4924 in murine Notch1-induced model of T-ALL showed leukemia regression and improved overall survival without any associated gut toxicity. Overall, these results substantiate the potential of targeting NOTCH1 and neddylation pathway in the treatment of NOTCH1-induced T-ALL. We used microarray to profile the gene expression in mouse intestinal stem cells upon NOTCH1 inhibition through GSI (DBZ treatment). This will allow us to explore the mechanisms of NOTCH1 inhibition in intestinal cell fate in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE245370 | GEO | 2025/04/01

REPOSITORIES: GEO

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Therapeutic targeting of the NOTCH1 and neddylation pathways in T cell acute lymphoblastic leukemia

Project description:Gamma Secretase Inhibitors (GSIs) effectively block the activation of oncogenic protein Notch homolog-1 (NOTCH1), a frequent event in T-cell Acute Lymphoblastic Leukemia (T-ALL). However, their clinical application is hampered by severe gastrointestinal toxicity due to the inhibition of NOTCH1 signaling and subsequent increase in goblet cell differentiation in the gut. Genome-wide CRISPR loss-of-function (LOF) screen in the colon cancer cell line LS174T identified the neddylation pathway as a main regulator of goblet cell differentiation upon NOTCH1 inhibition. Consistently, genetic deletion or pharmacologic inhibition of the neddylation pathway with the small molecule inhibitor MLN4924 rescued GSI-induced differentiation and cell death in LS174T cells. Mechanistically, neddylation inhibition by MLN4924 increases the protein stability of Hairy and enhancer of split-1 (HES1), a known NOTCH1 target and a regulator of absorptive and secretory cell fate decisions. Combined treatment with GSI and MLN4924 in murine Notch1-induced model of T-ALL showed leukemia regression and improved overall survival without any associated gut toxicity. Overall, these results substantiate the potential of targeting NOTCH1 and neddylation pathway in the treatment of NOTCH1-induced T-ALL. To elucidate the mechanisms mediating LS174T (adenocarcinoma cell line) differentiation upon NOTCH inhibition, we performed gene expression profiling in LS174T cells treated with vehicle (DMSO) or GSI (CompE) (250 nm) for 48 hours

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Preclinical analysis of the gamma secretase inhibitor PF-030840214 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia

Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer frequently associated with activating mutations in NOTCH1. Early studies identified NOTCH1 as an attractive therapeutic target for the treatment of T-ALL through the use of gamma-secretase inhibitors (GSIs). Here, we characterized the interaction between PF-03084014, a clinically-relevant GSI, and dexamethasone in preclinical models of glucocorticoid-resistant T-ALL. Combination treatment of the GSI PF-03084014 with glucocorticoids induced a synergistic antileukemic effect in human T-ALL cell lines and primary human T-ALL patient samples. Molecular characterization of the response to PF-03084014 plus glucocorticoids through gene expression profiling revealed transcriptional upregulation of the glucocorticoid receptor as the mechanism mediating the enhanced glucocorticoid response. Moreover, treatment with PF-03084014 and glucocorticoids in combination was highly efficacious in vivo, with enhanced reduction of tumor burden in a xenograft model of T-ALL. Finally, glucocorticoid treatment was highly effective at reversing PF-03084014-induced gastrointestinal toxicity via inhibition of goblet cell metaplasia. These results suggest that combination of PF-03084014 treatment with glucocorticoids may be well-tolerated and highly active for the treatment of glucorticoid-resistant T-ALL. Duplicate samples of the CUTLL1 T-ALL cell line were treated with vehicle only (DMSO), the gamma-secretase inhibitor PF-03084014 (1 microM), dexamethasone (1 microM), or PF-03084014 (1 microM). plus dexamethasone (1 microM) for 48 hours. Gene expression profiling was analyzed to identify gene expression signatures assocuated with glucocorticoid treatment (dexamethasone), inhibition of NOTCH1 by gamma secretase inhibitor (PF-03084014) or the combination of both treatments.

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Genome-scale CRISPR screen reveals neddylation to contribute to cisplatin resistance of testicular germ cell tumors II

Project description:Type II testicular germ cell tumors (TGCT) are the most prevalent tumors in young men. Patients suffering from cisplatin resistant TGCTs are facing very poor prognosis demanding novel therapeutic options. Neddylation is a known posttranslational modification mediating many important biological processes including tumorigenesis. Overactivation of neddylation pathway promotes carcinogenesis and tumor progression in various entities by inducing proteasomal degradation of tumor suppressors (e.g., p21, p27). We used a genome-scale CRISPR/Cas9 activation screen to identify cisplatin resistance factors. TGCT cell lines were treated with the neddylation inhibitor (MLN4924)/cisplatin/combination and investigated for changes in viability (XTT assay), apoptosis/cell cycle (flow cytometry) as well as in the transcriptome (3’mRNA sequencing). NAE1 overexpression was detected in cisplatin resistant colonies from the CRISPR screen. Inhibition of neddylation using MLN4924 increased cisplatin cytotoxicity in TGCT cell lines and sensitized cisplatin resistant cells towards cisplatin. Apoptosis, G2/M-phase cell cycle arrest, gH2A.X/P27 accumulation and mesoderm/endoderm differentiation was observed in TGCT cells while fibroblast cells were unaffected. We identified overactivation of neddylation as a factor for cisplatin resistance in TGCTs and highlighted the additive effect of NAE1 inhibition by MLN4924 in combination with cisplatin as a novel treatment option for TGCTs.

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Multilayered proteomics uncovers Notch/PKC targeting to overcome resistance to Notch inhibition in acute lymphoblastic leukemia

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