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Genome-wide CRISPR screen of MOLM13 cells after Idasanutlin treatment

ABSTRACT: Targeting MDM2 is an attractive therapeutic approach for TP53 wild-type (WT) tumors, including the majority of de novo acute myeloid leukemia (AML) cases. However, patients with WT TP53 have shown variable responses to MDM2 inhibitors in clinical trials, highlighting the need to identify additional biomarkers to maximize the chances of clinical success. We performed CRISPR-Cas9 knockout screens to identify genes that confer resistance to an MDM2 inhibitor idasanutlin. We did not find recurrent sgRNA hits or mutations in p53 downstream targets, such as CDKN1A, BAX, PMIAP1, and BBC3, apart from TP53. This was consistent with the results of individual knockout validation experiments and exome sequencing data from idasanutlin resistant cell lines generated form long-term exposure to low doses of idasanutlin. RNA-seq differential expression analysis revealed that major p53 downstream targets were upregulated in both idasanutlin-sensitive MOLM13 and resistant OCIAML3 cell lines after idasanutlin treatment. These findings highlight the pleiotropic functions of TP53 and suggest that the loss of individual downstream targets of TP53 does not significantly contribute to MDM2 inhibitor resistance.

ORGANISM(S): synthetic construct Homo sapiens

PROVIDER: GSE240977 | GEO | 2024/08/15

REPOSITORIES: GEO

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Idasanutlin differential expression in MOLM13 and OCIAML3

Project description:Targeting MDM2 is an attractive therapeutic approach for TP53 wild-type (WT) tumors, including the majority of de novo acute myeloid leukemia (AML) cases. However, patients with WT TP53 have shown variable responses to MDM2 inhibitors in clinical trials, highlighting the need to identify additional biomarkers to maximize the chances of clinical success. We performed CRISPR-Cas9 knockout screens to identify genes that confer resistance to an MDM2 inhibitor idasanutlin. We did not find recurrent sgRNA hits or mutations in p53 downstream targets, such as CDKN1A, BAX, PMIAP1, and BBC3, apart from TP53. This was consistent with the results of individual knockout validation experiments and exome sequencing data from idasanutlin resistant cell lines generated form long-term exposure to low doses of idasanutlin. RNA-seq differential expression analysis revealed that major p53 downstream targets were upregulated in both idasanutlin-sensitive MOLM13 and resistant OCIAML3 cell lines after idasanutlin treatment. These findings highlight the pleiotropic functions of TP53 and suggest that the loss of individual downstream targets of TP53 does not significantly contribute to MDM2 inhibitor resistance.

2024-08-15 | GSE240805 | GEO

ChIP-seq analysis to determine p53 binding profiles in the BV173 cell line before and after treatment with the MDM2 inhibitor idasanutlin

Project description:We performed ChIP-seq analysis in order to determine the transcriptional targets of p53 in the CML cell line BV173 as a result of p53 activation using the MDM2 inhibitor idasanutlin.

2023-12-19 | GSE218182 | GEO

MDM2 and MDM4 are Therapeutic Vulnerabilities in Malignant Rhabdoid Tumors

Project description:Malignant rhabdoid tumors (MRT) are highly aggressive pediatric cancers that respond poorly to current therapies. We screened several MRT cell lines each with large-scale RNAi, CRISPR-Cas9, and small-molecule libraries to identify potential drug targets specific for these cancers. We discovered MDM2 and MDM4, the canonical negative regulators of p53, as significant vulnerabilities. Using two compounds currently in clinical development, idasanutlin and ATSP-7041, we show that MRT cells are more sensitive than other p53 wild-type cancer cell lines to MDM2 and dual MDM2/4 inhibition in vitro. These compounds cause significant upregulation of the p53 pathway in MRT cells, and sensitivity is ablated by CRISPR-Cas9-mediated inactivation of TP53. We show that loss of SMARCB1, a subunit of the SWI/SNF (BAF) complex mutated in nearly all MRT, sensitizes cells to MDM2 and MDM2/4 inhibition by enhancing p53-mediated apoptosis. Both MDM2 and MDM2/4 inhibition slowed MRT xenograft growth in vivo, with a five-day idasanutlin pulse causing marked regression of all xenografts including durable complete responses in 50% of mice. Together, these studies identify a genetic connection between mutations in the SWI/SNF chromatin-remodeling complex and the tumor suppressor gene p53, and provide preclinical evidence to support the targeting of MDM2 and MDM4 in this often-fatal pediatric cancer.

2019-02-04 | GSE124508 | GEO

Bulk RNA-seq analysis of primary CML CD34+ cells (n=3) treated with idasanutlin alone or in combination with nilotinib in vitro

Project description:Bulk RNA-seq was performed on primary human CML CD34+ cells to understand the molecular consequences of treatment with the MDM2 inhibitor idasanutlin alone and in combination with the tyrosine kinase inhibitor nilotinib for 24 hrs and 72 hrs.

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Single cell RNA-seq analysis of the effects of idasanutlin and/or nilotinib on primary human CML cells engrafted into the bone marrow of immunocompromised mice

Project description:Single cell RNA-seq was performed on primary human CML cells engrafted into the bone marrow of immunocompromised mice to understand the molecular consequences of treatment with the tyrosine kinase inhibitor nilotinib alone and in combination with the MDM2 inhibitor idasanutlin.

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Transcriptional activity of a T-ALL PDX line following in vitro treatment with idasanutlin, navitoclax (ABT-263), or combination therapy

Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with an umet need for improved therapies. We explored the potentially synergic combination of MDM2 inhibition and Bcl-2, Bcl-xL inhibition through cotreatment of T-ALL models with idasanutlin and navitoclax. In order to understand the early transcriptional changes induced by this combination therapy, we performed RNA sequencing on drug treated cells.

2023-10-16 | GSE240444 | GEO

CUT&Tag of ARID1B and ARID2 in MOLM13 cells

Project description:MOLM13 cells were used to perform Cleavage Under Targets and Tagmentation (CUT&Tag) analysis to identify genomic binding sites of ARID1B and ARID2 in MLL-AF9 cells.

2022-03-08 | GSE188290 | GEO

Effect of wtp53-reactivating drug RITA on HCT116 cells

Project description:Since its discovery as a tumour suppressor some fifteen years ago, the transcription factor p53 has attracted paramount attention for its role as “the guardian of the genome”. TP53 mutations occur so frequently in cancer, regardless of patient age or tumour type, that they appear to be part of the life history of at least 50% of human tumours. In most tumours that retain wild-type p53, its function is inactivated due to deregulated HDM2, a protein which binds to p53 and which can inhibit the transcriptional activity of p53 and induce its degradation. RITA is a low-molecular-weight compound which addresses the second group of tumours retaining functionally reactive wt p53. It was found in a screening of the National Cancer Institute (NCI) library of low-molecular-weight compounds based on its ability to selectively kill wtp53-containing cells. RITA binds directly to p53 and diplaces its main destructor Mdm2, as well as inducing a shift in the conformation of p53. This is in contrast to the wtp53-reactivating compound Nutlin3a, which targets Mdm2, inhibiting its ability to degrade p53. Using microarray technology we have explored the effect of RITA on the transcriptome of isogenic cell-lines with knocked-out (KO) or intact (WT) TP53. While the effects on KO cells are below detection limit, the effects on WT cells are profound. The known p53 targets induced are predominately apoptotic, in contrast to the genes affected by Nutlin3a, which are exclusively growth-arrest genes. Keywords: Antitumor agent HCT116 parental and HCT116 p53-null (HCT116 TP53-/-) cells were subjected to treatment with 1uM RITA for 12h, or left untreated. The experiment was done in three independent biological replicates.

2009-02-28 | E-GEOD-11578 | biostudies-arrayexpress

Effect of wtp53-reactivating drug RITA on HCT116 cells

2009-02-28 | GSE11578 | GEO

miCLIP, RNA-Seq, and Ribo-Seq in MOLM13 cells

Project description:We studied the following conditions: m6A RNA methylation in MOLM13 AML cells; METTL3 deficiency on gene expression and translational efficiency

2017-09-18 | GSE98623 | GEO

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