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HCINAP regulates the DNA damage response and mediates the resistance of acute myelocytic leukemia cells to therapy

ABSTRACT: hCINAP regulates the DNA damage response and mediates the resistance of acute myelocytic leukemia cells to therapy

PROVIDER: PRJNA554810 | ENA |

REPOSITORIES: ENA

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hCINAP regulates the DNA damage response and mediates the resistance of acute myelocytic leukemia cells to therapy

Project description:Through RNA-seq of wildtype and hCINAP-deleted U2OS cells and whole genome bisulfite sequencing of the two U2OS cells, we show here that hCINAP is responsible for genomic stability and DNA damage response. Deletion of hCINAP directly decreased genomic stability and caused drug sensitivity. Also, when hCINAP is deleted, many genes are upregulated. These genes are involved in aging, DNA damage response and leukemia. In our wet lab experiment results, knockdown of hCINAP sensitizes a patient-derived xenograft (PDX) mouse model to chemotherapy. In clinical AML samples, low hCINAP expression is associated with a higher overall survival rate in patients. These results provide mechanistic insight into the function of hCINAP during the DNA damage response and its role in AML resistance to therapy. RNA-seq analysis was performed by ANNOROAD. Briefly, the total RNA from wild-type and knockout hCINAP U2OS cells was extracted, and sequences were performed with Illumina Solexa Ultrasequencing.

2019-07-22 | GSE134342 | GEO

hCINAP regulates the DNA-damage response and mediates the resistance of acute myelocytic leukemia cells to therapy.

Project description:Acute myeloid leukemia (AML) is a genetically heterogeneous malignant disorder of the hematopoietic system, characterized by the accumulation of DNA-damaged immature myeloid precursors. Here, we find that hCINAP is involved in the repair of double-stranded DNA breaks (DSB) and that its expression correlates with AML prognosis. Following DSB, hCINAP is recruited to damage sites where it promotes SENP3-dependent deSUMOylation of NPM1. This in turn results in the dissociation of RAP80 from the damage site and CTIP-dependent DNA resection and homologous recombination. NPM1 SUMOylation is required for recruitment of DNA repair proteins at the early stage of DNA-damage response (DDR), and SUMOylated NPM1 impacts the assembly of the BRCA1 complex. Knockdown of hCINAP also sensitizes a patient-derived xenograft (PDX) mouse model to chemotherapy. In clinical AML samples, low hCINAP expression is associated with a higher overall survival rate in patients. These results provide mechanistic insight into the function of hCINAP during the DNA-damage response and its role in AML resistance to therapy.

| S-EPMC6707248 | biostudies-literature

Tumor Suppressor IKZF1 Mediates Glucocorticoid Therapy Resistance in B Cell Precursor Acute Lymphoblastic Leukemia

Project description:Analysis of the effect of Prednisolone in mouse splenocytes with and without Ikzf1 at gene expression level. The hypothesis tested in the present study was that loss of Ikzf1 affects the induction and repression of the Glucocorticoid receptor target genes. Results provide important information of the differentially expressed genes regulated by Ikzf1 upon Prednisolone treatment, explaining the resistance towards Glucocorticoid-induced apoptosis in splenocytes harboring Ikzf1 loss. Total RNA was obtained from WT and Ikzf1+/- splenocytes subjected to 16 hours Prednsiolone treatment compared to untreated cells.

2015-02-04 | E-GEOD-65554 | biostudies-arrayexpress

BCL6 mediates Chemoresistance in Acute Myeloid Leukemia

Project description:BCL6 mediates Chemoresistance in Acute Myeloid Leukemia

| PRJNA549958 | ENA

Tumor Suppressor IKZF1 Mediates Glucocorticoid Therapy Resistance in B Cell Precursor Acute Lymphoblastic Leukemia

2015-02-04 | GSE65554 | GEO

Fatty acid metabolism mediates venetoclax resistance in acute myeloid leukemia stem cells

Project description:Fatty acid metabolism mediates venetoclax resistance in acute myeloid leukemia stem cells

| PRJNA656302 | ENA

Fatty acid metabolism mediates venetoclax resistance in acute myeloid leukemia stem cells

Project description:Fatty acid metabolism mediates venetoclax resistance in acute myeloid leukemia stem cells

| PRJNA649749 | ENA

Resistance mechanism to Notch inhibition and combination therapy in human T cell acute lymphoblastic leukemia

Project description:Gain-of-function mutations in NOTCH1 are among the most frequent genetic alterations in T cell acute lymphoblastic leukemia (T-ALL), making the Notch signaling pathway a promising therapeutic target for personalized medicine. Yet, a major limitation for long-term success of targeted therapy is relapse due to tumor heterogeneity or acquired resistance. Thus, we performed a genome-wide CRISPR-Cas9 screen to identify prospective resistance mechanisms to pharmacological NOTCH inhibitors and novel targeted combination therapies to efficiently combat T-ALL. Mutational loss of Phosphoinositide-3-Kinase regulatory subunit 1 (PIK3R1) causes resistance to Notch inhibition. PIK3R1 deficiency leads to increased PIK3/Akt signaling which regulates the spliceosome and cell cycle machinery, both at the transcriptional and post-translational level. Moreover, several therapeutic combinations have been identified, where simultaneous targeting of the cyclin-dependent kinases 4 and 6 (CDK4/6) and NOTCH proved to be the most efficacious in T-ALL xenotransplantation models.

2024-01-26 | PXD038908 | Pride

Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer

Project description:Standard cancer therapy targets tumor cells without considering the possible collateral damage on the tumor microenvironment that could impair therapy response. Employing patient-derived tumor organoids and primary stroma cells or a novel murine rectal cancer model, we show that interleukin-1a (IL-1a) dependent inflammatory cancer-associated fibroblast (iCAF) polarization triggers oxidative DNA damage in iCAFs leading to p53-mediated therapy-induced senescence associated with changes in matrisome composition, chemoradiotherapy resistance and disease progression. IL-1 inhibition, prevention of iCAF senescence or senolytic therapy sensitizes mice to irradiation. In rectal cancer patients a dominant iCAF gene signature as well as lower IL-1 receptor antagonist (IL-1RA) serum levels correlate with poor prognosis. Moreover, conditioned supernatant from patient tumor organoids renders fibroblasts susceptible to radiation-induced senescence in an IL-1-dependent manner. Collectively, we unravel a critical role for iCAFs in therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of CAF senescence.

2022-02-08 | PXD030422 | Pride

Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer

Project description:Standard cancer therapy targets tumor cells without considering the possible collateral damage on the tumor microenvironment that could impair therapy response. Employing patient-derived tumor organoids and primary stroma cells or a novel murine rectal cancer model, we show that interleukin-1 (IL-1 dependent inflammatory cancer-associated fibroblast (iCAF) polarization triggers oxidative DNA damage in iCAFs leading to p53-mediated therapy-induced senescence associated with changes in matrisome composition, chemoradiotherapy resistance and disease progression. IL-1 inhibition, prevention of iCAF senescence or senolytic therapy sensitizes mice to irradiation. In rectal cancer patients a dominant iCAF gene signature as well as lower IL-1 receptor antagonist (IL-1RA) serum levels correlate with poor prognosis. Moreover, conditioned supernatant from patient tumor organoids renders fibroblasts susceptible to radiation-induced senescence in an IL-1-dependent manner. Collectively, we unravel a critical role for iCAFs in therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of CAF senescence.

2022-02-08 | PXD020871 | Pride

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