Single-Cell Multi-Omics Identifies Chronic Inflammation as a Driver of TP53 mutant Leukaemic Evolution
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE226340 | GEO | 2023/05/10
REPOSITORIES: GEO
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Project description:Acute Myeloid Leukemia (AML) which occurs after an antecedent myeloproliferative neoplasm (MPN) has a dismal clinical prognosis and is not curative outside of the rare subset of patients who undergo successful allogeneic stem cell transplantation. As such, there is a pressing need for new mechanistic insights into how MPNs transform into AML and to use these insights to credential novel therapeutic approaches. The most common somatic mutational event which occurs in transformation from MPN to AML is mutation in TP53. However, the impact of TP53 allelic state on the ability to potentiate leukemic transformation, as well as the pathways involved in this process, have largely remained unresolved. Here we report the development of genetically accurate models of Jak2/Tp53 mutant MPN which undergoes progressive leukemic transformation with chromosomal instability similar to that observed in the clinical context. These models result in a fulminant erythroleukemia phenotype. We identify that leukemic transformation requires homozygous inactivation of TP53, and does not occur with heterozygous loss of Tp53. We further identify that the megakaryocyte erythroid progenitor (MEP) population is expanded prior to and after leukemic transformation, is characterized by progressive genomic instability (compared to other stem/progenitor compartments), and is capable of propagating the disease in vivo. Thus, the leukemia-initiating population is contained in the MEP compartment. Using gene-expression profiling we demonstrate that the BMP2/SMAD pathway (which is involved in self-renewal and DNA damage repair) is aberrantly activated in the leukemic phase of the disease. Importantly, attenuation of Bmp2 results in decreased self-renewal of leukemic cells in vitro and increased survival of leukemic mice in vivo, thus credentialing a biologic role for this pathway in leukemic transformation. Finally, given the loss of Tp53 function and associated disruption of DNA repair pathways, we hypothesized and subsequently identified that leukemic transformation is characterized by increased DNA damage. Using a synthetic-lethality strategy of targeting remaining DNA-repair pathways, using small-molecule inhibitors, in order to provoke biologically intolerable DNA damage and mitotic catastrophe, we demonstrate that Jak2/Tp53 mutant is highly sensitive to combined inhibition of WEE1 and PARP. This combination results in prolonged survival of mice and attenuates the leukemic phenotype. Collectively, these observations yield new mechanistic insights into the process of leukemic transformation resulting from TP53 alterations, and offer new, clinically-translatable, therapeutic options.
2022-05-24 | GSE180772 | GEO
Project description:Acute Myeloid Leukemia (AML) which occurs after an antecedent myeloproliferative neoplasm (MPN) has a dismal clinical prognosis and is not curative outside of the rare subset of patients who undergo successful allogeneic stem cell transplantation. As such, there is a pressing need for new mechanistic insights into how MPNs transform into AML and to use these insights to credential novel therapeutic approaches. The most common somatic mutational event which occurs in transformation from MPN to AML is mutation in TP53. However, the impact of TP53 allelic state on the ability to potentiate leukemic transformation, as well as the pathways involved in this process, have largely remained unresolved. Here we report the development of genetically accurate models of Jak2/Tp53 mutant MPN which undergoes progressive leukemic transformation with chromosomal instability similar to that observed in the clinical context. These models result in a fulminant erythroleukemia phenotype. We identify that leukemic transformation requires homozygous inactivation of TP53, and does not occur with heterozygous loss of Tp53. We further identify that the megakaryocyte erythroid progenitor (MEP) population is expanded prior to and after leukemic transformation, is characterized by progressive genomic instability (compared to other stem/progenitor compartments), and is capable of propagating the disease in vivo. Thus, the leukemia-initiating population is contained in the MEP compartment. Using gene-expression profiling we demonstrate that the BMP2/SMAD pathway (which is involved in self-renewal and DNA damage repair) is aberrantly activated in the leukemic phase of the disease. Importantly, attenuation of Bmp2 results in decreased self-renewal of leukemic cells in vitro and increased survival of leukemic mice in vivo, thus credentialing a biologic role for this pathway in leukemic transformation. Finally, given the loss of Tp53 function and associated disruption of DNA repair pathways, we hypothesized and subsequently identified that leukemic transformation is characterized by increased DNA damage. Using a synthetic-lethality strategy of targeting remaining DNA-repair pathways, using small-molecule inhibitors, in order to provoke biologically intolerable DNA damage and mitotic catastrophe, we demonstrate that Jak2/Tp53 mutant is highly sensitive to combined inhibition of WEE1 and PARP. This combination results in prolonged survival of mice and attenuates the leukemic phenotype. Collectively, these observations yield new mechanistic insights into the process of leukemic transformation resulting from TP53 alterations, and offer new, clinically-translatable, therapeutic options.
2022-05-24 | GSE180851 | GEO
Project description:Recent preclinical studies suggest that combining MEK and MDM2 inhibition synergize to induce apoptosis in RAS/BRAF-mutant and TP53 wild-type CRC models. In vitro, in RKO cell lines (poorly differentiated colon carcinoma cell line resistant to single agent targeting MDM2 and MEK and BRAF inhibition), the MDM2 plus MEK inhibitor combination generated a synergistic increase in apoptotic index. In vivo, in mice harboring human RKO colon tumor xenografts the combination of MDM2 plus MEK inhibition elicited 93% decreases in tumor volume.
This trial is to conduct a single-center, Phase 1 dose escalation study of trametinib combined with HDM201 (a HDM2 inhibitor) in patients with advanced/metastatic RAS/RAF mutant and TP53 wt CRC.
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Project description:High-grade serous ovarian cancer originates in the fallopian tube and is characterized by ubiquitous mutations in TP53. Here, we generated TP53 single-, TP53/BRCA1 and TP53/MYC double- and TP53/BRCA1/MYC triple-mutant subclones of the fallopian tube-derived cell line FNE1 using CRISPR/Cas9. These mutant subclones were subsequently subjected to RNA sequencing to determine the impact of these oncogenic mutations on signaling pathways.
2021-09-28 | GSE182487 | GEO
Project description:this study demonstrates the pre-clinical efcacy potential of RG7388 in the TP53 wild type/PPM1D mutant DIPG subgroup in the TP53 wild-type/PPM1D mutant DIPG subgroup mutant DIPG subgroup
2021-11-20 | GSE189152 | GEO
Project description:TP53-mutant blood cancers remain a major clinical challenge. BH3-mimetic drugs inhibit BCL-2 pro-survival proteins to promote cancer cell apoptosis. Despite acting downstream of TP53, functional TP53 is required for maximal cancer cell killing by BH3-mimetics through an unknown mechanism. Here, we report TP53 can be activated following BH3-mimetic induced mitochondrial outer membrane permeabilization, which leads to induction of BH3-only proteins, thereby potentiating the pro-apoptotic signal. TP53-deficient lymphomas lack this feed-forward loop, providing opportunities for survival and disease relapse after BH3-mimetic treatment. The therapeutic barrier imposed by defects in TP53 could be overcome by direct activation of the cGAS/STING pathway, which promotes apoptosis of blood cancer cells through TP53-independent BH3-only protein upregulation. Combining clinically relevant STING agonists with BH3-mimetics efficiently killed TP53-mutant mouse B lymphoma, human NK/T lymphoma and acute myeloid leukemia cells. This represents a promising therapy regime that can be fast-tracked to tackle TP53-mutant blood cancers in the clinic.
2024-04-25 | GSE261373 | GEO
Project description:The adaptor protein LNK (SH2B3) has emerged as an important protein in regulating B cell development B cell leukemia. Loss-of-function mutations in LNK (SH2B3) are found in Philadelphia chromosomeâlike acute lymphoblastic leukemia (Ph-like ALL), but how LNK regulates normal B cell development or promotes leukemogenesis remains unclear. We found that combined loss of Lnk and tumor suppressors Tp53 in mice triggers a highly aggressive and transplantable precursor B-ALL. This study aims to investigate the molecular mechanism by which LNK regulates B-ALL development. We performed expression profiling of bone marrow proB progenitors from WT, Tp53-/-, Lnk-/- and preleukemic healthy Tp53/Lnk double knockout (DKO) mice, as well as leukemic bone marrow cells from DKO mice that have developed B-ALL. Results suggest that Tp53-/-Lnk-/- B-ALLs display similar gene expression profiles to human Ph-like B-ALLs, suggesting this model for preclinical and molecular studies. B220+CD19+CD43+AA4.1+IgM-NK1.1-Ly6c- bone marrow proB cells were double sorted from WT, Tp53-/-, Lnk-/- and preleukemic healthy Tp53/Lnk double knockout (DKO) mice, as well as leukemic bone marrow cells from DKO mice that have developed B-ALL. RNA was isolated using miRNeasy kit from QIAGEN and processed using the NuGEN Pico kit. The microarray analysis was performed at the PENN Molecular Profiling/Genomics Facility using GeneChip Mouse Gene 2.0ST array (Affymetrix).
2016-04-01 | E-GEOD-76940 | biostudies-arrayexpress
Project description:In order to investigate the potential role of TP53 in regulating translation, HCT116 wild type and TP53 knockout cells were analyzed using both RNA sequencing, Ribosome sequencing and nascent proteome analysis. The cells were treated with 0.2 µg/ml Neocarcinostatin (NCS) to induce DNA damage and activate TP53.
2022-04-27 | PXD029512 | Pride
Project description:TP53 and ARID1A are frequently mutated across cancer but rarely in the same primary tumor. Endometrial cancer has the highest TP53-ARID1A mutual exclusivity rate. However, the functional relationship between TP53 and ARID1A mutations in the endometrium has not been elucidated. We used genetically engineered mice and in vivo genomic approaches to discern both unique and overlapping roles of TP53 and ARID1A in the endometrium. TP53 loss with oncogenic PIK3CA*H1047R in the endometrial epithelium results in features of endometrial hyperplasia, adenocarcinoma, and intraepithelial carcinoma. Mutant endometrial epithelial cells were transcriptome profiled and compared to control cells and ARID1A/PIK3CA mutant endometrium. In the context of either TP53 or ARID1A loss, PIK3CA mutant endometrium exhibited inflammatory pathway activation, but other gene expression programs differed based on TP53 or ARID1A status, such as epithelial-to-mesenchymal transition. Gene expression patterns observed in the genetic mouse models are reflective of human tumors with each respective genetic alteration. Consistent with TP53-ARID1A mutual exclusivity, the p53 pathway is activated following ARID1A loss in the endometrial epithelium, where ARID1A normally directly represses p53 pathway genes in vivo, including the stress-inducible transcription factor, ATF3. However, co-existing TP53-ARID1A mutations led to invasive adenocarcinoma associated with mutant ARID1A-driven ATF3 induction, reduced apoptosis, TP63+ squamous differentiation and invasion. These data suggest TP53 and ARID1A mutations drive shared and distinct tumorigenic programs in the endometrium and promote invasive endometrial cancer when existing simultaneously. Hence, TP53 and ARID1A mutations may co-occur in a subset of aggressive or metastatic endometrial cancers, with ARID1A loss promoting squamous differentiation and the acquisition of invasive properties.
2021-12-13 | GSE167275 | GEO
Project description:TP53 and ARID1A are frequently mutated across cancer but rarely in the same primary tumor. Endometrial cancer has the highest TP53-ARID1A mutual exclusivity rate. However, the functional relationship between TP53 and ARID1A mutations in the endometrium has not been elucidated. We used genetically engineered mice and in vivo genomic approaches to discern both unique and overlapping roles of TP53 and ARID1A in the endometrium. TP53 loss with oncogenic PIK3CA*H1047R in the endometrial epithelium results in features of endometrial hyperplasia, adenocarcinoma, and intraepithelial carcinoma. Mutant endometrial epithelial cells were transcriptome profiled and compared to control cells and ARID1A/PIK3CA mutant endometrium. In the context of either TP53 or ARID1A loss, PIK3CA mutant endometrium exhibited inflammatory pathway activation, but other gene expression programs differed based on TP53 or ARID1A status, such as epithelial-to-mesenchymal transition. Gene expression patterns observed in the genetic mouse models are reflective of human tumors with each respective genetic alteration. Consistent with TP53-ARID1A mutual exclusivity, the p53 pathway is activated following ARID1A loss in the endometrial epithelium, where ARID1A normally directly represses p53 pathway genes in vivo, including the stress-inducible transcription factor, ATF3. However, co-existing TP53-ARID1A mutations led to invasive adenocarcinoma associated with mutant ARID1A-driven ATF3 induction, reduced apoptosis, TP63+ squamous differentiation and invasion. These data suggest TP53 and ARID1A mutations drive shared and distinct tumorigenic programs in the endometrium and promote invasive endometrial cancer when existing simultaneously. Hence, TP53 and ARID1A mutations may co-occur in a subset of aggressive or metastatic endometrial cancers, with ARID1A loss promoting squamous differentiation and the acquisition of invasive properties.
2021-12-13 | GSE184498 | GEO