Expression data from mouse MLL/AF10(OM-LZ) myeloid leukemia cells harboring wild-type KRAS, KRAS-G12C, wild-type PTPN11, PTPN11-G503A, without or with Hoxa11
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE134586 | GEO | 2020/07/01
REPOSITORIES: GEO
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Project description:Expression data from mouse MLL/AF10(OM-LZ) myeloid leukemia cells harboring wild-type KRAS, KRAS-G12C, wild-type PTPN11, PTPN11-G503A, without or with Hoxa11
| PRJNA555634 | ENA
Project description:RAS-MAPK activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series of diangosis and relapsed ALL. To evaluate the specific role of RAS-MAPK activating mutations in chemotherapy resistance in ALL we used primary isogenic leukemia cells expressing either Kras wild type or a mutant oncogenic form of Kras (Kras G12D) Mechanistically, functional dissection of Kras wild type and mutant Kras (Kras G12D) isogenic ALL cells demonstrated induction of methotrexate resistance, but also improved response to vincristine, in mutant Kras-expressing ALL cells. These results pave the road for the development of tailored personalized therapies for the treatment of relapsed ALL
2018-11-01 | GSE75090 | GEO
Project description:<p>Although multi-agent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die due to chemo-refractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape and pattern of clonal evolution at relapse in pediatric ALL cases. These analyses showed that ALL relapses originate from a common ancestral precursor clone of the diagnosis and relapsed populations and frequently harbor mutations implicated in chemotherapy resistance. RAS-MAPK pathway activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series. Notably, while some cases showed emergence of RAS mutant clones at relapse, in others, RAS mutant clones present at diagnosis were replaced by RAS wild type populations. Mechanistically, functional dissection of mouse and human wild type Kras and mutant Kras (Kras G12D) isogenic leukemia cells demonstrated induction of methotrexate resistance, but also improved response to vincristine, in mutant Kras- expressing lymphoblasts. These results identify chemotherapy driven selection as a central mechanism of leukemia clonal evolution and pave the road for the development of tailored personalized therapies for the treatment of relapsed ALL. </p>
| phs001072 | dbGaP
Project description:We studied the KRAS and NRAS mutational status in pediatric MLL-AF4+ leukemia patients by means of ultra deep amplicon sequencing. The gene expression profiles of RAS wild type and RAS mutated patients were investigated by gene expression analysis. We showed that mutated patients were characterized by a RAS related expression signature.
2016-10-04 | GSE77416 | GEO
Project description:The RAS pathway is among the most frequently activated signaling nodes in cancer. However, the mechanisms that alter RAS activity in human pathologies are not yet fully understood. K128 ubiquitination is the most prevalent modification of the GTPase core domain in both NRAS and KRAS. The ubiquitination at K128 was decreased in cancer samples compared to normal tissue. We found that K128 ubiquitination creates an additional binding interface for RAS GTPase-activating proteins (GAP), NF1 and RASA1, which increases RAS binding to GAP proteins and promotes GAP-mediated GTP hydrolysis. K128 ubiquitination is transiently induced by growth factors or cytokines, which restricts the extent of wild-type RAS activation in a GAP-dependent manner. In contrast, the loss of K128 ubiquitination in the KRAS-G12D mutant promotes tumor growth by suppressing RAL/ TBK1 signaling and negatively regulating the autocrine circuit induced by mutant KRAS. Dysregulation of K128 ubiquitination unleashes both wild-type and mutant RAS signaling and triggers a senescence-associated secretory phenotype, driving RAS-driven tumorigenesis.
2024-05-31 | GSE261976 | GEO
Project description:Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an inducible KRAS-specific shRNA. We found 147 genes that promoted survival in the setting of KRAS suppression. In this model, the transcriptional co-activator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling. KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelial-mesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of oncogenic RAS signaling. We used microarrays to compare gene expression in HCT116 cells in which we suppressed KRAS expression doxycycline-inducible shRNA targeting KRAS compared to cells treated with media alone (no shKRAS induced). We express KRAS, LacZ, and YAP1 in each condition to identify genes transcriptionally involved in the rescue of KRAS suppression. HCT116 cells harboring doxycycline-inducible shKRAS (HCTtetK) expressing either LacZ, KRAS, or YAP1, were treated with doxycycline for 30 hours to suppress KRAS. Untreated (no doxycycline) cells expressing each ORF were used as control. Total RNA was collected using PerfectPure RNA Cultured Cell Kit (5Prime) and expression profiling was performed on Human Genome U133A 2.0 Array (Affymetrix) using the Dana Farber Cancer Institute Microarray Core.
2014-07-22 | E-GEOD-55942 | biostudies-arrayexpress
Project description:Cancer treatment decisions are increasingly guided by which specific genes are mutated within each patient’s tumor. For example, agents inhibiting the epidermal growth factor receptor (EGFR) benefit many colorectal cancer (CRC) patients, with the general exception of those whose tumor includes a KRAS mutation. However, among the various KRAS mutations, the G13D mutation behaves differently; for unknown reasons, CRC patients with the KRAS G13D mutation (also written KRASG13D) appear to benefit from the EGFR-blocking antibody cetuximab. Controversy surrounds this observation, because it appears to contradict the well-established mechanisms of EGFR signaling and of RAS mutations. Here, we identified a systems-level, mechanistic basis that explains why KRASG13D cancers respond to EGFR inhibition. We first investigated the problem with a computational model of RAS signaling, which unexpectedly revealed that the known biophysical differences between the three most common KRAS mutant proteins are sufficient to generate different sensitivities to inhibition. Computation and experimentation together revealed a non-intuitive, mutant-specific dependency of wild-type RAS activation by EGFR that is determined by the interaction strength between KRAS and the tumor suppressor neurofibromin (NF1). KRAS mutants that strongly interact with NF1 drive wild-type RAS activation in an EGFR independent manner through competitive inhibition of NF1, whereas KRAS G13D cells remain dependent upon EGFR for wild-type Ras activation because they cannot competitively inhibit NF1 due to a weak interaction between these two proteins. Overall, our work demonstrates how systems approaches enable mechanism-based inference in genomic medicine and can help identify patients for selective therapeutic strategies.
2020-05-27 | PXD014755 | Pride
Project description:We have recently discovered that deletion of Ptpn11, which codes for protein tyrosine phosphatase Shp2, blocks Bergmann glia (BG) formation and cerebellar foliation, whereas expressing a constitutively active Mek1 (Map2k1), Mek1DD, reverses the Ptpn11-deficient phenotypes, uncovering a previously unappreciated role of BG in folding of the cerebellar cortex. Relatively little is known regarding to the BG induction. The goal of the study was to determine molecular features of newly generated BG. To identify transcripts enriched in nascent BG, we performed RNA-seq of microdissected cerebellar tissues from wild type (WT), En1cre/+;Ptpn11F/F (Ptpn11-cKO), and En1cre/+;Ptpn11F/F;R26Mek1DD/+ (Ptpn11-cKO;MEK) embryos at E12.5, E13.5, and E14.5. As BG are initially formed at E13.5, we reasoned that BG-enriched transcripts should be increased from E12.5 to E14.5, decreased in Ptpn11-cKO cerebella, and restored in Ptpn11-cKO;MEK cerebella. By intersecting differentially expressed (DE) genes based on the above-mentioned assumptions, we wanted to identify genes that are specifically expressed in BG and affected by Ptpn11 deletion. Conclusions: though RNA-seq and subsequent validation, we have successfully identified genes that enriched in nascent BG in the developing mouse cerebellum.
2017-05-10 | GSE87104 | GEO
Project description:Mutations of the proto-oncogene KRas, together with the inactivation of the onco-suppressor genes APC and TP53, are considered to have an important role both in the carcinogenesis and in the colorectal tumor progression. The oncogene K-ras has activating mutations, especially in codon 12, in about 40% to 50% of colorectal carcinomas (Andreyev et al., 1998). The mechanism by which oncogenic K-ras alone contribuites to tumor progression in colon cancer is largely unknown. To this end, we have developed a model system where the colorectal adenocarcinoma cell line Colo741 has been stably trasfected with the Kras-G12V or Kras-G12D mutated oncogenes. Our results demonstrate how expression profiling data can be used to interpret changes in cellular characteristics induced by transfection and hence provide some clues as to the mechanisms by which different activated K-Ras impair processes mediated by endogenous wild-type KRas proteins.
2008-12-18 | GSE12398 | GEO
Project description:The experiment is a study of the effects of signal strength in the Ras pathway. In particular, we studied a gain-of-function mutant of Kras, KrasG12D. We generated these mutant mice and performed microarray analyses on RNA extracted from whole skin, comparing KrasG12D mice to wild-type mice, with three replicates of each.
2011-06-03 | E-MTAB-700 | biostudies-arrayexpress