Enhancer-activated RET confers protection against oxidative stress to the MLL-rearranged acute myeloid leukemia cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE241738 | GEO | 2024/03/04
REPOSITORIES: GEO
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Project description:KMT2A-MLLT3, a fusion protein formed by the t(9;11) translocation in acute myeloid leukemia, is an epigenetic transcription factor that is known to regulate a unique leukemic gene expression profile. We show that rearranged during transfection (RET) proto-oncogene is highly overexpressed in the KMT2A-MLLT3 subgroup. In addition to biochemical studies, the RNA-seq and ATAC seq analyses have been performed in KMT2A-MLLT3 positive MOLM-13 AML cell line, compared to the umbilical cord blood-driven CD34+ hematopoietic stem progenitor cells.
2024-03-04 | GSE241867 | GEO
Project description:RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, in RET-rearranged LADC has not been reported. The aims of the study are to explore anti-tumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC. Using structural modeling and in vitro analysis, we demonstrated that dovitinib induced cell cycle arrest at G0/G1 phase and apoptosis by selective inhibition of RET kinase activity and ERK1/2 signaling in RET-rearranged LC-2/ad cells. Strong anti-tumor effect of dovitinib was observed in LC-2/ad tumor xenograft model. To identify the acquired resistance mechanisms to dovitinib, LC-2/ad cells were exposed to increasing concentrations of dovitinib to generate LC-2/ad DR cells. Gene set enrichment analysis of gene expression and receptor tyrosine kinase assay revealed that Src, a central gene in focal adhesion , was activated in LC-2/ad DR cells. Saracatinib, a src kinase inhibitor, suppressed ERK1/2 phosphorylation and growth of LC-2/ad DR cells. Taken together, these findings suggest that dovitinib can be a potential therapeutic option for RET-rearranged LADC, in which acquired resistance to dovitinib can be overcome by targeting Src. To identify potential mechanisms of acquired resistance to dovitinib, we established LC-2/ad DR cells with acquired resistance to dovitinib by exposing LC-2/ad cells to increasing doses of dovitinib. LC-2/ad DR cells showed strong resistance to dovitinib (IC50> 3 μmol/L). Next, LC-2/ad and LC-2/ad DR cells were subjected to genome-wide gene expression profiling using cDNA microarray.
2015-09-01 | E-GEOD-69226 | biostudies-arrayexpress
Project description:RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, in RET-rearranged LADC has not been reported. The aims of the study are to explore anti-tumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC. Using structural modeling and in vitro analysis, we demonstrated that dovitinib induced cell cycle arrest at G0/G1 phase and apoptosis by selective inhibition of RET kinase activity and ERK1/2 signaling in RET-rearranged LC-2/ad cells. Strong anti-tumor effect of dovitinib was observed in LC-2/ad tumor xenograft model. To identify the acquired resistance mechanisms to dovitinib, LC-2/ad cells were exposed to increasing concentrations of dovitinib to generate LC-2/ad DR cells. Gene set enrichment analysis of gene expression and receptor tyrosine kinase assay revealed that Src, a central gene in focal adhesion , was activated in LC-2/ad DR cells. Saracatinib, a src kinase inhibitor, suppressed ERK1/2 phosphorylation and growth of LC-2/ad DR cells. Taken together, these findings suggest that dovitinib can be a potential therapeutic option for RET-rearranged LADC, in which acquired resistance to dovitinib can be overcome by targeting Src.
2015-09-01 | GSE69226 | GEO
Project description:MLL-rearranged acute myeloid leukemia (AML) remains a fatal disease with a high rate of relapse and therapeutic failure due to chemotherapy resistance. In analysis of our Affymetrix microarray profiling of human AML and normal control samples, we found that ALOX5 is especially down-regulated in MLL-rearranged AML. Our colony forming/replating and bone marrow transplantation (BMT) assays showed that Alox5 exhibited a moderate anti-tumor effect both in vitro and in vivo. Strikingly, leukemic cells with Alox5 overexpression showed a significantly higher sensitivity to the standard chemotherapeutic agents, i.e., doxorubicin (DOX) and cytarabine (Ara-C). The drug-sensitizing role of Alox5 was further confirmed in human and murine MLL-rearranged AML cell models in vitro, as well as in the in vivo MLL-rearranged AML BMT model coupled with treatment of “5+3” (i.e. DOX plus Ara-C) regimen. Our RNA-seq analysis showed that Stat and K-Ras signaling pathways were negatively correlated with Alox5 overexpression in MLL-AF9-leukemic blast cells, implying targeting those pathways likely contributes to Alox5’s functions. Collectively, our work shows that ALOX5 plays a moderate anti-tumor role and functions as a drug sensitizer, with a therapeutic potential, in MLL-rearranged AML.
2017-06-09 | GSE94840 | GEO
Project description:Members of the TALE (Three-amino acid loop extension) family of atypical homeodomain-containing transcription factors are prominent downstream effectors of oncogenic fusion proteins generated from translocations involving the mixed lineage leukemia (MLL) gene. A particular well-characterized member of this protein family is MEIS1, which together with HOXA proteins, orchestrates a transcriptional program required for the maintenance of MLL-rearranged acute myeloid leukemia (AML). Although TALE family proteins are mainly described as transcriptional activators TGIF1 (TGF-β induced factor) / TGIF2 are considered as transcriptional repressors. However, as their function in MLL-rearranged AML is largely unknown, we tested the potential importance of TGIF1 in the maintenance of MLL-rearranged AML. We find that expression of TGIF1 in MLL-AF9 transformed cells (MAF9) leads to cell cycle exit and differentiation in vitro and delayed leukemic onset in vivo. In accordance, MLL-rearranged patient blasts display lower levels of TGIF1 and TGIF1 expression in general correlates positively with survival. Mechanistically, we show that TGIF1 interferes with a MEIS1-dependent transcriptional program by associating to MEIS1-bound region in a competitive manner. Collectively, these findings demonstrate that TALE family members can act both positively and negatively on transcriptional programs responsible for the maintenance of MLL-rearranged AML.
2014-11-11 | GSE55287 | GEO
Project description:Acute Myeloid Leukemia (AML) is associated with a number of genetic and epigenetic events that result in malignant transformation of hematopoietic cells. In particular, transcription factors essential for normal hematopoiesis and stem cell function are often found mutated leading to the formation of leukemic stem cells and the accumulation of immature blasts. Among them, translocations involving the mixed lineage leukemia (MLL) gene at chromosome band 11q23 are one of the most commonly events (~10 %) and is associated with poor prognosis in human leukemias. Whereas the downstream effects of MLL-fusion proteins are well established, the modes on which these effects are mediated are still unclear and whether MLL-fusion proteins are dependent on other transcriptional regulators or act alone remains elusive. To investigate this we searched gene expression profiles from patients with MLL-rearranged AML compared with normal hematopoietic progenitor cells for transcriptional regulators and found targets of C/EBPα to be up-regulated in the AML samples, suggesting that C/EBPα might collaborate with MLL-fusion proteins in the initial transformation process. We could show that transformation by MLL-fusion proteins is dependent on C/EBPα activity both in early progenitors as well as in GMPs. In contrast, C/EBPα was found to be indispensable in an already established leukemia. These finding led us to study the early transcriptional changes induced by MLL-ENL expression and we identified a combined C/EBPα / MLL-ENL transcriptional signature. Collectivly, our data shows that C/EBPα configure a proper chromatin state required for MLL-fusions to induce malignant transformation. Histone modification profiles (H3K4me3 and H3K27me3) in haematopoietic progenitor cells (preGM, wild type and Cebpa knock out), and C/EBPα binding in GMP cells
2013-12-10 | E-GEOD-47003 | biostudies-arrayexpress
Project description:The aim of the study was to investigate the role of TGIF1 in MLL-AF9 transformed cells Members of the TALE (Three-amino acid loop extension) family of atypical homeodomain-containing transcription factors are prominent downstream effectors of oncogenic fusion proteins generated from translocations involving the mixed lineage leukemia (MLL) gene. A particular well-characterized member of this protein family is MEIS1, which together with HOXA proteins, orchestrates a transcriptional program required for the maintenance of MLL-rearranged acute myeloid leukemia (AML). Although TALE family proteins are mainly described as transcriptional activators TGIF1 (TGF-β induced factor) / TGIF2 are considered as transcriptional repressors. However, as their function in MLL-rearranged AML is largely unknown, we tested the potential importance of TGIF1 in the maintenance of MLL-rearranged AML. We find that expression of TGIF1 in MLL-AF9 transformed cells (MAF9) leads to cell cycle exit and differentiation in vitro and delayed leukemic onset in vivo. In accordance, MLL-rearranged patient blasts display lower levels of TGIF1 and TGIF1 expression in general correlates positively with survival. Mechanistically, we show that TGIF1 interferes with a MEIS1-dependent transcriptional program by associating to MEIS1-bound region in a competitive manner. Collectively, these findings demonstrate that TALE family members can act both positively and negatively on transcriptional programs responsible for the maintenance of MLL-rearranged AML.
2014-11-11 | GSE55713 | GEO
Project description:Leukemias that harbor translocations involving the mixed lineage leukemia gene (MLL) possess unique biological characteristics and often have an unfavorable prognosis. Gene expression analyses demonstrate a distinct profile for MLL-rearranged leukemias with consistent high-level expression of select Homeobox genes including HOXA9. Here, we investigated the effects of HOXA9 suppression in MLL-rearranged and MLL-germline leukemias utilizing RNAi. Gene expression profiling after HOXA9 suppression demonstrated co-downregulation of a program highly expressed in human MLL-AML (this study) and murine MLL-leukemia (Krivtsov et al. 2006) stem cells including HOXA10, MEIS1, PBX3 and MEF2C. Our data indicates an important role for HOXA9 in human MLL-rearranged leukemias, and suggests targeting HOXA9 or downstream programs may be a novel therapeutic option. Experiment Overall Design: RNA was purified from t(9;11) MOLM-14 AML cells 44h after transduction in triplicates with 2 of the two most effective HOXA9shRNA constructs (3 x 1F3-HOXA9shRNA; 3 x 2A5-HOXA9shRNA) or GFP-controlshRNA (6x).
2009-01-26 | E-GEOD-13714 | biostudies-arrayexpress
Project description:Many cases of acute myeloid leukemia (AML) are associated with mutational activation of RTKs such as FLT3. However, RTK inhibitors have limited clinical efficacy as single agents, indicating that AML is driven by concomitant activation of different signaling molecules. We used a functional genomic approach to identify RET, encoding an RTK not previously implicated in AML, as essential gene in different AML subtypes, and observed that RET-dependent AML cells show activation of RET signaling via ARTN/GFRA3 and NRTN/GFRA2 ligand/co-receptor complexes.
2018-12-21 | GSE111678 | GEO
Project description:Acute myeloid leukemia (AML) carrying MLL rearrangements. We applied WGBS and the informME analysis pipeline to investigate the role of DNA methylation stochasticity in MLL-rearranged AML.
2020-03-02 | GSE135869 | GEO