Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA384956 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Targeting the MTF2-MDM2 Axis Sensitizes Refractory Acute Myeloid Leukemia to Chemotherapy
| PRJNA384954 | ENA
Project description:Targeting the MTF2-MDM2 Axis Sensitizes Refractory Acute Myeloid Leukemia to Chemotherapy [RNA-Seq]
| PRJNA384957 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below. Deep sequencing has revealed that epigenetic modifiers are the most mutated genes in acute myeloid leukemia (AML). Thus, elucidating epigenetic dysregulation in AML is crucial to understand disease mechanisms. Here, we demonstrate that Metal Response Element Binding Transcription Factor 2/Polycomblike 2 (MTF2/PCL2) plays a fundamental role in the Polycomb repressive complex 2 (PRC2) and that its loss elicits an altered epigenetic state underlying refractory AML. Unbiased systems analyses identified the loss of MTF2-PRC2 repression of MDM2 as central to, and therefore a biomarker for, refractory AML. Thus, immature MTF2- deficient CD34+CD38- cells overexpress MDM2, thereby inhibiting p53 that leads to chemoresistance due to defects in cell cycle regulation and apoptosis. Targeting this dysregulated signaling pathway by MTF2 overexpression or MDM2 inhibitors sensitized refractory patient leukemic cells to induction chemotherapeutics and prevented relapse in AML patient-derived xenograft (PDX) mice. Therefore, we have uncovered a direct epigenetic mechanism by which MTF2 functions as a tumor suppressor required for AML chemotherapeutic sensitivity and identified a potential therapeutic strategy to treat refractory AML.
2018-07-31 | GSE98380 | GEO
Project description:Deep sequencing has revealed that epigenetic modifiers are the most mutated genes in acute myeloid leukemia (AML). Thus, elucidating epigenetic dysregulation in AML is crucial to understand disease mechanisms. Here, we demonstrate that Metal Response Element Binding Transcription Factor 2/Polycomblike 2 (MTF2/PCL2) plays a fundamental role in the Polycomb repressive complex 2 (PRC2) and that its loss elicits an altered epigenetic state underlying refractory AML. Unbiased systems analyses identified the loss of MTF2-PRC2 repression of MDM2 as central to, and therefore a biomarker for, refractory AML. Thus, immature MTF2- deficient CD34+CD38- cells overexpress MDM2, thereby inhibiting p53 that leads to chemoresistance due to defects in cell cycle regulation and apoptosis. Targeting this dysregulated signaling pathway by MTF2 overexpression or MDM2 inhibitors sensitized refractory patient leukemic cells to induction chemotherapeutics and prevented relapse in AML patient-derived xenograft (PDX) mice. Therefore, we have uncovered a direct epigenetic mechanism by which MTF2 functions as a tumor suppressor required for AML chemotherapeutic sensitivity and identified a potential therapeutic strategy to treat refractory AML.
2018-07-31 | GSE98378 | GEO
Project description:Deep sequencing has revealed that epigenetic modifiers are the most mutated genes in acute myeloid leukemia (AML). Thus, elucidating epigenetic dysregulation in AML is crucial to understand disease mechanisms. Here, we demonstrate that Metal Response Element Binding Transcription Factor 2/Polycomblike 2 (MTF2/PCL2) plays a fundamental role in the Polycomb repressive complex 2 (PRC2) and that its loss elicits an altered epigenetic state underlying refractory AML. Unbiased systems analyses identified the loss of MTF2-PRC2 repression of MDM2 as central to, and therefore a biomarker for, refractory AML. Thus, immature MTF2- deficient CD34+CD38- cells overexpress MDM2, thereby inhibiting p53 that leads to chemoresistance due to defects in cell cycle regulation and apoptosis. Targeting this dysregulated signaling pathway by MTF2 overexpression or MDM2 inhibitors sensitized refractory patient leukemic cells to induction chemotherapeutics and prevented relapse in AML patient-derived xenograft (PDX) mice. Therefore, we have uncovered a direct epigenetic mechanism by which MTF2 functions as a tumor suppressor required for AML chemotherapeutic sensitivity and identified a potential therapeutic strategy to treat refractory AML.
2018-07-31 | GSE98343 | GEO
Project description:Differentiating agents have been proposed to overcome the impaired cellular differentiation in acute myeloid leukemia (AML). However, only the combinations of all-trans retinoic acid or arsenic trioxide with chemotherapy have been successful, and only in treating acute promyelocytic leukemia (also called AML3). Here we showed that iron homeostasis is an effective target in the treatment of AML. Iron chelating therapy induces the differentiation of leukemia blasts and normal bone marrow precursors into monocytes/macrophages in a manner involving modulation of reactive oxygen species expression and the activation of mitogen-activated protein kinases (MAPK). Thirty percent of the genes most strongly induced by iron deprivation are also targeted by vitamin D3 (VD), a well-known differentiating agent. Iron chelating agents induce expression and phosphorylation of the VD receptor, and iron deprivation and VD act synergistically. VD magnifies activation of MAPK JNK and the induction of VD receptor target genes. When used to treat one AML patient refractory to chemotherapy, the combination of iron chelating agents and VD resulted in reversal of pancytopenia and blast differentiation. We propose that iron availability modulates myeloid cell commitment, and that targeting this cellular differentiation pathway together with conventional differentiating agents provides new therapeutic modalities for AML. This study presents 8 arrays 4x44K Agilent.
2010-03-23 | E-TABM-925 | biostudies-arrayexpress
Project description:EVI1 is one of the famous poor prognostic markers for a chemotherapy-resistant acute myeloid leukemia (AML). To identify molecular targets on the surface of leukemia cells with EVI1high expression, we compared the gene expression profiles of several AML cell lines by DNA microarray To search for novel molecular targets in refractory myeloid leukemia with high EVI1 expression, we initially analyzed the gene expression profiles of 12 human myeloid cell lines. Four cell lines with chromosome 3q26 abnormalities (UCSD/AML1, HNT-34, Kasumi-3 and MOLM-1) expressed EVI1High, and eight myeloid cell lines without chromosome 3q26 abnormalities (HEL, HL-60, K052, THP-1, FKH-1, K051, NH and OIH-1) expressed low levels of EVI1 (EVI1Low)
2012-01-18 | E-GEOD-35159 | biostudies-arrayexpress
Project description:This report explores the effect of Hif-1alpha deletion, using a conditional mouse model, together with standard chemotherapy regimen to evaluate leukemia stem cell (LSC) targeting in a murine model of MLL-AF9 driven acute myeloid leukemia (AML). This study reveals that Hif-1alpha-deleted leukemias displayed a faster disease progression after chemotherapy.
2019-01-23 | GSE119484 | GEO
Project description:Pharmacological inhibition of WIP1 sensitizes acute myeloid leukemia cells to MDM2 inhibitor Nutlin-3a
| PRJNA657008 | ENA
Project description:Although Bcr-Abl kinase inhibitors have proven effective in the treatment of chronic myeloid leukemia (CML), they generally fail to completely eradicate Bcr-Abl+ leukemia cells. To identify genes whose inhibition sensitizes Bcr-Abl+ leukemias to killing by Bcr-Abl inhibitors, we performed an RNAi-based synthetic lethal screen with imatinib in CML cells. This screen identified numerous components of a Wnt/Ca2+/NFAT signaling pathway. Antagonism of this pathway led to impaired NFAT activity, decreased cytokine production and enhanced sensitivity to Bcr-Abl inhibition. Furthermore, NFAT inhibition with cyclosporin A facilitated leukemia cell elimination by the Bcr-Abl inhibitor dasatinib and markedly improved survival in a mouse model of Bcr-Abl+ acute lymphoblastic leukemia (ALL). Targeting this pathway in combination with Bcr-Abl inhibition could improve treatment of Bcr-Abl+ leukemias. We utilized a genome-wide shRNA library in combination with microarray analysis to screen for gene targets in chronic myeloid leukemia cells that cooperate with imatinib.
2010-07-15 | E-GEOD-21499 | biostudies-arrayexpress