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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling by array of human cytogenetically normal acute myeloid leukemia patient samples with FLT3 internal tandem duplications

ABSTRACT: Oligonucleotide expression microarray data used for expression signature associated with FLT3 internal tandem duplications(FLT3-ITD) in samples from older patients with cytogenetically normal AML

ORGANISM(S): Homo sapiens

SUBMITTER: Guido Marcucci

PROVIDER: E-TABM-1029 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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FLT3 internal tandem duplication associates with adverse outcome and gene- and microRNA-expression signatures in patients 60 years of age or older with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study.

Whitman Susan P SP Maharry Kati K Radmacher Michael D MD Becker Heiko H Mrózek Krzysztof K Margeson Dean D Holland Kelsi B KB Wu Yue-Zhong YZ Schwind Sebastian S Metzeler Klaus H KH Wen Jing J Baer Maria R MR Powell Bayard L BL Carter Thomas H TH Kolitz Jonathan E JE Wetzler Meir M Moore Joseph O JO Stone Richard M RM Carroll Andrew J AJ Larson Richard A RA Caligiuri Michael A MA Marcucci Guido G Bloomfield Clara D CD

Blood 20100723 18

The clinical impact of FLT3-internal tandem duplications (ITDs), an adverse prognostic marker in adults aged < 60 years with primary cytogenetically normal acute myeloid leukemia (CN-AML), requires further investigation in older patients. In CN-AML patients aged ≥ 60 years treated on Cancer and Leukemia Group B frontline trials, we found that FLT3-ITD remained associated with shorter disease-free survival (P < .001; hazard ratio = 2.10) and overall survival (P < .001; hazard ratio = 1.97) in mul ...[more]

PMID: 20656931

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MicroRNA profiling by array of older patients with cytogenetically normal AML with or without FLT3 internal tandem duplications

Project description:microRNA expression microarray data used for expression signature associated with FLT3-ITD in samples from older patients with cytogenetically normal AML

2010-07-22 | E-TABM-1032 | biostudies-arrayexpress

PRMT1-mediated FLT3 arginine methylation is required for maintenance of FLT3-ITD+ Acute Myeloid Leukemia

Project description:The presence of FLT3-ITD mutations in patients with acute myeloid leukemia (AML) is associated with poor clinical outcome. FLT3 tyrosine kinase inhibitors (TKIs), although effective in kinase ablation, do not eliminate FLT3-ITD+ leukemia stem cells (LSCs) which are potential sources of disease relapse, prompting us to ask whether FLT3-ITD protein regulates the AML LSCs survival through a kinase-independent mechanism. Here, we show that expression of PRMT1, the primary type I arginine methyltransferase, significantly increases in LSC-enriched CD34+CD38- populations relative to normal counterparts. Genetic PRMT1 depletion blocked AML CD34+ cell survival, and had more potent effects in AML cells from patients harboring FLT3-ITD. Our genome wide analysis of gene expression and PRMT1 conditional KO mouse study confirmed that PRMT1 preferentially cooperates with FLT3-ITD contributing to AML cell maintenance. Mechanistically, PRMT1 catalyzed FLT3-ITD protein methylation at arginines 972/973, and PRMT1 promoted leukemia cell growth in a FLT3 methylation-dependent manner. Moreover, effects of FLT3-ITD methylation in AML cells were in part due to crosstalk with FLT3-ITD phosphorylation at tyrosine 969 (Y969). Importantly, FLT3 methylation persisted in FLT3-ITD+ AML cells following TKI (AC220) treatment, indicating that methylation occurs independently of kinase activity. Finally, in both patient-derived xenograft (PDX) and murine AML models, combined administration of AC220 with a type I PRMT inhibitor (MS023) enhanced elimination of FLT3-ITD+ AML relative to AC220 treatment alone. Our study demonstrates that PRMT1-mediated FLT3 methylation promotes LSC activity and suggests that combining PRMT1 inhibition with FLT3 TKI treatment could be a promising approach to selectively target FLT3-ITD+ LSCs.

2021-11-10 | GSE122435 | GEO

PRMT1-mediated FLT3 arginine methylation promotes FLT3-ITD+ Acute Myeloid Leukemia maintenance

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Expression profile of hematopoietic stem and progenitor cell (HSPC) compartment of FLT3-ITD and FLT3-ITD miR-155-/- mice

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CircMYBL2 Regulates FLT3-ITD FLT3AML Translation in AML

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Phosphoproteome Analysis Reveals Differential Mode of Action of Sorafenib in Wildtype and Mutated FLT3 AML Cells

Project description:Constitutively activating internal tandem duplication (ITD) alterations of the receptor tyrosine kinase FLT3 (Fms-like tyrosine kinase 3) are common in acute myeloid leukemia (AML) and classifies FLT3 as an attractive therapeutic target. So far, application of FLT3 small molecule inhibitors such as Sorafenib has resulted only in partial and transient clinical responses in FLT3-ITD+ patients. Only recently, a prolonged event-free survival has been observed in AML patients who were treated with Sorafenib in addition to standard therapy. Here, we studied the Sorafenib effect on proliferation in a panel of 13 FLT3-ITD- and FLT3-ITD+ AML cell lines. Sorafenib IC50 values ranged from 0.001 to 5.6 µM, whereas FLT3-ITD+ cells (MOLM-13, MV4;11) were found more sensitive to Sorafenib than FLT3-ITD- cells. However, we identified two FLT3-ITD- cell lines (MONO-MAC-1 and OCI-AML-2) which were also Sorafenib sensitive. Phosphoproteome analyses revealed that the affected pathways differed in Sorafenib sensitive FLT3-ITD- and FLT3-ITD+ cells. In MV4;11 cells Sorafenib suppressed mTOR signalling by inhibiting direct inhibition of FLT3. In MONO-MAC-1 cells Sorafenib inhibited the MEK/ERK pathway by inhibition of the RET tyrosine kinase. These data suggest that the FLT3 status in AML patients might not be the only predictive factor for a response to Sorafenib.

2017-05-02 | PXD004442 | Pride

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