Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA279028 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:FLT3/ITD-SmoM2 mice developed rapidly fatal myeloid leukemia compared to FLT3/ITD only mice, suggesting that overactivation of the Hedgehog signaling pathway via SmoM2 can drive myeloid disease progression We used the Affymetrix Mouse 430_2.0 microarray to detail global gene expression responsible for disease progression in sorted bone marrow cells and found that the Hedgehog signaling pathway contributes to disease progression by enhancing FLT3 signaling
2015-03-21 | GSE67134 | GEO
Project description:Transcriptional profiling of murine bone marrow c-kit+, Sca-1+ lineage neative (KSL) cells from p21CDKN1a-/- and p21+/+ overexpressing Flt3/ITD. The goal was to determine the effect on global gene expression by loss of p21 in Flt3/ITD transformed KSL cells Internal tandem duplication (ITD) mutations in the Flt3 gene (Flt3-ITD) are associated with poor prognosis in patients with acute myeloid leukemia (AML). Few inhibitors of Flt3-ITD are effective against Flt3-ITD+ AML due to the development of drug-resistance. In this study, we demonstrate that Flt3-ITD activates a novel pathway involving p21Cdkn1a (p21) and pre-B cell leukemia transcription factor 1 (Pbx1) that attenuates Flt3-ITD cell proliferation and is involved in the development drug resistance. Flt3-ITD up-regulated p21 expression in mouse bone marrow c-kit+-Sca-1+-Lin- (KSL) cells and in Ba/F3 cells. Loss of p21 expression enhanced growth factor-independent proliferation and sensitivity to cytarabine as a consequence of enriching the S+G2/M phase population concomitant with a significant increase in the expression of Pbx1, but not Evi-1, in Flt3-ITD+ cells. This enhancement of cell proliferation by loss of p21 was partially abrogated when Pbx1 expression was silenced in Flt3-ITD+ primary bone marrow colony-forming cells (CFCs) and Ba/F3 cells. Antagonizing Flt3-ITD using AC220, a selective inhibitor of Flt3-ITD, decreased the expression of p21, coincident with the up-regulation of Pbx1 mRNA and a rapid decline in the number of viable Flt3-ITD+ Ba/F3 cells, however the cells eventually became refractory to AC220. Overexpressing p21 in Flt3-ITD+ Ba/F3 cells delayed the emergence of cells refractory to AC220, whereas silencing p21 accelerated their development. These data demonstrate that Flt3-ITD is capable of inhibiting the proliferation of Flt3-ITD+ cells through the p21/Pbx1 axis and that antagonizing Flt3-ITD contributes to the subsequent development of cells refractory to Flt3-ITD inhibitor by disrupting p21 expression. biological replicates: 3 KSL cell replicates overexpressing ITD-Flt3 from p21+/+ and p21-/- cells, 1 KSL cell replicate from p21+/+ and p21-/- cells
2015-11-20 | E-GEOD-75200 | biostudies-arrayexpress
Project description:Transcriptional profiling of murine bone marrow c-kit+, Sca-1+ lineage neative (KSL) cells from p21CDKN1a-/- and p21+/+ overexpressing Flt3/ITD. The goal was to determine the effect on global gene expression by loss of p21 in Flt3/ITD transformed KSL cells Internal tandem duplication (ITD) mutations in the Flt3 gene (Flt3-ITD) are associated with poor prognosis in patients with acute myeloid leukemia (AML). Few inhibitors of Flt3-ITD are effective against Flt3-ITD+ AML due to the development of drug-resistance. In this study, we demonstrate that Flt3-ITD activates a novel pathway involving p21Cdkn1a (p21) and pre-B cell leukemia transcription factor 1 (Pbx1) that attenuates Flt3-ITD cell proliferation and is involved in the development drug resistance. Flt3-ITD up-regulated p21 expression in mouse bone marrow c-kit+-Sca-1+-Lin- (KSL) cells and in Ba/F3 cells. Loss of p21 expression enhanced growth factor-independent proliferation and sensitivity to cytarabine as a consequence of enriching the S+G2/M phase population concomitant with a significant increase in the expression of Pbx1, but not Evi-1, in Flt3-ITD+ cells. This enhancement of cell proliferation by loss of p21 was partially abrogated when Pbx1 expression was silenced in Flt3-ITD+ primary bone marrow colony-forming cells (CFCs) and Ba/F3 cells. Antagonizing Flt3-ITD using AC220, a selective inhibitor of Flt3-ITD, decreased the expression of p21, coincident with the up-regulation of Pbx1 mRNA and a rapid decline in the number of viable Flt3-ITD+ Ba/F3 cells, however the cells eventually became refractory to AC220. Overexpressing p21 in Flt3-ITD+ Ba/F3 cells delayed the emergence of cells refractory to AC220, whereas silencing p21 accelerated their development. These data demonstrate that Flt3-ITD is capable of inhibiting the proliferation of Flt3-ITD+ cells through the p21/Pbx1 axis and that antagonizing Flt3-ITD contributes to the subsequent development of cells refractory to Flt3-ITD inhibitor by disrupting p21 expression.
2015-11-20 | GSE75200 | GEO
Project description:Murine bone marrow c-kit+, Sca-1+ lineage neative cells (KSL) from p21CDKN1a-/- vs p21+/+ mice, Flt3/ITD transfected KSL cells and nontransfected KSL cells
| PRJNA302785 | ENA
Project description:The study was a comparison of gene expression using RNA-seq. We analyzed the stem and progenitor cells from WT and Vav-cre+ Tet2fl/fl Flt3-ITD (T2F3) mice. We isolated stem cells LSK (lin- sca+ kit+) and granulocyte-macrophage progenitors GMP (lin- sca- kit+ fcgr+ cd34+) cells from bone marrow. Comparisons were made across genotypes WT vs. T2F3 and cell types LSK vs. GMP. Comparison of WT and Tet2-/-Flt3ITD bone marrow stem and progenitor cells.
2015-05-01 | E-GEOD-57244 | biostudies-arrayexpress
Project description:The study was a comparison of gene expression using RNA-seq. We analyzed the stem and progenitor cells from WT and Vav-cre+ Tet2fl/fl Flt3-ITD (T2F3) mice. We isolated stem cells LSK (lin- sca+ kit+) and granulocyte-macrophage progenitors GMP (lin- sca- kit+ fcgr+ cd34+) cells from bone marrow. Comparisons were made across genotypes WT vs. T2F3 and cell types LSK vs. GMP.
2015-05-01 | GSE57244 | GEO
Project description:Expression profile of hematopoietic stem and progenitor cell (HSPC) compartment of FLT3-ITD and FLT3-ITD miR-155-/- mice
| PRJNA342137 | ENA
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
Project description:The miR-155-dependent differences in gene expression in the HSPC compartment of FLT3-ITD mice is unknown. In this experiment, we performed RNA sequencing on FLT3-ITD and FLT3-ITD miR-155-/- mouse LKS cells.
2017-09-08 | GSE86526 | GEO
Project description:FLT3 activating mutations cause myeloproliferative neoplasms by deregulating hematopoietic progenitor cell growth, and acute myeloid leukemia is on the rise. Investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop inherent and acquired resistance to FLT3 targeted therapy. FLT3 inhibitor resistance in AML is dependent on co-occurring mutations, parallel survival pathways, and/or subsequent FLT3-ITD mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options. We identified two novel naphthyridine-based FLT3 inhibitors (HSN608 and HSN748) that specifically target FLT3-ITD at sub-nanomolar concentrations and are effective against drug-resistant secondary mutations. In the current study, we evaluated these compounds antileukemic activity against FLT3-ITD and gatekeeper mutations in drug-resistant AML, relapsed/refractory AMLs with FLT3 mutations, and in vivo mouse models with combinations of epigenetic mutations TET2 with FLT3-ITD, and AML patients PDX. In these model systems, we demonstrate that HSN748 outperforms the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3-ITD.
2022-12-07 | MSV000090855 | MassIVE