Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA111157 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The tumorigenesis capacity of MLL-AF4 alone is insufficient for causing leukemia. Based on the finding that an Flt3 gene mutation in the tyrosine kinase domain (TKD) was observed in approximately 15% of MLL leukemia, we investigated synergistic leukemogenesis effects of the two genes in vitro. In a mouse IL3-dependent cell line, 32Dc, the expression of MLL-AF4 and Flt3 TKD was induced using a lentiviral vector. We performed gene expression profiling in the MLL-AF4 and the Flt3 TKD+MLL-AF4 expressing 32Dc cells. The enhancement of Hox genes expression was not identified. However, instead, the expression of S100A6, which was involved in the control of cell proliferation, was synergistically enhanced in the presence of both MLL-AF4 and Flt3 TKD genes. We performed gene expression profiling: 32Dc vs. MLL-AF4 expressing 32Dc, 32Dc vs. Flt3 TKD+MLL-AF4 expressing 32Dc, and MLL-AF4 expressing 32Dc vs. Flt3 TKD+MLL-AF4 expressing 32Dc. A single sample for each expressing cells was analyzed.
2009-03-31 | E-GEOD-14236 | biostudies-arrayexpress
Project description:The tumorigenesis capacity of MLL-AF4 alone is insufficient for causing leukemia. Based on the finding that an Flt3 gene mutation in the tyrosine kinase domain (TKD) was observed in approximately 15% of MLL leukemia, we investigated synergistic leukemogenesis effects of the two genes in vitro. In a mouse IL3-dependent cell line, 32Dc, the expression of MLL-AF4 and Flt3 TKD was induced using a lentiviral vector. We performed gene expression profiling in the MLL-AF4 and the Flt3 TKD+MLL-AF4 expressing 32Dc cells. The enhancement of Hox genes expression was not identified. However, instead, the expression of S100A6, which was involved in the control of cell proliferation, was synergistically enhanced in the presence of both MLL-AF4 and Flt3 TKD genes.
2009-03-31 | GSE14236 | GEO
Project description:MLL-AF4 is a hallmark genomic aberration which arises prenatally in high-risk infant acute lymphoblastic leukemia (ALL). In human embryonic stem cells (hESCs), MLL-AF4 skewed hemato-endothelial specification but was not sufficient for transformation. Additional cooperating genetic insults seem required for MLL-AF4-mediated leukemogenesis. FLT3 is highly expressed in MLL-AF4+ ALL through activating mutations (FLT3-TKD or FLT3-ITD) or increased transcriptional expression, being therefore considered a potential cooperating event in MLL-AF4+ ALL. Here, we explored the developmental impact of FLT3 activation on its own or in cooperation with MLL-AF4 in the hematopoietic fate of hESCs. FLT3 activation did not impact specification of CD45-CD31+ hemogenic precursors but significantly enhanced the formation of CD45+CD34+ and CD45+ blood cells and blood progenitors with clonogenic potential. Importantly, FLT3 activation through FLT3 mutations or FLT3-WT overexpression completely abrogated hematopoietic differentiation from MLL-AF4-expressing hESCs, indicating that FLT3 activation cooperates with MLL-AF4 to inhibit human embryonic hematopoiesis. Cell cycle/apoptosis analyses suggest that FLT3 activation directly impacts hESC specification rather than selective proliferation/survival of hESC-emerging hematopoietic derivatives. Transcriptional profiling supported the limited impact of FLT3 activation on hESC specification towards CD45-hemogenic precursors and the enhanced hematopoiesis upon FLT3 activation, and inhibited hematopoiesis upon MLL-AF4 expression in FLT3-activated hESCs which was associated to large transcriptional changes and regulation of master early hematopoietic genes. Also, although FLT3 activation and MLL-AF4 cooperate to inhibit embryonic hematopoiesis the underlying molecular/genetic mechanisms differ depending on how FLT3 activation is achieved. Finally, FLT3 activation did not cooperate with MLL-AF4 to immortalize/transform hESC-derived hematopoietic cells. 18 samples were analyzed. CD45- hemogenic precursors EV, 2 biological rep CD45- hemogenic precursors FLT3-TKD, 2 biological rep CD45- hemogenic precursors FLT3-WT, 2 biological rep CD45- hemogenic precursors FLT3-TKD/MLLAF4, 2 biological rep CD45- hemogenic precursors FLT3-WT/MLLAF4, 2 biological rep CD45+ blood cells EV, 1 biological rep CD45+ blood cells FLT3-TKD, 2 biological rep CD45+ blood cells FLT3-WT, 2 biological rep CD45+ blood cells FLT3-TKD/MLLAF4, 2 biological rep CD45+ blood cells FLT3-WT/MLLAF4, 1 biological rep
2013-06-04 | E-GEOD-40103 | biostudies-arrayexpress
Project description:MLL-AF4 is a hallmark genomic aberration which arises prenatally in high-risk infant acute lymphoblastic leukemia (ALL). In human embryonic stem cells (hESCs), MLL-AF4 skewed hemato-endothelial specification but was not sufficient for transformation. Additional cooperating genetic insults seem required for MLL-AF4-mediated leukemogenesis. FLT3 is highly expressed in MLL-AF4+ ALL through activating mutations (FLT3-TKD or FLT3-ITD) or increased transcriptional expression, being therefore considered a potential cooperating event in MLL-AF4+ ALL. Here, we explored the developmental impact of FLT3 activation on its own or in cooperation with MLL-AF4 in the hematopoietic fate of hESCs. FLT3 activation did not impact specification of CD45-CD31+ hemogenic precursors but significantly enhanced the formation of CD45+CD34+ and CD45+ blood cells and blood progenitors with clonogenic potential. Importantly, FLT3 activation through FLT3 mutations or FLT3-WT overexpression completely abrogated hematopoietic differentiation from MLL-AF4-expressing hESCs, indicating that FLT3 activation cooperates with MLL-AF4 to inhibit human embryonic hematopoiesis. Cell cycle/apoptosis analyses suggest that FLT3 activation directly impacts hESC specification rather than selective proliferation/survival of hESC-emerging hematopoietic derivatives. Transcriptional profiling supported the limited impact of FLT3 activation on hESC specification towards CD45-hemogenic precursors and the enhanced hematopoiesis upon FLT3 activation, and inhibited hematopoiesis upon MLL-AF4 expression in FLT3-activated hESCs which was associated to large transcriptional changes and regulation of master early hematopoietic genes. Also, although FLT3 activation and MLL-AF4 cooperate to inhibit embryonic hematopoiesis the underlying molecular/genetic mechanisms differ depending on how FLT3 activation is achieved. Finally, FLT3 activation did not cooperate with MLL-AF4 to immortalize/transform hESC-derived hematopoietic cells.
2013-06-04 | GSE40103 | GEO
Project description:ITD mutations in the FLT3 gene occur in the 30% of acute myeloid leukemia patients. The integration of ITD in the tyrosine kinase domain (TKD-ITD) of the FLT3 receptor has been shown to confer resistance to standard chemotherapy treatment. We applied state-of-the-art, high-sensitive, mass spectrometry (MS)-based (phospho)proteomics to investigate the molecular mechanisms underlying the sensitivity to cytarabine therapy in FLT3-ITD cells.
2023-07-20 | PXD038638 | Pride
Project description:Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 (FLT3) gene occurs in 30% acute myeloid leukemias (AML) and confers a poor prognosis. Thirteen relapsed or chemo-refractory FLT3-ITD+ AML patients were treated with sorafenib (200-400 mg twice daily). Twelve patients showed clearance or near clearance of bone marrow (BM) myeloblasts after 27 (range 21–84) days with evidence of differentiation of leukemia cells. The sorafenib response was lost in most patients after 72 (range 54–287) days but the FLT3 and downstream effectors remained suppressed. Four pairs patients (before sorafenib treatment and after sorafenib relapse), total eight samples from four patients at the two time-points were subjected to microarray analysis. Gene expression profiling showed that leukemia cells which have become sorafenib resistant expressed a number of genes including ALDH1A1, JAK3 and MMP15, whose functions were unknown in AML. NOD/SCID mice transplanted with leukemia cells from patients before and during sorafenib resistance recapitulated the clinical results. Both ITD and tyrosine kinase domain (TKD) mutations at D835 were identified in leukemia initiating cells (LIC) from samples before sorafenib treatment. LIC bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggested that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations and might provide important leads to further improvement of treatment outcome with FLT3 inhibitors. RNA from CD33+CD34+ myeloblasts at pre-sorafenib-treatment and post-sorafenib-relapse were collected and subjected to microarray analysis
2012-02-18 | E-GEOD-35907 | biostudies-arrayexpress
Project description:<p>FLT3 mutations are commonly detected in Acute Myeloid Leukemia (AML) patients and are associated with poor prognosis. Crenolanib, a potent type I pan-FLT3 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=FLT3" target="_blank">GeneID:2322</a>) inhibitor, is effective against both internal tandem duplications (ITD) and resistance-conferring tyrosine kinase domain (TKD) mutations. While crenolanib monotherapy has demonstrated significant clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. To investigate the mechanisms of crenolanib resistance, we performed whole exome sequencing of AML patient samples before and after crenolanib treatment (122 samples from 59 patients). Unlike other FLT3 inhibitors, crenolanib did not induce FLT3 activation loop mutations, and mutations of the FLT3 "gatekeeper" residue were infrequent. Instead, mutations of NRAS (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=NRAS" target="_blank">GeneID:4893</a>) and IDH2 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=IDH2" target="_blank">GeneID:3418</a>) arose, mostly as FLT3-independent subclones, while TET2 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=TET2" target="_blank">GeneID:54790</a>) and IDH1 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=IDH1" target="_blank">GeneID:3417</a>) predominantly co-occurred with the FLT3-mutant clone and were enriched in crenolanib poor-responders. The remaining patients exhibited post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse non-FLT3 genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restored crenolanib sensitivity.</p>
| phs001628 | dbGaP
Project description:The interaction of Menin (MEN1) and MLL (MLL1, KMT2A) is a dependency and potential therapeutic opportunity against NPM1 mutant (NPM1mut) and MLL-rearranged (MLL-r) leukemias. Concomitant activating driver mutations in the gene encoding the tyrosine kinase FLT3 occur in both leukemias and are particularly common in the NPM1mut subtype. Transcriptional profiling upon pharmacological inhibition of the Menin-MLL complex revealed specific changes in gene expression with downregulation of the MEIS1 transcription factor and its transcriptional target gene FLT3 being most pronounced. Combining Menin-MLL inhibition with specific small molecule kinase inhibitors of FLT3 phosphorylation resulted in a significantly superior reduction of phosphorylated FLT3 and transcriptional suppression of genes downstream to FLT3 signaling. The drug combination induced synergistic inhibition of proliferation as well as enhanced apoptosis and differentiation compared to single-drug treatment in models of human and murine NPM1mut and MLL-r leukemias harboring an FLT3 mutation. Primary AML cells harvested from patients with NPM1mut FLT3mut AML showed significantly better responses to combined Menin and FLT3 inhibition than to single-drug or vehicle control treatment, while AML cells with wildtype NPM1, MLL, and FLT3 were not affected by any of the two drugs. In vivo treatment of leukemic animals with MLL-r FLT3mut leukemia reduced leukemia burden significantly and prolonged survival compared to the single-drug and vehicle control groups. Our data suggest that combined Menin-MLL and FLT3 inhibition represents a novel and promising therapeutic strategy for patients with NPM1mut or MLL-r leukemia and concurrent FLT3 mutation.
2020-07-01 | GSE144759 | GEO
Project description:Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 (FLT3) gene occurs in 30% acute myeloid leukemias (AML) and confers a poor prognosis. Thirteen relapsed or chemo-refractory FLT3-ITD+ AML patients were treated with sorafenib (200-400 mg twice daily). Twelve patients showed clearance or near clearance of bone marrow (BM) myeloblasts after 27 (range 21–84) days with evidence of differentiation of leukemia cells. The sorafenib response was lost in most patients after 72 (range 54–287) days but the FLT3 and downstream effectors remained suppressed. Four pairs patients (before sorafenib treatment and after sorafenib relapse), total eight samples from four patients at the two time-points were subjected to microarray analysis. Gene expression profiling showed that leukemia cells which have become sorafenib resistant expressed a number of genes including ALDH1A1, JAK3 and MMP15, whose functions were unknown in AML. NOD/SCID mice transplanted with leukemia cells from patients before and during sorafenib resistance recapitulated the clinical results. Both ITD and tyrosine kinase domain (TKD) mutations at D835 were identified in leukemia initiating cells (LIC) from samples before sorafenib treatment. LIC bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggested that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations and might provide important leads to further improvement of treatment outcome with FLT3 inhibitors.
2012-02-18 | GSE35907 | GEO
Project description:In leukemogenesis Notch signaling can be up- and down-regulated in a context-dependent manner. Here we report that deletion of hairy and enhancer of split-1 (Hes1) promotes acute myeloid leukemia (AML) development induced by the MLL-AF9 fusion protein. Subsequently, the FMS-like tyrosine kinase 3 (FLT3) was up-regulated in mouse cells of a Hes1- or RBP-J-null background. MLL-AF9-expressing Hes1-null AML cells showed enhanced proliferation and ERK phosphorylation following FLT3 ligand stimulation. FLT3 inhibition efficiently abrogated proliferation of MLL-AF9-induced Hes1-null AML cells. Furthermore, an agonistic anti-Notch2 antibody induced apoptosis of MLL-AF9-induced AML cells in a Hes1-wild type but not a Hes1-null background. These observations demonstrate that Hes1 mediates tumor suppressive roles of Notch signaling in AML development by down-regulating FLT3 expression. 4 samples are analyzed, two pairs of MLL-AF9/Hes1-/- and MLL-AF9/Hes1+/+ leukemic bone marrows.
2017-05-02 | E-GEOD-50234 | biostudies-arrayexpress