KIF11 and its inhibitor SB-743921 inhibit acute myeloid leukaemia (AML) by blocking the cell cycle
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PROVIDER: PRJNA1231385 | ENA |
REPOSITORIES: ENA
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Project description:Acute myeloid leukaemia (AML) is a highly heterogeneous haematological malignancy with limited prognostic improvement despite evolving therapeutic strategies.KIF11 is a member of the kinesin family and a microtubule-associated motility protein that plays a key role in spindle dynamics during cellular mitosis and is overexpressed in leukaemias including AML. Studies have shown that inhibition of KIF11 leads to spindle pole collapse, which prevents chromosome segregation and leads to cell death; this identifies KIF11 as a potential therapeutic target.SB-743921, a novel selective inhibitor of KIF11, has shown anti-tumour activity in a variety of cancers, including breast, lung, and cholangiocarcinoma. Our study shows that SB-743921 can effectively inhibit the proliferation of AML cells and induce cell cycle arrest, thereby hindering tumour growth. In vitro experiments showed that SB-743921 exhibited significant cytotoxicity against several AML cell lines, and its IC50 value indicated that these cells were very sensitive to SB-743921. Further in vivo studies in AML mouse models treated with SB-743921 showed that the drug significantly delayed tumour progression while prolonging survival with minimal toxic side effects. In addition, RNA sequencing analysis showed that SB-743921 inhibited tumour cell proliferation by down-regulating key signalling pathways, including MYC, E2F and G2M. These findings suggest that KIF11 plays a crucial role in the onset and progression of AML. As its inhibitor, SB-743921 has significant anti-tumour effects and is an innovative targeted agent for the treatment of AML. This discovery provides new insights into potential clinical applications for the treatment of this challenging malignancy.
2025-08-19 | GSE291010 | GEO
Project description:In the fire ant Solenopsis invicta, a colony queen number is determined by the founding queen's genotypes at the 13 Mb supergene with the non-recombining variants SB and Sb. Single-queen colonies are always headed by SB/SB queens while multiple-queens colonies are always headed by SB/Sb queens. The two variants of the supergene, SB and Sb are completely linked to the two alleles (B and b) of the gene Gp-9. SB/SB and SB/Sb queens differ in many physiological traits including their maturation rate and odor. To explain why SB/SB and SB/Sb queens have different odors, and why SB/SB virgins mature faster and accumulate more fat, we measured expression of ~6000 genes in virgin queens 1 and 11 days after eclosion and in reproductive queens. Keywords: fire ants, Solenopsis invicta, Supergene, queen, Gp-9, social form, maturation, fat storage, queen odor, cuticular hydrocarbon, worker discrimination, monogyne, polygyne, transposon, chemical signaling
2012-11-07 | GSE42062 | GEO
Project description:In the fire ant Solenopsis invicta, a colony queen number is determined by the founding queen's genotypes at the 13 Mb supergene with the non-recombining variants SB and Sb. Single-queen colonies are always headed by SB/SB queens while multiple-queens colonies are always headed by SB/Sb queens. The two variants of the supergene, SB and Sb are completely linked to the two alleles (B and b) of the gene Gp-9. SB/SB and SB/Sb queens differ in many physiological traits including their maturation rate and odor. To explain why SB/SB and SB/Sb queens have different odors, and why SB/SB virgins mature faster and accumulate more fat, we measured expression of ~6000 genes in virgin queens 1 and 11 days after eclosion and in reproductive queens. Keywords: fire ants, Solenopsis invicta, Supergene, queen, Gp-9, social form, maturation, fat storage, queen odor, cuticular hydrocarbon, worker discrimination, monogyne, polygyne, transposon, chemical signaling Six-condition experiment: 1-day-old SB/SB virgins, 1-day-old SB/Sb virgins, 11-day-old SB/SB virgins, 11-day-old SB/Sb virgins, SB/SB reproductive queens, SB/Sb reproductive queens. Biological replicates: 8 for 1-day-old SB/SB virgins and 1-day-old SB/Sb virgins that were collected in 2008; 8 for 1-day-old SB/SB virgins, 1-day-old SB/Sb virgins that were collected in 2009; 7 for 11-day-old SB/SB virgins and 11-day-old SB/Sb virgins that were collected in 2008; 8 for 11-day-old SB/SB virgins and 11-day-old SB/Sb virgins that were collected in 2009; 8 for SB/SB and SB/Sb reproductive queens (only collected in 2009). Samples were labeled with Cy3 and were compared to the same common reference RNA labeled with Cy5. Samples from 2008 were hybridized on the microarrays batch I and samples from 2009 were hybridized on the microarrays batch J.
2012-11-07 | E-GEOD-42062 | biostudies-arrayexpress
Project description:The branched-chain amino acid (BCAA) pathway and high levels of BCAA transaminase 1 (BCAT1) have recently been associated with aggressiveness in several cancer entities. However, the mechanistic role of BCAT1 in this process remains largely uncertain. Here, by performing high-resolution proteomic analysis of human acute myeloid leukaemia (AML) stem-cell and non-stem-cell populations, we find the BCAA pathway enriched and BCAT1 protein and transcripts overexpressed in leukaemia stem cells. We show that BCAT1, which transfers α-amino groups from BCAAs to α-ketoglutarate (αKG), is a critical regulator of intracellular αKG homeostasis. Further to its role in the tricarboxylic acid cycle, αKG is an essential cofactor for αKG-dependent dioxygenases such as Egl-9 family hypoxia inducible factor 1 (EGLN1) and the ten-eleven translocation (TET) family of DNA demethylases. Knockdown of BCAT1 in leukaemia cells caused accumulation of αKG, leading to EGLN1-mediated HIF1α protein degradation. This resulted in a growth and survival defect and abrogated leukaemia-initiating potential. By contrast, overexpression of BCAT1 in leukaemia cells decreased intracellular αKG levels and caused DNA hypermethylation through altered TET activity. AML with high levels of BCAT1 (BCAT1high) displayed a DNA hypermethylation phenotype similar to cases carrying a mutant isocitrate dehydrogenase (IDHmut), in which TET2 is inhibited by the oncometabolite 2-hydroxyglutarate11,12. High levels of BCAT1 strongly correlate with shorter overall survival in IDHWTTET2WT, but not IDHmut or TET2mutAML. Gene sets characteristic for IDHmut AML13 were enriched in samples from patients with an IDHWTTET2WTBCAT1high status. BCAT1highAML showed robust enrichment for leukaemia stem-cell signatures14,15, and paired sample analysis showed a significant increase in BCAT1 levels upon disease relapse. In summary, by limiting intracellular αKG, BCAT1 links BCAA catabolism to HIF1α stability and regulation of the epigenomic landscape, mimicking the effects of IDH mutations. Our results suggest the BCAA–BCAT1–αKG pathway as a therapeutic target to compromise leukaemia stem-cell function in patients with IDHWTTET2WT AML.
2020-02-21 | PXD008307 | Pride
Project description:Antimony (Sb) pollution, especially released from mining activities has already been widely recognized as a global concern. To gauge strategies for the remediation of an Sb-contaminated ecosystem, the exploration of native microbiota Sb(III) resistance mechanism is of great significance. Acinetobacter is one of the bacterial genera abundantly thriving in Sb(III)-contaminated environments, the scientific elaboration of Sb(III)-resistance mechanisms of Acinetobacter is imperative. Proteomics experiment was performed (Acinetobacter johnsonii JH7 with and without Sb(III) addtion) to probe its pattern of proteins change under Sb(III) stress. We hope that the mechanisms of Sb(III) resistance of Acinetobacter could be revealed by using iTRAQ this time.
2020-01-20 | PXD017203 |
Project description:Transcriptional profiling of primary human malignant B cells from patients with chronic lymphocytic leukaemia (CLL), comparing untreated CLL cells with CLL cells that have been treated 24h with 200nM mithramycin. Mithramycin intercalates into GC-rich regions of DNA to inhibit binding of the transcription factor SP1. The goal of this experiment is to gain understanding of the genes regulated by SP1 in primary CLL cells.
2022-12-14 | GSE210348 | GEO
Project description:Sb contaminated soil Metagenomic assembly
| PRJNA1268697 | ENA
Project description:In our study, blocking A2aR with ZM241385 was found to inhibit Foxp3 expression in Treg cells of septic mice. Therefore, we used flow cytometry to sort mouse spleen CD4+CD25+ cells for transcriptome sequencing in an attempt to discover the mechanism by which blocking A2aR affects Foxp3 expression. The specific groupings were as follows: naive groups (N1-N5), CLP groups (C1-C5), CLP+A2aR antagonist groups (Z1-Z6).
2023-10-03 | GSE244227 | GEO
Project description:DNA methylation profiling of 48 samples to determine a DNA methylation signature specific to leukaemic bone marrow samples. Matching Leukaemia bone marrow and day 28 remission bone marrow or post induction follow up (follow up up to 2 years post induction) genomic DNA were extracted from archived microscope smear slides from 11 children diagnosed with TEL/AML positive Acute Lymphoblastic Leukaemia (ALL). Unmatched bone marrow samples from an additional 8 children were also analysed. Primary tissue control samples from CD34+ and CD19+ bone marrow from adult and childhood samples as well as model cell lines (cancer and non cancerous) were compared to primary diseased samples. Disease specific DNA methylation changes were identified from these results and then verified using SEQUENOM EpiTYPER. A total of 48 samples were analysed by Infinium DNA methylation analysis. As per manufacturer's protocols. Replicates were performed on one primary tumour sample and one cell line sample.
2012-12-31 | E-GEOD-29189 | biostudies-arrayexpress
Project description:DNA methylation profiling of 48 samples to determine a DNA methylation signature specific to leukaemic bone marrow samples. Matching Leukaemia bone marrow and day 28 remission bone marrow or post induction follow up (follow up up to 2 years post induction) genomic DNA were extracted from archived microscope smear slides from 11 children diagnosed with TEL/AML positive Acute Lymphoblastic Leukaemia (ALL). Unmatched bone marrow samples from an additional 8 children were also analysed. Primary tissue control samples from CD34+ and CD19+ bone marrow from adult and childhood samples as well as model cell lines (cancer and non cancerous) were compared to primary diseased samples. Disease specific DNA methylation changes were identified from these results and then verified using SEQUENOM EpiTYPER.
2012-12-31 | GSE29189 | GEO