Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA132887 | ENA |
REPOSITORIES: ENA
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Project description:Acute myeloid leukemia (AML) progression and relapse is fueled by self-renewing leukemic stem cells (LSCs) whose molecular determinants have been difficult to discern from normal hematopoietic stem cells (HSCs) or to uncover in screening approaches focused on general AML cell properties. We have identified a unique set of RNA binding proteins (RBPs) that are enriched in human AML LSCs but repressed in HSCs. Using an in vivo two step CRISPR-Cas9-mediated screening approach to specifically score for cancer stem cell functionality, we found 32 RBPs essential for LSC propagation and self- renewal in MLL-AF9 translocated AML. Using knockdown or small molecule approaches we show that targeting key hit RBP ELAVL1 impaired LSC-driven in vivo leukemic reconstitution and selectively depleted primitive AML cells vs. normal hematopoietic stem and progenitors. Importantly, knockdown of Elavl1 spared HSCs while significantly reducing LSC numbers across genetically diverse leukemias. Integrative RNA-seq and eCLIP-seq profiling revealed hematopoietic differentiation, RNA splicing and mitochondrial metabolism as key features defining the leukemic ELAVL1-mRNA interactome with the mitochondrial import protein TOMM34 being a direct ELAVL1-stabilized target whose inhibition impairs AML propagation.
2023-03-13 | GSE224548 | GEO
Project description:Beta-catenin signaling is required for establishment of leukemic stem cells (LSCs) in acute myeloid leukemia (AML), yet the upstream regulators that can augment this pathway are unknown. Through genome-wide gene expression analysis and functional studies, we identified an important role for GPR84 in MLL AML. Suppression of GPR84 significantly inhibited cell growth in pre-LSCs, reduced LSC frequency and impaired reconstitution of MLL AML. Furthermore, GPR84 conferred a growth advantage to Hoxa9/Meis1a transduced hematopoietic stem cells (HSCs). Our microarray analysis demonstrated that GPR84 overexpression significantly up-regulated a small set of MLL-fusion targets and beta-catenin co-effectors, and down-regulated a hematopoietic cell cycle inhibitor. These data thus reveal a previously unrecognized role of GPR84 in the maintenance of fully developed AML by sustaining aberrant beta-catenin signaling in LSCs. HSC-derived Hoxa9/Meis1a pre-LSCs were transduced with GPR84 cDNA or empty vector, and replated in methylcellulose supplemented with cytokines. Each group contains triplicate samples.
2014-10-15 | E-MTAB-1932 | biostudies-arrayexpress
Project description:Leukemic stem cells (LSCs) fuel relapse in acute myeloid leukemia (AML), but therapies tailored at eradicating LSCs without harming healthy hematopoietic stem cells (HSCs) are lacking. FLT3 is frequently mutated in AML and associated with relapse; but FLT3 targeting has met with limited clinical success. This raises questions of whether more potent inhibitors would increase effectiveness but whether toxicity to HSC would become limiting. Here, we tested the consequence of complete FLT3 ablation using CRISPR/Cas9 FLT3 knock-out (FLT3-KO) in human HSCs and LSCs followed by functional xenograft assays to test their ability to regenerate human hematopoiesis and leukemia, respectively. FLT3-KO in HSCs from human fetal liver, cord blood and adult bone marrow showed no impairment in multilineage hematopoiesis in primary and secondary xenografts. By contrast, FLT3-KO LSCs from 6 of 7 FLT3-ITD mutated AMLs were able to generate short-term engraftment but were completely exhausted by 12 weeks. Thus, FLT3 is essential for LSC long-term propagation. This dependency was unique to FLT3-ITD AML samples as non-FLT3-ITD AML samples generated leukemic grafts upon FLT3-KO. Transcriptomic analysis revealed that FLT3-KO induced downregulation of DNA repair and cell cycle checkpoints, uniquely in FLT3-ITD AML, but not in healthy HSCs or other AMLs. Our research highlights a critical distinction between healthy HSCs and LSCs: whereas healthy hematopoiesis proceeds unperturbed upon FLT3-KO, FLT3-ITD leukemogenesis is impaired through elimination of LSCs. This evidence underscores the necessity for more potent FLT3-targeting and places FLT3 as an ideal therapeutic target to selectively eradicate LSCs, while sparing HSC.
2025-06-01 | GSE268962 | GEO
Project description:We performed the first genome-wide expression analysis directly comparing the expression profile of highly enriched normal human hematopoietic stem cells (HSC) and leukemic stem cells (LSC) from patients with acute myeloid leukemia (AML). Comparing the expression signature of normal HSC to that of LSC, we identified 3,005 differentially expressed genes. Using 2 independent analyses, we identified multiple pathways that are aberrantly regulated in leukemic stem cells compared with normal HSC. Several pathways, including Wnt signaling, MAP Kinase signaling, and Adherens Junction, are well known for their role in cancer development and stem cell biology. Other pathways have not been previously implicated in the regulation of cancer stem cell functions, including Ribosome and T Cell Receptor Signaling pathway. This study demonstrates that combining global gene expression analysis with detailed annotated pathway resources applied to highly enriched normal and malignant stem cell populations, can yield an understanding of the critical pathways regulating cancer stem cells. Experiment Overall Design: Total RNAs were isolated from both AML stem cells (9 patients) and normal bone marrow hematopoietic stem cells (HSCs) (4 control subjects).
2009-08-12 | E-GEOD-17054 | biostudies-arrayexpress
Project description:Leukemia stem cells (LSCs) give rise to mature leukemia blasts and are the major cause of therapy resistance and relapse in acute myeloid leukemia (AML). We propose a novel strategy to eliminate heterogeneous LSCs but spare hematopoietic stem cells (HSCs) by targeting essential genes that are highly expressed in LSCs than that in HSCs. Nucleoporin 214 (NUP214) is determined as a dose-dependently essential gene (DDEG) in LSCs. Homozygous deletion of Nup214 eliminates LSCs and HSCs; however, Nup214 haploinsufficiency impairs LSC maintenance but spares HSCs by selectively inducing ferroptosis of LSCs. Mechanistically, NUP214 locates to chromatin and interacted with Sub1 to inhibit the transcription of heme oxygenase-1 (Hmox1) and arachidonate 15-lipoxygenase (Alox15), thus protecting LSCs against lipid peroxidation. We screened and identified a small molecule 0449-b as a molecular glue that links NUP214 and an NEDD8 E3 ligase, Rbx2, to induce neddylation and degradation of NUP214. 0449-b shows efficacy in selective eradication of LSCs but has a negligible effect on normal hematopoietic stem and progenitor cells. These biological and chemical findings provide a valuable strategy to eliminate LSCs by targeting DDEGs.
2025-07-29 | GSE302498 | GEO
Project description:Leukemia stem cells (LSCs) give rise to mature leukemia blasts and are the major cause of therapy resistance and relapse in acute myeloid leukemia (AML). We propose a novel strategy to eliminate heterogeneous LSCs but spare hematopoietic stem cells (HSCs) by targeting essential genes that are highly expressed in LSCs than that in HSCs. Nucleoporin 214 (NUP214) is determined as a dose-dependently essential gene (DDEG) in LSCs. Homozygous deletion of Nup214 eliminates LSCs and HSCs; however, Nup214 haploinsufficiency impairs LSC maintenance but spares HSCs by selectively inducing ferroptosis of LSCs. Mechanistically, NUP214 locates to chromatin and interacted with Sub1 to inhibit the transcription of heme oxygenase-1 (Hmox1) and arachidonate 15-lipoxygenase (Alox15), thus protecting LSCs against lipid peroxidation. We screened and identified a small molecule 0449-b as a molecular glue that links NUP214 and an NEDD8 E3 ligase, Rbx2, to induce neddylation and degradation of NUP214. 0449-b shows efficacy in selective eradication of LSCs but has a negligible effect on normal hematopoietic stem and progenitor cells. These biological and chemical findings provide a valuable strategy to eliminate LSCs by targeting DDEGs.
2025-07-29 | GSE302497 | GEO
Project description:Leukemia stem cells (LSCs) give rise to mature leukemia blasts and are the major cause of therapy resistance and relapse in acute myeloid leukemia (AML). We propose a novel strategy to eliminate heterogeneous LSCs but spare hematopoietic stem cells (HSCs) by targeting essential genes that are highly expressed in LSCs than that in HSCs. Nucleoporin 214 (NUP214) is determined as a dose-dependently essential gene (DDEG) in LSCs. Homozygous deletion of Nup214 eliminates LSCs and HSCs; however, Nup214 haploinsufficiency impairs LSC maintenance but spares HSCs by selectively inducing ferroptosis of LSCs. Mechanistically, NUP214 locates to chromatin and interacted with Sub1 to inhibit the transcription of heme oxygenase-1 (Hmox1) and arachidonate 15-lipoxygenase (Alox15), thus protecting LSCs against lipid peroxidation. We screened and identified a small molecule 0449-b as a molecular glue that links NUP214 and an NEDD8 E3 ligase, Rbx2, to induce neddylation and degradation of NUP214. 0449-b shows efficacy in selective eradication of LSCs but has a negligible effect on normal hematopoietic stem and progenitor cells. These biological and chemical findings provide a valuable strategy to eliminate LSCs by targeting DDEGs.
2025-07-29 | GSE273653 | GEO
Project description:Leukemia stem cells (LSCs) give rise to mature leukemia blasts and are the major cause of therapy resistance and relapse in acute myeloid leukemia (AML). We propose a novel strategy to eliminate heterogeneous LSCs but spare hematopoietic stem cells (HSCs) by targeting essential genes that are highly expressed in LSCs than that in HSCs. Nucleoporin 214 (NUP214) is determined as a dose-dependently essential gene (DDEG) in LSCs. Homozygous deletion of Nup214 eliminates LSCs and HSCs; however, Nup214 haploinsufficiency impairs LSC maintenance but spares HSCs by selectively inducing ferroptosis of LSCs. Mechanistically, NUP214 locates to chromatin and interacted with Sub1 to inhibit the transcription of heme oxygenase-1 (Hmox1) and arachidonate 15-lipoxygenase (Alox15), thus protecting LSCs against lipid peroxidation. We screened and identified a small molecule 0449-b as a molecular glue that links NUP214 and an NEDD8 E3 ligase, Rbx2, to induce neddylation and degradation of NUP214. 0449-b shows efficacy in selective eradication of LSCs but has a negligible effect on normal hematopoietic stem and progenitor cells. These biological and chemical findings provide a valuable strategy to eliminate LSCs by targeting DDEGs.
2025-07-29 | GSE302494 | GEO
Project description:Leukemia stem cells (LSCs) give rise to mature leukemia blasts and are the major cause of therapy resistance and relapse in acute myeloid leukemia (AML). We propose a novel strategy to eliminate heterogeneous LSCs but spare hematopoietic stem cells (HSCs) by targeting essential genes that are highly expressed in LSCs than that in HSCs. Nucleoporin 214 (NUP214) is determined as a dose-dependently essential gene (DDEG) in LSCs. Homozygous deletion of Nup214 eliminates LSCs and HSCs; however, Nup214 haploinsufficiency impairs LSC maintenance but spares HSCs by selectively inducing ferroptosis of LSCs. Mechanistically, NUP214 locates to chromatin and interacted with Sub1 to inhibit the transcription of heme oxygenase-1 (Hmox1) and arachidonate 15-lipoxygenase (Alox15), thus protecting LSCs against lipid peroxidation. We screened and identified a small molecule 0449-b as a molecular glue that links NUP214 and an NEDD8 E3 ligase, Rbx2, to induce neddylation and degradation of NUP214. 0449-b shows efficacy in selective eradication of LSCs but has a negligible effect on normal hematopoietic stem and progenitor cells. These biological and chemical findings provide a valuable strategy to eliminate LSCs by targeting DDEGs.
2025-07-29 | GSE273651 | GEO
Project description:Leukemia stem cells (LSCs) give rise to mature leukemia blasts and are the major cause of therapy resistance and relapse in acute myeloid leukemia (AML). We propose a novel strategy to eliminate heterogeneous LSCs but spare hematopoietic stem cells (HSCs) by targeting essential genes that are highly expressed in LSCs than that in HSCs. Nucleoporin 214 (NUP214) is determined as a dose-dependently essential gene (DDEG) in LSCs. Homozygous deletion of Nup214 eliminates LSCs and HSCs; however, Nup214 haploinsufficiency impairs LSC maintenance but spares HSCs by selectively inducing ferroptosis of LSCs. Mechanistically, NUP214 locates to chromatin and interacted with Sub1 to inhibit the transcription of heme oxygenase-1 (Hmox1) and arachidonate 15-lipoxygenase (Alox15), thus protecting LSCs against lipid peroxidation. We screened and identified a small molecule 0449-b as a molecular glue that links NUP214 and an NEDD8 E3 ligase, Rbx2, to induce neddylation and degradation of NUP214. 0449-b shows efficacy in selective eradication of LSCs but has a negligible effect on normal hematopoietic stem and progenitor cells. These biological and chemical findings provide a valuable strategy to eliminate LSCs by targeting DDEGs.
2025-07-29 | GSE273648 | GEO