Genome-wide comparison of AML leukemic stem cells (LSCs) and normal human hematopoietic stem cells (HSCs).
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE24395 | GEO | 2010/09/30
SECONDARY ACCESSION(S): PRJNA132887
REPOSITORIES: GEO
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Project description:Gene expression analysis of AML LSCs vs normal HSCs Total RNA obtained from FACS-sorted AML-LSCs (n=12) and normal HSCs (n=5) were subjected to the microarray analysis
2010-09-30 | E-GEOD-24395 | biostudies-arrayexpress
Project description:The cyclin-dependent kinases (CDK) CDK6 and CDK4 have redundant functions in regulating cell-cycle progression. We describe a novel role for CDK6 in hematopoietic and leukemic stem cells (HSCs and LSCs) that exceeds its function as cell-cycle regulator. Although hematopoiesis appears regular under steady state conditions Cdk6-/- HSCs do not efficiently repopulate upon competitive transplantation and Cdk6-deficient mice are significantly more susceptible to 5-fluorouracil (5-FU) treatment. We find that activation of HSCs requires CDK6, which interferes with transcription of key regulators including Egr1. The central role of Egr1 is supported by transcriptional profiling of HSCs. The impaired repopulation capacity extends to BCR-ABLp210+ leukemic stem cells. Transplantation with BCR-ABLp210+-infected bone marrow (BM) from Cdk6-/- mice fails to induce disease although recipient mice do harbor LSCs. Egr1 knock-down in cdk6-/- BCR-ABLp210+ LSKs significantly enhances colony formation underlining the importance of the Cdk6-Egr1 axis. Our findings define CDK6 as an important regulator of stem cell activation and as essential component of a transcriptional complex that suppresses Egr1 in HSCs and LSCs. Four-condition experiment, Untreated or polyI:C-treated CDK6-/- cells versus untreated or polyI:C-treated wild-type cells. Biological replicates: 3 untreated replicates, 3 polyI:C-treated replicates.
2015-02-20 | E-GEOD-62012 | 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:The cyclin-dependent kinases (CDK) CDK6 and CDK4 have redundant functions in regulating cell-cycle progression. We describe a novel role for CDK6 in hematopoietic and leukemic stem cells (HSCs and LSCs) that exceeds its function as cell-cycle regulator. Although hematopoiesis appears regular under steady state conditions Cdk6-/- HSCs do not efficiently repopulate upon competitive transplantation and Cdk6-deficient mice are significantly more susceptible to 5-fluorouracil (5-FU) treatment. We find that activation of HSCs requires CDK6, which interferes with transcription of key regulators including Egr1. The central role of Egr1 is supported by transcriptional profiling of HSCs. The impaired repopulation capacity extends to BCR-ABLp210+ leukemic stem cells. Transplantation with BCR-ABLp210+-infected bone marrow (BM) from Cdk6-/- mice fails to induce disease although recipient mice do harbor LSCs. Egr1 knock-down in cdk6-/- BCR-ABLp210+ LSKs significantly enhances colony formation underlining the importance of the Cdk6-Egr1 axis. Our findings define CDK6 as an important regulator of stem cell activation and as essential component of a transcriptional complex that suppresses Egr1 in HSCs and LSCs.
2015-02-20 | GSE62012 | GEO
Project description:The transcription factors STAT5A and STAT5B are critical in hematopoiesis and leukemia. They are widely believed to have redundant functions but we describe a unique role for STAT5B in driving the self-renewal of hematopoietic and leukemic stem cells (HSCs/LSCs). We find STAT5B to be specifically activated in HSCs and LSCs, where it induces many genes associated with quiescence and self-renewal, including the surface marker CD9. Levels of CD9 represent a prognostic marker for patients with STAT5-driven leukemia and our findings suggest that anti-CD9 antibodies may be useful in their treatment to target and eliminate LSCs. We show that it is vital to consider STAT5A and STAT5B as distinct entities in normal and malignant hematopoiesis.
2021-12-31 | GSE178648 | GEO
Project description:Despite rapid advances in mapping genetic drivers and gene expression changes in hematopoietic stem cells (HSCs), there is a relative paucity of studies at the protein level. Here, we perform a deep, multi-omic characterization (epigenome, transcriptome and proteome) of HSCs carrying a loss-of-function mutation in Tet2, a key driver of increased self-renewal in blood cancers. Using state-of-the-art, multiplexed, low-input mass spectrometry (MS)-based proteomics, we profile wildtype (WT) and TET2-deficient (Tet2-/-) HSCs and show that the proteome captures previously unrecognized molecular processes which define the pre-leukemic HSC molecular landscape. Specifically, we obtain more accurate stratification of WT and Tet2-/- HSCs than transcriptomic approaches and identify extracellular matrix (ECM) molecules as novel points of dysregulation upon TET2 loss. HSC expansion assays using ECM-functionalized hydrogels confirm a selective effect on the expansion of Tet2-mutant HSCs. Taken together, our study represents a comprehensive molecular characterization of Tet2-mutant HSCs and identifies a previously unanticipated role of ECM molecules in regulating self-renewal of disease-driving HSCs.
2025-11-13 | PXD059814 | Pride
Project description:The small GTPase RAN plays a role in the biogenesis of mature miR-126, which is supplied by the bone marrow arterioles to leukemic stem cells (LSCs). MiR-126 supports the homeostasis of LSCs that initiate and maintain acute myeloid leukemia (AML). While therapeutic targeting of RAN has been difficult due to its structural features, through molecular dynamics simulations and docking studies, we have identified MAR-3.6.2 as a novel allosteric inhibitor that binds in a cryptic pocket in the C-terminal domain of RAN. We showed that MAR-3.6.2 disrupted RAN interaction with its guanine nucleotide exchange factor RCC1 and prevented the nuclear switch of RAN-GDP to RAN-GTP. This in turn led to RAN nuclear retention and reduced the RAN/XPO5-mediated export of pre-miR-126, thereby limiting mature miR-126 biogenesis in endothelial cells and their exogenous supply of mature miR-126 to LSCs. In a MllPTD/WT/Flt3ITD/ITD AML murine model, MAR-3.6.2 reduced leukemia burden, prolonged survival, and decreased LSC frequency in secondary transplants. These findings highlight MAR-3.6.2 and future, potential derivates as a promising small molecule-based approach to eradicate AML LSCs via inhibition of RAN/XPO5 trafficking and block of miR-126 biogenesis.
2026-03-15 | GSE324546 | GEO
Project description:Gata2, a zinc finger TF, is essential for the generation and survival of HSCs in the embryo and has been implicated in the pathogenesis of AML, yet the requirement for Gata2 in adult HSCs and LSCs remains unclear. Using a conditional mouse model where Gata2 was deleted specifically in hematopoietic cells, we show that knockout of Gata2 leads to a rapid and complete cell-autonomous loss of adult HSCs. In Meis1a/Hoxa9 driven AML, deletion of Gata2 impedes maintenance and self-renewal of LSCs. We then performed RNA-seq from sorted control and Gata2 KO LSCs (CD45.2+ c-Kit+) after pIpC treatment in transplanted mice.
2019-06-25 | GSE133245 | GEO
Project description:Blood production is sustained by hematopoietic stem cells (HSCs), which are typically the only blood cells capable of long-term self-renewal. HSCs exhibit and depend on low levels of protein synthesis to self-renew. However, the mechanisms by which HSCs regulate protein synthesis to maintain their self-renewal capacity during proliferative stress and leukemogenesis remain unknown. Here we show CD99, a protein upregulated in leukemia stem cells (LSCs) in acute myeloid leukemia (AML), is required for the self-renewal of proliferating HSCs and LSCs. We found that loss of CD99 in HSCs and LSCs leads to increased protein synthesis and that their self-renewal capacity can be restored by translation inhibition. These data demonstrate a functional role for CD99 in constraining protein synthesis, which may promote the clonal expansion of HSCs and LSCs that leads to AML. Furthermore, these studies demonstrate that similar to HSCs, LSCs depend on maintenance of tightly regulated protein synthesis rates.
2026-01-28 | GSE233596 | GEO
Project description:Persistence of leukemic stem cells (LSC) after chemotherapy is thought to be responsible for relapse and prevents the curative treatment of acute myeloid leukemia (AML) patients. LSC and normal hematopoietic stem cells (HSC) share many characteristics and co-exist in the bone marrow of AML patients. For the development of successful LSC-targeted therapy, enabling eradication of LSC while sparing HSC, the identification of differences between LSC and HSC residing within the AML bone marrow is crucial. For identification of these LSC targets, as well as for AML LSC characterization, discrimination between LSC and HSC within the AML bone marrow is imperative. Here we show that normal CD34+CD38- HSC present in AML bone marrow, identified by their lack of aberrant immunophenotypic and molecular marker expression and low scatter properties, are a distinct sub-population of cells with high ALDH activity (ALDH(bright)). The ALDH(bright) compartment contains, besides normal HSC, more differentiated, normal CD34+CD38+ progenitors. Furthermore, we show that in CD34-negative AML, containing solely normal CD34+ cells, LSC are CD34- and ALDH(low). In CD34-positive AML, LSC are also ALDH(low) but can be either CD34+ or CD34-. In conclusion, although malignant AML blasts have varying ALDH activity, a common feature of all AML cases is that LSC have lower ALDH activity than the CD34+CD38- HSC that co-exist with these LSC in the AML bone marrow. Our findings form the basis for combined functionally and immunophenotypically based identification and purification of LSC and HSC within the AML bone marrow, aiming at development of highly specific anti-LSC therapy.
| S-EPMC3823975 | biostudies-literature