CaMK2D is a critical regulator of coactivation of leukemia stem cell factors in acute myeloid leukemia.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE161032 | GEO | 2021/11/08
REPOSITORIES: GEO
Similar Datasets
Project description:Acute myeloid leukemia (AML) patients suffer from chemo-resistance, high relapse frequency, and low overall survival rate, outcomes driven by leukemic stem cells (LSCs). Understanding the molecular mechanisms that support these primitive leukemic cells is crucial for developing effective AML therapeutics. In the present study, we demonstrate that upregulation of the splicing factor RBM17 preferentially marks and sustains the primitive compartment of AML. We performed shotgun proteomics to characterize the proteome changes upon RBM17 knockdown in AMl cells. In addition, we used proteomics to analyze the proteome changes after knockdown of EIF4A2, a direct splicing substrate of RBM17 in AML cells.
2022-08-12 | PXD026780 | Pride
Project description:Relapse of acute myeloid leukemia (AML) is highly aggressive and often treatment refractory. We analyzed previously published AML relapse cohorts and found that 40% of relapses occur without changes in driver mutations, suggesting that non-genetic mechanisms drive relapse in a large proportion of cases. We therefore characterized epigenetic patterns of AML relapse using 26 matched diagnosis-relapse samples with ATAC-seq. This analysis identified a relapse-specific chromatin accessibility signature for mutationally stable AML, suggesting that AML undergoes epigenetic evolution at relapse independent of mutational changes. Analysis of leukemia stem cell (LSC) chromatin changes at relapse indicated that this leukemic compartment underwent significantly less epigenetic evolution than non-LSCs, while epigenetic changes in non-LSCs reflected overall evolution of the bulk leukemia. Finally, we used single-cell ATAC-seq paired with mitochondrial sequencing (mtscATAC) to map clones from diagnosis into relapse along with their epigenetic features. We found that distinct mitochondrially-defined clones exhibit more similar chromatin accessibility at relapse relative to diagnosis, demonstrating convergent epigenetic evolution in relapsed AML. These results demonstrate that epigenetic evolution is a feature of relapsed AML and that convergent epigenetic evolution can occur following treatment with induction chemotherapy.
2024-04-17 | GSE256495 | GEO
Project description:Despite the advanced understanding of disease mechanisms, the current therapeutic regimens fail to cure most patients with acute myeloid leukemia (AML). In the present study, we address the role of protein synthesis control in AML leukemia stem cell (LSC) function and leukemia propagation. We apply a murine model of mixed-lineage leukemia-rearranged AML to demonstrate that LSCs synthesize more proteins per hour compared with the bulk of leukemia. Using a genetic model that permits inducible and graded regulation of ribosomal subunit joining, we show that defective ribosome assembly leads to a significant survival advantage by selectively eradicating LSCs but not normal hematopoietic stem and progenitor cells. Finally, transcriptomic and proteomic analyses identify a rare subset of LSCs with immature stem cell signature and high ribosome content that underlies the resistance to defective ribosome assembly. Collectively, our study unveils a critical requirement of high protein synthesis rate for LSC function, highlighting ribosome assembly as a therapeutic target in AML.
2024-10-08 | PXD038318 | Pride
Project description:Relapse, associated with therapy resistance, is a major clinical problem in acute myeloid leukemia (AML), yet little is known about the underlying molecular mechanisms. Using genome wide gene expression profiling on 11 paired samples from diagnosis and relapse, we show that the expression of a substantial number of genes was altered in a highly consistent manner between these disease stages. Furthermore, the relapse associated gene expression profile was significantly enriched for leukemia stem cell (LSC) genes, indicating that recurring AML is characterized by increased stemness, and supporting the concept that it is due to the outgrowth of chemotherapy resistant LSCs. Paired peripheral blood samples from the times of diagnosis and relapse were obtained from 11 patients with cytogenetically normal AML. cRNA was hybridized to Affymetrix human ST1.1 arrays.
2015-03-05 | E-GEOD-66525 | biostudies-arrayexpress
Project description:Acute myeloid leukemia is characterized by a minor fraction of primitive leukemia stem cells (LSCs) that sustain disease propagation and may be at the origin of late relapse. Yet, LSC contribution to early therapy resistance and AML regeneration remains controversial. We prospectively identified LSCs in NPM1-mutated AML patients and xenografts by means of a microRNA-126 reporter and single cell RNA sequencing, precisely discriminating LSCs from regenerating hematopoiesis, and assessed their longitudinal response to chemotherapy. We here show that chemotherapy resulted in distinct outcomes within AML subpopulations: while the bulk leukemia proliferated and differentiated with expression of oxidative-phosphorylation signatures, persisting miR-126high LSCs enforced protective stemness and dormancy features, along with a generalized inflammatory and senescence-associated response. miR-126high LSCs were enriched at diagnosis in patients with chemotherapy-refractory AML. We derived a novel miR-126high LSC transcriptional signature, which robustly stratified patients for overall survival in large AML cohorts, shining the spotlight on LSCs as determinants of early therapy resistance.
2023-02-06 | GSE185991 | GEO
Project description:Acute myeloid leukemia is characterized by a minor fraction of primitive leukemia stem cells (LSCs) that sustain disease propagation and may be at the origin of late relapse. Yet, LSC contribution to early therapy resistance and AML regeneration remains controversial. We prospectively identified LSCs in NPM1-mutated AML patients and xenografts by means of a microRNA-126 reporter and single cell RNA sequencing, precisely discriminating LSCs from regenerating hematopoiesis, and assessed their longitudinal response to chemotherapy. We here show that chemotherapy resulted in distinct outcomes within AML subpopulations: while the bulk leukemia proliferated and differentiated with expression of oxidative-phosphorylation signatures, persisting miR-126high LSCs enforced protective stemness and dormancy features, along with a generalized inflammatory and senescence-associated response. miR-126high LSCs were enriched at diagnosis in patients with chemotherapy-refractory AML. We derived a novel miR-126high LSC transcriptional signature, which robustly stratified patients for overall survival in large AML cohorts, shining the spotlight on LSCs as determinants of early therapy resistance.
2023-02-06 | GSE185834 | GEO
Project description:Acute myeloid leukemia is characterized by a minor fraction of primitive leukemia stem cells (LSCs) that sustain disease propagation and may be at the origin of late relapse. Yet, LSC contribution to early therapy resistance and AML regeneration remains controversial. We prospectively identified LSCs in NPM1-mutated AML patients and xenografts by means of a microRNA-126 reporter and single cell RNA sequencing, precisely discriminating LSCs from regenerating hematopoiesis, and assessed their longitudinal response to chemotherapy. We here show that chemotherapy resulted in distinct outcomes within AML subpopulations: while the bulk leukemia proliferated and differentiated with expression of oxidative-phosphorylation signatures, persisting miR-126high LSCs enforced protective stemness and dormancy features, along with a generalized inflammatory and senescence-associated response. miR-126high LSCs were enriched at diagnosis in patients with chemotherapy-refractory AML. We derived a novel miR-126high LSC transcriptional signature, which robustly stratified patients for overall survival in large AML cohorts, shining the spotlight on LSCs as determinants of early therapy resistance.
2023-02-06 | GSE185824 | GEO
Project description:Standard chemotherapy for acute myeloid leukemia (AML) targets proliferative cells and efficiently induces complete remission; however, many patients relapse and die of their disease. Relapse is caused by leukemia stem cells (LSCs), the cells with self-renewal capacity. Self-renewal and proliferation are mutually exclusive in normal hematopoietic stem cells (HSCs) in steady state conditions. If these functions are also mutually exclusive in LSCs, then antiproliferative therapies may fail to target self-renewal, allowing for relapse. We investigated whether proliferation and self-renewal are mutually exclusive in LSCs as they often are in HSCs. Using single-cell RNA sequencing, we identified distinct transcriptional profiles within LSCs of Mll-AF9/NRASG12V murine AML. We used single-cell qPCR and found that these genes were also differentially expressed in primary human LSCs and normal human HSPCs. A smaller subset of these genes was upregulated in LSCs relative to HSPCs; this smaller subset of genes constitutes “LSC-specific” genes in human AML. To assess the differences between these profiles, we identified cell surface markers, CD69 and CD36, whose genes were differentially expressed between these profiles. Using in vivo mouse reconstitution assays, we found that only CD69High LSCs were capable of self-renewal and were poorly proliferative. In contrast, CD36High LSCs were unable to transplant leukemia but were highly proliferative. These data demonstrate that the transcriptional foundations of self-renewal and proliferation are distinct in LSCs as they often are in normal stem cells and suggest that therapeutic strategies that target self-renewal, in addition to proliferation, are critical to prevent relapse and improve survival in AML.
2019-11-25 | GSE140896 | GEO
Project description:Acute Myeloid Leukemia (AML) is a heterogeneous disease on both inter- and intra-patient levels. In many patients, relapse is driven by a relatively small pool of Leukemia Stem Cells (LSCs) that are able to resist therapeutic perturbation and drive proliferation of the malignant AML blast pool. Due to the low frequency of LSCs and high degree of heterogeneity between and within patients, inspecting these specimens at the single cell level is critical to identifying the true relapse driving cells and tailoring therapies towards these cells.
2023-07-05 | GSE232559 | GEO
Project description:Relapse, associated with therapy resistance, is a major clinical problem in acute myeloid leukemia (AML), yet little is known about the underlying molecular mechanisms. Using genome wide gene expression profiling on 11 paired samples from diagnosis and relapse, we show that the expression of a substantial number of genes was altered in a highly consistent manner between these disease stages. Furthermore, the relapse associated gene expression profile was significantly enriched for leukemia stem cell (LSC) genes, indicating that recurring AML is characterized by increased stemness, and supporting the concept that it is due to the outgrowth of chemotherapy resistant LSCs.
2015-03-16 | GSE66525 | GEO